Publications

Director of Admissions/Associate Director, Medical Scientist Training Program (2017 - Present) Co-Director Cancer Nanotechnology Program, Department of Radiology, Stanford School of Medicine (2016 - Present) Director of Advanced Residency Training Program, Stanford University School of Medicine (2018 - Present) Director of Translational Research and Applied Medicine, Department of Medicine, Stanford University School of Medicine (2011 - Present)

Publications

  • MYC and Twist1 cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity. eLife Dhanasekaran, R., Baylot, V., Kim, M., Kuruvilla, S., Bellovin, D. I., Adeniji, N., Rajan Kd, A., Lai, I., Gabay, M., Tong, L., Krishnan, M., Park, J., Hu, T., Barbhuiya, M. A., Gentles, A. J., Kannan, K., Tran, P. T., Felsher, D. W. 2020; 9

    Abstract

    Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 predict poor survival (p=4.3*10-10), CCL2/IL13 expression (p<10-109) and TAM infiltration (p<10-96). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, MYC and TWIST1 generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.

    View details for DOI 10.7554/eLife.50731

    View details for PubMedID 31933479

  • CROSS-SPECIES COMPREHENSIVE PROTEOMIC ANALYSIS OF HEPATOCELLULAR CARCINOMA (HCC) TO IDENTIFY PLASMA BIOMARKERS OF VASCULAR INVASION Krishnan, M., Arjunan, V., Kothary, N., Felsher, D., Dhanasekaran, R. WILEY. 2019: 74A
  • A Tale of Two Complications of Obesity: NASH and Hepatocellular Carcinoma HEPATOLOGY Dhanasekaran, R., Felsher, D. W. 2019; 70 (3): 1056–58

    View details for DOI 10.1002/hep.30649

    View details for Web of Science ID 000483692800023

  • The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth. Cell metabolism Gouw, A. M., Margulis, K., Liu, N. S., Raman, S. J., Mancuso, A., Toal, G. G., Tong, L., Mosley, A., Hsieh, A. L., Sullivan, D. K., Stine, Z. E., Altman, B. J., Schulze, A., Dang, C. V., Zare, R. N., Felsher, D. W. 2019

    Abstract

    Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed invivo lipidomic changes upon MYC induction across different cancers, for example, aglobal increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis.

    View details for DOI 10.1016/j.cmet.2019.07.012

    View details for PubMedID 31447321

  • MYC regulates the HIF-2alpha stemness pathway via Nanog and Sox2 to maintain self-renewal in cancer stem cells versus non-stem cancer cells. Cancer research Das, B., Pal, B., Bhuyan, R., Li, H., Sarma, A., Gayan, S., Talukdar, J., Sandhya, S., Bhuyan, S., Gogoi, G., Gouw, A. M., Baishya, D., Gotlib, J. R., Kataki, A. C., Felsher, D. W. 2019

    Abstract

    Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T cell leukemia, MYC maintains self-renewal in Sca1+ CSCs versus Sca-1- non-CSCs. MYC preferentially bound to the promoter and activated HIF-2alpha in Sca-1+ cells only. Further, the reprogramming factors Nanog and Sox2 facilitated MYC regulation of HIF-2alpha in Sca-1+ versus Sca-1- cells. Reduced expression of HIF-2alpha inhibited the self-renewal of Sca-1+ cells; this effect was blocked through suppression of reactive oxygen species (ROS) by N-acetyl cysteine (NAC) or the knock down of p53, Nanog or Sox2. Similar results were seen in ABCG2+ CSCs versus ABCG2- non-CSCs from primary human T cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF-2alpha stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.

    View details for DOI 10.1158/0008-5472.CAN-18-2847

    View details for PubMedID 31266772

  • Mistletoe extract Fraxini inhibits the proliferation of liver cancer by down-regulating c-Myc expression SCIENTIFIC REPORTS Yang, P., Jiang, Y., Pan, Y., Ding, X., Rhea, P., Ding, J., Hawke, D. H., Felsher, D., Narla, G., Lu, Z., Lee, R. T. 2019; 9
  • A Tale of Two Complications of Obesity: Nonalcoholic steatohepatitis (NASH) and Hepatocellular carcinoma (HCC). Hepatology (Baltimore, Md.) Dhanasekaran, R., Felsher, D. W. 2019

    Abstract

    Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease in developed countries and its incidence is rapidly increasing. Cirrhosis, and the dreaded complication of hepatocellular carcinoma (HCC), are the major drivers of morbidity and mortality in NASH. Conventional understanding has been that chronic liver damage leads to a cycle of cell death, regeneration and fibrosis during which HCC precursor cells undergo malignant transformation and lead to cancer initiation. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30958566

  • Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription. Cell chemical biology Struntz, N. B., Chen, A., Deutzmann, A., Wilson, R. M., Stefan, E., Evans, H. L., Ramirez, M. A., Liang, T., Caballero, F., Wildschut, M. H., Neel, D. V., Freeman, D. B., Pop, M. S., McConkey, M., Muller, S., Curtin, B. H., Tseng, H., Frombach, K. R., Butty, V. L., Levine, S. S., Feau, C., Elmiligy, S., Hong, J. A., Lewis, T. A., Vetere, A., Clemons, P. A., Malstrom, S. E., Ebert, B. L., Lin, C. Y., Felsher, D. W., Koehler, A. N. 2019

    Abstract

    The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppressestumor growth invivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.

    View details for DOI 10.1016/j.chembiol.2019.02.009

    View details for PubMedID 30880155

  • Conditional Upregulation of IFN-α Alone Is Sufficient to Induce Systemic Lupus Erythematosus. Journal of immunology (Baltimore, Md. : 1950) Akiyama, C., Tsumiyama, K., Uchimura, C., Honda, E., Miyazaki, Y., Sakurai, K., Miura, Y., Hashiramoto, A., Felsher, D. W., Shiozawa, S. 2019

    Abstract

    The cause of systemic lupus erythematosus (SLE) is unknown. IFN-α has been suggested as a causative agent of SLE; however, it was not proven, and to what extent and how IFN-α contributes to the disease is unknown. We studied the contribution of IFN-α to SLE by generating inducible IFN-α transgenic mice and directly show that conditional upregulation of IFN-α alone induces a typical manifestation of SLE in the mice not prone to autoimmunity, such as serum immune complex, autoantibody against dsDNA (anti-dsDNA Ab), and the organ manifestations classical to SLE, such as immune complex-deposited glomerulonephritis, classical splenic onion-skin lesion, alopecia, epidermal liquefaction, and positive lupus band test of the skin. In the spleen of mice, activated effector CD4 T cells, IFN-γ-producing CD8 T cells, B220+CD86+ cells, and CD11c+CD86+ cells were increased, and the T cells produced increased amounts of IL-4, IL-6, IL-17, and IFN-γ and decreased IL-2. In particular, activated CD3+CD4-CD8- double-negative T cells positive for TCRαβ, B220, CD1d-teteramer, PD-1, and Helios (that produced increased amounts of IFN-γ, IL-4, IL-17, and TNF-α) were significantly expanded. They infiltrated into kidney and induced de novo glomerulonephritis and alopecia when transferred into naive recipients. Thus, sole upregulation of IFN-α is sufficient to induce SLE, and the double-negative T cells expanded by IFN-α are directly responsible for the organ manifestations, such as lupus skin disease or nephritis.

    View details for DOI 10.4049/jimmunol.1801617

    View details for PubMedID 31324723

  • Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index. Scientific reports Li, Y., Thomas, D., Deutzmann, A., Majeti, R., Felsher, D. W., Dill, D. L. 2019; 9 (1): 16775

    Abstract

    Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

    View details for DOI 10.1038/s41598-019-53290-3

    View details for PubMedID 31727951

  • Mistletoe extract Fraxini inhibits the proliferation of liver cancer by down-regulating c-Myc expression. Scientific reports Yang, P., Jiang, Y., Pan, Y., Ding, X., Rhea, P., Ding, J., Hawke, D. H., Felsher, D., Narla, G., Lu, Z., Lee, R. T. 2019; 9 (1): 6428

    Abstract

    Mistletoe (Viscum album) is a type of parasitic plant reported to have anticancer activity including in hepatocellular carcinoma (HCC). However, the mechanism of mistletoe's anticancer activity, and its effectiveness in treating HCC are not fully understood. We report here that mistletoe extracts, including Fraxini (grown on ash trees) and Iscador Q and M (grown on oak and maple trees), exert strong antiproliferative activity in Hep3B cells, with median inhibitory concentrations (IC50) of 0.5 µg/mL, 7.49 µg/mL, and 7.51 µg/mL, respectively. Results of Reversed Phase Proteomic Array analysis (RPPA) suggests that Fraxini substantially down-regulates c-Myc expression in Hep3B cells. Fraxini-induced growth inhibition (at a concentration of 1.25 μg/ml) was less pronounced in c-Myc knockdown Hep3B cells than in control cells. Furthermore, in the Hep3B xenograft model, Fraxini-treated (8 mg/kg body weight) mice had significantly smaller tumors (34.6 ± 11.9 mm3) than control mice (161.6 ± 79.4 mm3, p < 0.036). Similarly, c-Myc protein expression was reduced in Fraxini treated Hep3B cell xenografts compared to that of control mice. The reduction of c-Myc protein levels in vitro Hep3B cells appears to be mediated by the ubiquitin-proteasome system. Our results suggest the importance of c-Myc in Fraxini's antiproliferative activity, which warrants further investigation.

    View details for PubMedID 31015523

  • MYC Functions As a Master Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies Swaminathan, S., Heftdal, L., Liefwalker, D. F., Dhanasekaran, R., Deutzmann, A., Horton, C., Mosley, A., Liebersbach, M., Maecker, H. T., Felsher, D. AMER SOC HEMATOLOGY. 2018
  • Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. Journal for immunotherapy of cancer Lai, I., Swaminathan, S., Baylot, V., Mosley, A., Dhanasekaran, R., Gabay, M., Felsher, D. W. 2018; 6 (1): 125

    Abstract

    Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity. Treatment with IL-12-LNP significantly reduced liver tumor burden measured by dynamic magnetic resonance imaging (MRI), and increased survival of MYC-induced HCC transgenic mice in comparison to control mice. Importantly, IL-12-LNP exhibited no effect on transgenic MYC levels confirming that its therapeutic efficacy was not related to the downregulation of a driver oncogene. IL-12-LNP elicited marked infiltration of activated CD44+ CD3+ CD4+ T helper cells into the tumor, and increased the production of Interferon gamma (IFNgamma). Collectively, our findings suggest that IL-12-LNP administration may be an effective immunotherapy against HCC.

    View details for PubMedID 30458889

  • O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis JOURNAL OF CLINICAL INVESTIGATION Taparra, K., Wang, H., Malek, R., Lafargue, A., Barbhuiya, M. A., Wang, X., Simons, B. W., Ballew, M., Nugent, K., Groves, J., Williams, R. D., Shiraishi, T., Verdone, J., Yildirir, G., Henry, R., Zhang, B., Wong, J., Wang, K., Nelkin, B. D., Pienta, K. J., Felsher, D., Zachara, N. E., Tran, P. T. 2018; 128 (11): 4924–37

    Abstract

    Mutant KRAS drives glycolytic flux in lung cancer, potentially impacting aberrant protein glycosylation. Recent evidence suggests aberrant KRAS drives flux of glucose into the hexosamine biosynthetic pathway (HBP). HBP is required for various glycosylation processes, such as protein N- or O-glycosylation and glycolipid synthesis. However, its function during tumorigenesis is poorly understood. One contributor and proposed target of KRAS-driven cancers is a developmentally conserved epithelial plasticity program called epithelial-mesenchymal transition (EMT). Here we showed in novel autochthonous mouse models that EMT accelerated KrasG12D lung tumorigenesis by upregulating expression of key enzymes of the HBP pathway. We demonstrated that HBP was required for suppressing KrasG12D-induced senescence, and targeting HBP significantly delayed KrasG12D lung tumorigenesis. To explore the mechanism, we investigated protein glycosylation downstream of HBP and found elevated levels of O-linked β-N-acetylglucosamine (O-GlcNAcylation) posttranslational modification on intracellular proteins. O-GlcNAcylation suppressed KrasG12D oncogene-induced senescence (OIS) and accelerated lung tumorigenesis. Conversely, loss of O-GlcNAcylation delayed lung tumorigenesis. O-GlcNAcylation of proteins SNAI1 and c-MYC correlated with the EMT-HBP axis and accelerated lung tumorigenesis. Our results demonstrated that O-GlcNAcylation was sufficient and required to accelerate KrasG12D lung tumorigenesis in vivo, which was reinforced by epithelial plasticity programs.

    View details for PubMedID 30130254

  • The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma ONCOGENE Miess, H., Dankworth, B., Gouw, A. M., Rosenfeldt, M., Schmitz, W., Jiang, M., Saunders, B., Howell, M., Downward, J., Felsher, D. W., Peck, B., Schulze, A. 2018; 37 (40): 5435–50

    Abstract

    Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells. Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation. VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1α and HIF-2α. Restoration of functional VHL via exogenous expression of pVHL reverted ccRCC cells to an oxidative metabolism and rendered them insensitive to the induction of ferroptosis. VHL reconstituted cells also exhibited reduced lipid storage and higher expression of genes associated with oxidiative phosphorylation and fatty acid metabolism. Importantly, inhibition of β-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells. We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer. Together, our data suggest that reduced fatty acid metabolism due to inhibition of β-oxidation renders renal cancer cells highly dependent on the GSH/GPX pathway to prevent lipid peroxidation and ferroptotic cell death.

    View details for PubMedID 29872221

    View details for PubMedCentralID PMC6173300

  • MYC-driven lymphomas suppress NK surveillance by blocking maturation of early NK cells Heftdal, L. D., Swaminathan, S., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2018
  • The MYC oncogene is a global regulator of the immune response BLOOD Casey, S. C., Baylot, V., Felsher, D. W. 2018; 131 (18): 2007–15

    Abstract

    The MYC proto-oncogene is a gene product that coordinates the transcriptional regulation of a multitude of genes that are essential to cellular programs required for normal as well as neoplastic cellular growth and proliferation, including cell cycle, self-renewal, survival, cell growth, metabolism, protein and ribosomal biogenesis, and differentiation. Here, we propose that MYC regulates these programs in a manner that is coordinated with a global influence on the host immune response. MYC had been presumed to contribute to tumorigenesis through tumor cell-intrinsic influences. More recently, MYC expression in tumor cells has been shown to regulate the tumor microenvironment through effects on both innate and adaptive immune effector cells and immune regulatory cytokines. Then, MYC was shown to regulate the expression of the immune checkpoint gene products CD47 and programmed death-ligand 1. Similarly, other oncogenes, which are known to modulate MYC, have been shown to regulate immune checkpoints. Hence, MYC may generally prevent highly proliferative cells from eliciting an immune response. MYC-driven neoplastic cells have coopted this mechanism to bypass immune detection. Thus, MYC inactivation can restore the immune response against a tumor. MYC-induced tumors may be particularly sensitive to immuno-oncology therapeutic interventions.

    View details for PubMedID 29514782

  • Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC). Oncotarget Dhanasekaran, R., Gabay-Ryan, M., Baylot, V., Lai, I., Mosley, A., Huang, X., Zabludoff, S., Li, J., Kaimal, V., Karmali, P., Felsher, D. W. 2018; 9 (5): 5517–28

    Abstract

    Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.

    View details for PubMedID 29464015

  • Administration of low-dose combination anti-CTLA4, anti-CD137, and anti-OX40 into murine tumor or proximal to the tumor draining lymph node induces systemic tumor regression CANCER IMMUNOLOGY IMMUNOTHERAPY Hebb, J. O., Mosley, A. R., Vences-Catalan, F., Rajasekaran, N., Rosen, A., Ellmark, P., Felsher, D. W. 2018; 67 (1): 47–60

    Abstract

    The delivery of immunomodulators directly into the tumor potentially harnesses the existing antigen, tumor-specific infiltrating lymphocytes, and antigen presenting cells. This can confer specificity and generate a potent systemic anti-tumor immune response with lower doses and less toxicity compared to systemic administration, in effect an in situ vaccine. Here, we test this concept using the novel combination of immunomodulators anti-CTLA4, -CD137, and -OX40. The triple combination administered intratumorally at low doses to one tumor of a dual tumor mouse model had dramatic local and systemic anti-tumor efficacy in lymphoma (A20) and solid tumor (MC38) models, consistent with an abscopal effect. The minimal effective dose was 10 μg each. The effect was dependent on CD8 T-cells. Intratumoral administration resulted in superior local and distant tumor control compared to systemic routes, supporting the in situ vaccine concept. In a single tumor A20 model, injection close to the tDLN resulted in similar efficacy as intratumoral and significantly better than targeting a non-tDLN, supporting the role of the tDLN as a viable immunotherapy target in addition to the tumor itself. Distribution studies confirmed expected concentration of antibodies in tumor and tDLN, in keeping with the anti-tumor results. Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.

    View details for PubMedID 28905118

  • MYC through HIF-2 alpha regulates the altruistic stemness program in human leukemia stem cells. Pal, B., Sarma, A., Talukdar, J., Bhuyan, S., Sandhya, S., Gayan, S., Gogoi, G., Baishya, D., Kataki, A., Felsher, D. W., Das, B. AMER ASSOC CANCER RESEARCH. 2017: 61–62
  • MYC is the master switch between tumor dormancy and relapse in Hepatocellular carcinoma (HCC) Dhanasekaran, R., Baylot, V., Mosley, A., Felsher, D. WILEY. 2017: 966A
  • DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt's lymphoma ONCOTARGET Poole, C. J., Zheng, W., Lodh, A., Yevtodiyenko, A., Liefwalker, D., Li, H., Felsher, D. W., van Riggelen, J. 2017; 8 (44): 76898–920

    Abstract

    Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt's lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EμSRα-tTA;tet-o-MYC) and human Burkitt's lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt's lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.

    View details for PubMedID 29100357

  • KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study (vol 50, pg 123, 2016) LEUKEMIA RESEARCH Swords, R. T., Greenberg, P. L., Wei, A. H., Durrant, S., Advani, A. S., Hertzberg, M. S., Lewis, I. D., Rivera, G., Gratzinger, D., Fan, A. C., Felsher, D. W., Cortes, J. E., Watts, J. M., Yarranton, G. T., Walling, J. M., Lancet, J. E. 2017; 59: 65

    View details for PubMedID 28575698

  • MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma NATURE COMMUNICATIONS Bailey, S. T., Smith, A. M., Kardos, J., Wobker, S. E., Wilson, H. L., Krishnan, B., Saito, R., Lee, H., Zhang, J., Eaton, S. C., Williams, L. A., Manocha, U., Peters, D. J., Pan, X., Carroll, T. J., Felsher, D. W., Walter, V., Zhang, Q., Parker, J. S., Yeh, J., Moffitt, R. A., Leung, J. Y., Kim, W. Y. 2017; 8: 15770

    Abstract

    Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.

    View details for PubMedID 28593993

  • Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Gouw, A. M., Eberlin, L. S., Margulis, K., Sullivan, D. K., Toal, G. G., Tong, L., Zare, R. N., Felsher, D. W. 2017; 114 (17): 4300-4305

    Abstract

    KRAS gene mutation causes lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, we show that KRAS activates lipogenesis, and this activation results in distinct proteomic and lipid signatures. By gene expression analysis, KRAS is shown to be associated with a lipogenesis gene signature and specific induction of fatty acid synthase (FASN). Through desorption electrospray ionization MS imaging (DESI-MSI), specific changes in lipogenesis and specific lipids are identified. By the nanoimmunoassay (NIA), KRAS is found to activate the protein ERK2, whereas ERK1 activation is found in non-KRAS-associated human lung tumors. The inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cellular proliferation of KRAS-associated lung cancer cells. Hence, KRAS is associated with activation of ERK2, induction of FASN, and promotion of lipogenesis. FASN may be a unique target for KRAS-associated lung adenocarcinoma remediation.

    View details for DOI 10.1073/pnas.1617709114

    View details for PubMedID 28400509

  • MYC: Master Regulator of Immune Privilege. Trends in immunology Casey, S. C., Baylot, V., Felsher, D. W. 2017

    Abstract

    Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1. We discuss here how oncogenes, and in particular MYC, suppress immune surveillance, and how oncogene-targeted therapies may restore the immune response against tumors.

    View details for DOI 10.1016/j.it.2017.01.002

    View details for PubMedID 28233639

    View details for PubMedCentralID PMC5378645

  • KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study. Leukemia research Swords, R. T., Greenberg, P. L., Wei, A. H., Durrant, S., Advani, A. S., Hertzberg, M. S., Lewis, I. D., Rivera, G., Gratzinger, D., Fan, A. C., Felsher, D. W., Cortes, J. E., Watts, J. M., Yarranton, G. T., Walling, J. M., Lancet, J. E. 2016; 50: 123-131

    Abstract

    EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.

    View details for DOI 10.1016/j.leukres.2016.09.012

    View details for PubMedID 27736729

  • BIM-mediated apoptosis and oncogene addiction. Aging Li, Y., Deutzmann, A., Felsher, D. W. 2016; 8 (9): 1834-1835

    View details for DOI 10.18632/aging.101072

    View details for PubMedID 27688082

    View details for PubMedCentralID PMC5076438

  • Metabolic vulnerabilities of MYC-induced cancer ONCOTARGET Gouw, A. M., Toal, G. G., Felsher, D. W. 2016; 7 (21): 29879–80

    View details for PubMedID 26863454

  • BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia ONCOTARGET Li, Y., Deutzmann, A., Choi, P. S., Fan, A. C., Felsher, D. W. 2016; 7 (19): 26926-26934

    Abstract

    Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.

    View details for DOI 10.18632/oncotarget.8731

    View details for Web of Science ID 000377741700001

  • MYC regulates the antitumor immune response through CD47 and PD-L1 SCIENCE Casey, S. C., Tong, L., Li, Y., Do, R., Walz, S., FitzGerald, K. N., Gouw, A. M., Baylot, V., Guetgemann, I., Eilers, M., Felsher, D. W. 2016; 352 (6282): 227-231

    Abstract

    TheMYConcogene codes for a transcription factor that is overexpressed in many human cancers. Here we show thatMYCregulates the expression of two immune checkpoint proteins on the tumor cell surface, the innate immune regulator, CD47 ( C: luster of D: ifferentiation 47) and the adaptive immune checkpoint, PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 mRNA and protein. MYC was found to bind directly to the promoters of the CD47 and PD-L1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the anti-tumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed and tumors continued to grow. Thus MYC appears to initiate and maintain tumorigenesis in part through the modulation of immune regulatory molecules.

    View details for DOI 10.1126/science.aac9935

    View details for Web of Science ID 000373681600047

    View details for PubMedID 26966191

  • NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis NATURE Ma, C., Kesarwala, A. H., Eggert, T., Medina-Echeverz, J., Kleiner, D. E., Jin, P., Stroncek, D. F., Terabe, M., Kapoor, V., ElGindi, M., Han, M., Thornton, A. M., Zhang, H., Egger, M., Luo, J., Felsher, D. W., McVicar, D. W., Weber, A., Eikenwalder, M. H., Greten, T. F. 2016; 531 (7593): 253-?

    Abstract

    Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.

    View details for DOI 10.1038/nature16969

    View details for Web of Science ID 000371665100046

    View details for PubMedID 26934227

    View details for PubMedCentralID PMC4786464

  • Affordable Cancer Medications Are Within Reach but We Need a Different Approach. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Felsher, D. W., Lowe, L. 2016; 34 (18): 2194–95

    View details for PubMedID 27161965

  • BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia. Oncotarget Li, Y., Deutzmann, A., Choi, P. S., Fan, A. C., Felsher, D. W. 2016

    Abstract

    Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.

    View details for PubMedID 27095570

  • Designing a broad-spectrum integrative approach for cancer prevention and treatment SEMINARS IN CANCER BIOLOGY Block, K. I., Gyllenhaal, C., Lowe, L., Amedei, A., Amin, A. R., Amin, A., Aquilano, K., Arbiser, J., Arreola, A., Arzumanyan, A., Ashraf, S. S., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A., Bishayeen, A., Blain, S. W., Block, P. B., Boosani, C. S., Carey, T. E., Carnero, A., Carotenuto, M., Casey, S. C., Chakrabarti, M., Chaturvedi, R., Chen, G. Z., Chenx, H., Chen, S., Chen, Y. C., Choi, B. K., Ciriolo, M. R., Coley, H. M., Collins, A. R., Connell, M., Crawford, S., Curran, C. S., Dabrosin, C., Damia, G., Dasgupta, S., DeBerardinis, R. J., Decker, W. K., Dhawan, P., Diehl, A. M., Dong, J., Dou, Q. P., Drew, J. E., Elkord, E., El-Rayes, B., Feitelson, M. A., Felsher, D. W., Ferguson, L. R., Fimognari, C., Firestone, G. L., Frezza, C., Fujii, H., Fuster, M. M., Generali, D., Georgakilas, A. G., Gieseler, F., Gilbertson, M., Green, M. F., Grue, B., Guha, G., Halicka, D., Helferich, W. G., Heneberg, P., Hentosh, P., Hirschey, M. D., Hofseth, L. J., Holcombe, R. F., Honoki, K., Hsu, H., Huang, G. S., Jensen, L. D., Jiang, W. G., Jones, L. W., Karpowicz, P. A., Keith, W. N., Kerkar, S. P., Khan, G. N., Khatami, M., Ko, Y. H., Kucuk, O., Kulathinal, R. J., Kumar, N. B., Kwon, B. S., Le, A., Lea, M. A., Lee, H., Lichtor, T., Lin, L., Locasale, J. W., Lokeshwar, B. L., Longo, V. D., Lyssiotis, C. A., MacKenzie, K. L., Malhotra, M., Marino, M., Martinez-Chantar, M. L., Matheu, A., Maxwell, C., McDonnell, E., Meeker, A. K., Mehrmohamadi, M., Mehta, K., Michelotti, G. A., Mohammad, R. M., Mohammed, S. I., Morre, D. J., Muqbil, I., Muralidhar, V., Murphy, M. P., Nagaraju, G. P., Nahta, R., Niccolai, E., Nowsheen, S., Panis, C., Pantano, F., Parslow, V. R., Pawelec, G., Pedersen, P. L., Poore, B., Poudyal, D., Prakash, S., Prince, M., Raffaghello, L., Rathmell, J. C., Rathmell, W. K., Ray, S. K., Reichrath, J., Rezazadeh, S., Ribatti, D., Ricciardiello, L., Robey, R. B., Rodier, F., Rupasinghe, H. P., Russo, G. L., Ryan, E. P., Samadi, A. K., Sanchez-Garcia, I., Sanders, A. J., Santini, D., Sarkar, M., Sasada, T., Saxena, N. K., Shackelford, R. E., Kumara, H. M., Sharma, D., Shin, D. M., Sidransky, D., Siegelin, M. D., Signori, E., Singh, N., Sivanand, S., Sliva, D., Smythe, C., Spagnuolo, C., Stafforini, D. M., Stagg, J., Subbarayan, P. R., Sundin, T., Talib, W. H., Thompson, S. K., Tran, P. T., Ungefroren, H., Vander Heiden, M. G., Venkateswaran, V., Vinay, D. S., Vlachostergios, P. J., Wang, Z., Wellendx, K. E., Whelan, R. L., Yang, E. S., Yang, H., Yang, X., Yaswen, P., Yedjou, C., Yin, X., Zhu, J., Zollo, M. 2015; 35: S276-S304

    Abstract

    Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

    View details for DOI 10.1016/j.semcancer.2015.09.007

    View details for PubMedID 26590477

  • Cancer prevention and therapy through the modulation of the tumor microenvironment. Seminars in cancer biology Casey, S. C., Amedei, A., Aquilano, K., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A. E., Boosani, C. S., Chen, S., Ciriolo, M. R., Crawford, S., Fujii, H., Georgakilas, A. G., Guha, G., Halicka, D., Helferich, W. G., Heneberg, P., Honoki, K., Keith, W. N., Kerkar, S. P., Mohammed, S. I., Niccolai, E., Nowsheen, S., Vasantha Rupasinghe, H. P., Samadi, A., Singh, N., Talib, W. H., Venkateswaran, V., Whelan, R. L., Yang, X., Felsher, D. W. 2015; 35: S199-223

    View details for DOI 10.1016/j.semcancer.2015.02.007

    View details for PubMedID 25865775

  • MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell metabolism Altman, B. J., Hsieh, A. L., Sengupta, A., Krishnanaiah, S. Y., Stine, Z. E., Walton, Z. E., Gouw, A. M., Venkataraman, A., Li, B., Goraksha-Hicks, P., Diskin, S. J., Bellovin, D. I., Simon, M. C., Rathmell, J. C., Lazar, M. A., Maris, J. M., Felsher, D. W., Hogenesch, J. B., Weljie, A. M., Dang, C. V. 2015; 22 (6): 1009-1019

    View details for DOI 10.1016/j.cmet.2015.09.003

    View details for PubMedID 26387865

  • Cancer prevention and therapy through the modulation of the tumor microenvironment. Seminars in cancer biology Casey, S. C., Amedei, A., Aquilano, K., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A. E., Boosani, C. S., Chen, S., Ciriolo, M. R., Crawford, S., Fujii, H., Georgakilas, A. G., Guha, G., Halicka, D., Helferich, W. G., Heneberg, P., Honoki, K., Keith, W. N., Kerkar, S. P., Mohammed, S. I., Niccolai, E., Nowsheen, S., Vasantha Rupasinghe, H. P., Samadi, A., Singh, N., Talib, W. H., Venkateswaran, V., Whelan, R. L., Yang, X., Felsher, D. W. 2015; 35: S199-223

    Abstract

    Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

    View details for DOI 10.1016/j.semcancer.2015.02.007

    View details for PubMedID 25865775

  • ARF: Connecting senescence and innate immunity for clearance AGING-US Kearney, A. Y., Anchang, B., Plevritis, S., Felsher, D. W. 2015; 7 (9): 613-615

    Abstract

    We have found evidence suggesting that ARF and p53 are essential for tumor regression upon MYC inactivation through distinct mechanisms ARF through p53-independent affect, is required to for MYC to regulate the expression of genes that are required for both the induction of cellular senescence as well as recruitment of innate immune activation. Our observations have possible implications for mechanisms of therapeutic resistance to targeted oncogene inactivation.

    View details for PubMedID 26412380

  • The effect of environmental chemicals on the tumor microenvironment CARCINOGENESIS Casey, S. C., Vaccari, M., Al-Mulla, F., Al-Temaimi, R., Amedei, A., Barcellos-Hoff, M. H., Brown, D. G., Chapellier, M., Christopher, J., Curran, C., Forte, S., Hamid, R. A., Heneberg, P., Koch, D. C., Krishnakumar, P. K., Laconi, E., Maguer-Satta, V., Marongiu, F., Memeo, L., Mondello, C., Raju, J., Roman, J., Roy, R., Ryan, E. P., Ryeom, S., Salem, H. K., Scovassi, A. I., Singh, N., Soucek, L., Vermeulen, L., Whitfield, J. R., Woodrick, J., Colacci, A., Bisson, W. H., Felsher, D. W. 2015; 36: S160-S183

    Abstract

    Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

    View details for DOI 10.1093/carcin/bgv035

    View details for PubMedID 26106136

  • Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis Goodson, W. H., Lowe, L., Carpenter, D. O., Gilbertson, M., Manaf Ali, A., Lopez de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A. K., Collins, A. R., Ward, A., Salzberg, A. C., Colacci, A., Olsen, A., Berg, A., Barclay, B. J., Zhou, B. P., Blanco-Aparicio, C., Baglole, C. J., Dong, C., Mondello, C., Hsu, C., Naus, C. C., Yedjou, C., Curran, C. S., Laird, D. W., Koch, D. C., Carlin, D. J., Felsher, D. W., Roy, D., Brown, D. G., Ratovitski, E., Ryan, E. P., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F. L., van Schooten, F. J., Goldberg, G. S., Wagemaker, G., Nangami, G., Calaf, G. M., Williams, G., Wolf, G. T., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Ab Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H. K., Hsu, H., Park, H. H., Koturbash, I., Miousse, I. R., Scovassi, A. I., Klaunig, J. E., Vondrácek, J., Raju, J., Roman, J., Wise, J. P., Whitfield, J. R., Woodrick, J., Christopher, J. A., Ochieng, J., Martinez-Leal, J. F., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K. R., Narayanan, K. B., Cohen-Solal, K. A., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L. S., Lin, L., Li, L., Gulliver, L., McCawley, L. J., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M. F., Chapellier, M., Williams, M. A., Wade, M., Manjili, M. H., Lleonart, M., Xia, M., Gonzalez, M. J., Karamouzis, M. V., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N. B., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P. K., Vadgama, P., Marignani, P. A., Ghosh, P. M., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Sing Leung, P., Nangia-Makker, P., Cheng, Q. S., Robey, R. B., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R. K., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R. C., Palorini, R., Abd Hamid, R., Langie, S. A., Eltom, S., Brooks, S. A., Ryeom, S., Wise, S. S., Bay, S. N., Harris, S. A., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S. C., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Rathmell, W. K., Engström, W., Decker, W. K., Bisson, W. H., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z. 2015; 36: S254-96

    Abstract

    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

    View details for DOI 10.1093/carcin/bgv039

    View details for PubMedID 26106142

  • Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis JOURNAL OF CLINICAL INVESTIGATION Xiang, Y., Stine, Z. E., Xia, J., Lu, Y., O'Connor, R. S., Altman, B. J., Hsieh, A. L., Gouw, A. M., Thomas, A. G., Gao, P., Sun, L., Song, L., Yan, B., Slusher, B. S., Zhuo, J., Ooi, L. L., Lee, C. G., Mancuso, A., McCallion, A. S., Le, A., Milone, M. C., Rayport, S., Felsher, D. W., Dang, C. V. 2015; 125 (6): 2293-2306

    Abstract

    Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell-autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy.

    View details for DOI 10.1172/JCI75836

    View details for Web of Science ID 000355573900018

    View details for PubMedID 25915584

    View details for PubMedCentralID PMC4497742

  • Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead CARCINOGENESIS Goodson, W. H., Lowe, L., Carpenter, D. O., Gilbertson, M., Ali, A. M., de Cerain Salsamendi, A. L., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A. K., Collins, A. R., Ward, A., Salzberg, A. C., Colacci, A., Olsen, A., Berg, A., Barclay, B. J., Zhou, B. P., Blanco-Aparicio, C., Baglole, C. J., Dong, C., Mondello, C., Hsu, C., Naus, C. C., Yedjou, C., Curran, C. S., Laird, D. W., Koch, D. C., Carlin, D. J., Felsher, D. W., Roy, D., Brown, D. G., Ratovitski, E., Ryan, E. P., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F. L., van Schooten, F. J., Goldberg, G. S., Wagemaker, G., Nangami, G., Calaf, G. M., Williams, G., Wolf, G. T., Koppen, G., Brunborg, G., Lyerly, H. K., Krishnan, H., Ab Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H. K., Hsu, H., Park, H. H., Koturbash, I., Miousse, I. R., Scovassi, A. I., Klaunig, J. E., Vondracek, J., Raju, J., Roman, J., Wise, J. P., Whitfield, J. R., Woodrick, J., Christopher, J. A., Ochieng, J., Fernando Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K. R., Narayanan, K. B., Cohen-Solal, K. A., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L. S., Lin, L., Li, L., Gulliver, L., McCawley, L. J., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M. F., Chapellier, M., Williams, M. A., Wade, M., Manjili, M. H., Lleonart, M., Xia, M., Gonzalez, M. J., Karamouzis, M. V., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N. B., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P. K., Vadgama, P., Marignani, P. A., Ghosh, P. M., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P. S., Nangia-Makker, P., Cheng, Q. (., Robey, R. B., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R. K., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R. C., Palorini, R., Abd Hamid, R., Langie, S. A., Eltom, S., Brooks, S. A., Ryeom, S., Wise, S. S., Bay, S. N., Harris, S. A., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S. C., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Rathmell, W. K., Engstrom, W., Decker, W. K., Bisson, W. H., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z. 2015; 36: S254-S296

    Abstract

    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

    View details for DOI 10.1093/carcin/bgv039

    View details for Web of Science ID 000357048100013

  • MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shroff, E. H., Eberlin, L. S., Dang, V. M., Gouw, A. M., Gabay, M., Adam, S. J., Bellovin, D. I., Tran, P. T., Philbrick, W. M., Garcia-Ocana, A., Casey, S. C., Li, Y., Dang, C. V., Zare, R. N., Felsher, D. W. 2015; 112 (21): 6539-6544

    Abstract

    The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.

    View details for DOI 10.1073/pnas.1507228112

    View details for PubMedID 25964345

  • p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia ONCOTARGET Yetil, A., Anchang, B., Gouw, A. M., Adam, S. J., Zabuawala, T., Parameswaran, R., van Riggelen, J., Plevritis, S., Felsher, D. W. 2015; 6 (6): 3563-3577

    Abstract

    MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.

    View details for PubMedID 25784651

  • miR-17-92 explains MYC oncogene addiction. Molecular & cellular oncology Li, Y., Casey, S. C., Choi, P. S., Felsher, D. W. 2014; 1 (4)

    Abstract

    MYC regulates tumorigenesis by coordinating the expression of thousands of genes. We found that MYC appears to regulate the decisions between cell survival versus death and self-renewal versus senescence through the microRNA miR-17-92 cluster. Addiction to the MYC oncogene may therefore in fact be an addiction to miR-17-92.

    View details for DOI 10.4161/23723548.2014.970092

    View details for PubMedID 27308380

    View details for PubMedCentralID PMC4905255

  • Oncogene addiction: resetting the safety switch? Oncotarget Li, Y., Choi, P. S., Felsher, D. W. 2014; 5 (18): 7986-7987

    Abstract

    Commentary on: Li Y, Choi PS, Casey SC, Dill DL, Felsher DW. MYC through miR-17-92 Suppresses Specific Target Genes to Maintain Survival, Autonomous Proliferation, and a Neoplastic State. Cancer Cell. 2014 ;26:262-72.

    View details for PubMedID 25275297

  • Activation of Cre Recombinase Alone Can Induce Complete Tumor Regression PLOS ONE Li, Y., Choi, S., Casey, S. C., Felsher, D. W. 2014; 9 (9)
  • Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance. Proceedings of the National Academy of Sciences of the United States of America Choi, P. S., Li, Y., Felsher, D. W. 2014; 111 (32): E3316-24

    Abstract

    Many cancers exhibit sensitivity to the inhibition of a single genetic lesion, a property that has been successfully exploited with oncogene-targeted therapeutics. However, inhibition of single oncogenes often fails to result in sustained tumor regression due to the emergence of therapy-resistant cells. Here, we report that MYC-driven lymphomas frequently acquire activating mutations in β-catenin, including a previously unreported mutation in a splice acceptor site. Tumors with these genetic lesions are highly dependent on β-catenin for their survival and the suppression of β-catenin resulted in marked apoptosis causally related to a decrease in Bcl-xL expression. Using a novel inducible inhibitor of β-catenin, we illustrate that, although MYC withdrawal or β-catenin inhibition alone results in initial tumor regression, most tumors ultimately recurred, mimicking the clinical response to single-agent targeted therapy. Importantly, the simultaneous combined inhibition of both MYC and β-catenin promoted more rapid tumor regression and successfully prevented tumor recurrence. Hence, we demonstrated that MYC-induced tumors are addicted to mutant β-catenin, and the combined inactivation of MYC and β-catenin induces sustained tumor regression. Our results provide a proof of principle that targeting multiple oncogene addicted pathways can prevent therapeutic resistance.

    View details for DOI 10.1073/pnas.1406123111

    View details for PubMedID 25071175

    View details for PubMedCentralID PMC4136575

  • Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance. Proceedings of the National Academy of Sciences of the United States of America Choi, P. S., Li, Y., Felsher, D. W. 2014; 111 (32): E3316-24

    View details for DOI 10.1073/pnas.1406123111

    View details for PubMedID 25071175

  • MYC through miR-17-92 Suppresses Specific Target Genes to Maintain Survival, Autonomous Proliferation, and a Neoplastic State. Cancer cell Li, Y., Choi, P. S., Casey, S. C., Dill, D. L., Felsher, D. W. 2014; 26 (2): 262-272

    Abstract

    The MYC oncogene regulates gene expression through multiple mechanisms, and its overexpression culminates in tumorigenesis. MYC inactivation reverses turmorigenesis through the loss of distinguishing features of cancer, including autonomous proliferation and survival. Here we report that MYC via miR-17-92 maintains a neoplastic state through the suppression of chromatin regulatory genes Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim. The enforced expression of miR-17-92 prevents MYC suppression from inducing proliferative arrest, senescence, and apoptosis and abrogates sustained tumor regression. Knockdown of the five miR-17-92 target genes blocks senescence and apoptosis while it modestly delays proliferative arrest, thus partially recapitulating miR-17-92 function. We conclude that MYC, via miR-17-92, maintains a neoplastic state by suppressing specific target genes.

    View details for DOI 10.1016/j.ccr.2014.06.014

    View details for PubMedID 25117713

  • Alteration of the lipid profile in lymphomas induced by MYC overexpression. Proceedings of the National Academy of Sciences of the United States of America Eberlin, L. S., Gabay, M., Fan, A. C., Gouw, A. M., Tibshirani, R. J., Felsher, D. W., Zare, R. N. 2014; 111 (29): 10450-10455

    Abstract

    Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas.

    View details for DOI 10.1073/pnas.1409778111

    View details for PubMedID 24994904

  • Inactivation of MYC reverses tumorigenesis JOURNAL OF INTERNAL MEDICINE Li, Y., Casey, S. C., Felsher, D. W. 2014; 276 (1): 52-60

    Abstract

    The MYC proto-oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. When pathologically activated in the correct epigenetic and genetic contexts, MYC bypasses these mechanisms and drives many of the 'hallmark' features of cancer, including uncontrolled tumour growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis and altered cellular metabolism. MYC also dictates tumour cell fate by enforcing self-renewal and by abrogating cellular senescence and differentiation programmes. Moreover, MYC influences the tumour microenvironment, including activating angiogenesis and suppressing the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/joim.12237

    View details for Web of Science ID 000337787500006

  • MYC Activation Is a Hallmark of Cancer Initiation and Maintenance COLD SPRING HARBOR PERSPECTIVES IN MEDICINE Gabay, M., Li, Y., Felsher, D. W. 2014; 4 (6)
  • MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harbor perspectives in medicine Gabay, M., Li, Y., Felsher, D. W. 2014; 4 (6)

    Abstract

    The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.

    View details for DOI 10.1101/cshperspect.a014241

    View details for PubMedID 24890832

  • Bioorthogonal cyclization-mediated in situ self-assembly of small-molecule probes for imaging caspase activity in vivo. Nature chemistry Ye, D., Shuhendler, A. J., Cui, L., Tong, L., Tee, S. S., Tikhomirov, G., Felsher, D. W., Rao, J. 2014; 6 (6): 519-526

    Abstract

    Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and already this has been used widely to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling the self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employ an optimized first-order bioorthogonal cyclization reaction to control the self-assembly of a fluorescent small molecule, and demonstrate its in vivo applicability by imaging caspase-3/7 activity in human tumour xenograft mouse models of chemotherapy. The fluorescent nanoparticles assembled in situ were imaged successfully in both apoptotic cells and tumour tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo.

    View details for DOI 10.1038/nchem.1920

    View details for PubMedID 24848238

    View details for PubMedCentralID PMC4031611

  • An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. Immunologic research Casey, S. C., Li, Y., Felsher, D. W. 2014; 58 (2-3): 282-291

    Abstract

    Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often "oncogene addicted." The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4(+) T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shutdown of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are involved not only in tumor initiation, tumor progression, and immunosurveillance, but also in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.

    View details for DOI 10.1007/s12026-014-8503-6

    View details for PubMedID 24791942

  • Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer cell Cao, Z., Ding, B., Guo, P., Lee, S. B., Butler, J. M., Casey, S. C., Simons, M., Tam, W., Felsher, D. W., Shido, K., Rafii, A., Scandura, J. M., Rafii, S. 2014; 25 (3): 350-365

    Abstract

    Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

    View details for DOI 10.1016/j.ccr.2014.02.005

    View details for PubMedID 24651014

  • Angiocrine Factors Deployed by Tumor Vascular Niche Induce B Cell Lymphoma Invasiveness and Chemoresistance CANCER CELL Cao, Z., Ding, B., Guo, P., Lee, S. B., Butler, J. M., Casey, S. C., Simons, M., Tam, W., Felsher, D. W., Shido, K., Rafii, A., Scandura, J. M., Refii, S. 2014; 25 (3): 350-365

    Abstract

    Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

    View details for DOI 10.1016/j.ccr.2014.02.005

    View details for Web of Science ID 000333233400012

  • Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 566-?

    Abstract

    A major drawback with current cancer therapy is the prevalence of unrequired dose-limiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional "theranostic" nanoparticles (TNPs) is described for enzyme-specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO-ICTs (TNPs). Significant cell death is observed in TNP-treated MMP-14 positive MMTV-PyMT breast cancer cells in vitro, but not MMP-14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.

    View details for DOI 10.1002/smll.201301456

    View details for PubMedID 24038954

  • Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small Ansari, C., Tikhomirov, G. A., Hong, S. H., Falconer, R. A., Loadman, P. M., Gill, J. H., Castaneda, R., Hazard, F. K., Tong, L., Lenkov, O. D., Felsher, D. W., Rao, J., Daldrup-Link, H. E. 2014; 10 (3): 566-575

    View details for DOI 10.1002/smll.201301456

    View details for PubMedID 24038954

  • Inactivation of MYC reverses tumorigenesis. Journal of internal medicine Li, Y., Casey, S. C., Felsher, D. W. 2014

    Abstract

    The MYC proto-oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. When pathologically activated in the correct epigenetic and genetic contexts, MYC bypasses these mechanisms and drives many of the 'hallmark' features of cancer, including uncontrolled tumour growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis and altered cellular metabolism. MYC also dictates tumour cell fate by enforcing self-renewal and by abrogating cellular senescence and differentiation programmes. Moreover, MYC influences the tumour microenvironment, including activating angiogenesis and suppressing the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis. This article is protected by copyright. All rights reserved.

    View details for PubMedID 24645771

  • Activation of Cre recombinase alone can induce complete tumor regression. PloS one Li, Y., Choi, P. S., Casey, S. C., Felsher, D. W. 2014; 9 (9)

    Abstract

    The Cre/loxP system is a powerful tool for generating conditional genomic recombination and is often used to examine the mechanistic role of specific genes in tumorigenesis. However, Cre toxicity due to its non-specific endonuclease activity has been a concern. Here, we report that tamoxifen-mediated Cre activation in vivo induced the regression of primary lymphomas in p53-/- mice. Our findings illustrate that Cre activation alone can induce the regression of established tumors.

    View details for DOI 10.1371/journal.pone.0107589

    View details for PubMedID 25208064

    View details for PubMedCentralID PMC4160265

  • Oncogene withdrawal engages the immune system to induce sustained cancer regression. Journal for immunotherapy of cancer Casey, S. C., Li, Y., Fan, A. C., Felsher, D. W. 2014; 2: 24-?

    Abstract

    The targeted inactivation of a single oncogene can induce dramatic tumor regression, suggesting that cancers are "oncogene addicted." Tumor regression following oncogene inactivation has been thought to be a consequence of restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and cellular senescence. However, recent observations illustrate that oncogene addiction is highly dependent upon the host immune cells. In particular, CD4(+) helper T cells were shown to be essential to the mechanism by which MYC or BCR-ABL inactivation elicits "oncogene withdrawal." Hence, immune mediators contribute in multiple ways to the pathogenesis, prevention, and treatment of cancer, including mechanisms of tumor initiation, progression, and surveillance, but also oncogene inactivation-mediated tumor regression. Data from both the bench and the bedside illustrates that the inactivation of a driver oncogene can induce activation of the immune system that appears to be essential for sustained tumor regression.

    View details for DOI 10.1186/2051-1426-2-24

    View details for PubMedID 25089198

  • STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma ONCOGENE Bisikirska, B. C., Adam, S. J., Alvarez, M. J., Rajbhandari, P., Cox, R., Lefebvre, C., Wang, K., Rieckhof, G. E., Felsher, D. W., Califano, A. 2013; 32 (45): 5283-5291

    Abstract

    The MYC protooncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. Besides constituting a formidable therapeutic target, MYC also has an essential function in normal physiology, thus creating the need for context-specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, whereas its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC-addicted tumors in vivo, thus providing a novel viable target for treating these malignancies.Oncogene advance online publication, 26 November 2012; doi:10.1038/onc.2012.543.

    View details for DOI 10.1038/onc.2012.543

    View details for Web of Science ID 000326922100004

    View details for PubMedID 23178486

  • Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma JOURNAL OF HEPATOLOGY Kapanadze, T., Gamrekelashvili, J., Ma, C., Chan, C., Zhao, F., Hewitt, S., Zender, L., Kapoor, V., Felsher, D. W., Manns, M. P., Korangy, F., Greten, T. F. 2013; 59 (5): 1007-1013

    Abstract

    Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease.The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages.An accumulation of MDSC was found in mice with HCC irrespectively of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN-induced HCC. Enhanced expression of genes associated with MDSC generation (GM-CSF, VEGF, IL-6, IL-1 and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF over-expression or anti-KC and anti-GM-CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib.Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied.

    View details for Web of Science ID 000325754200016

    View details for PubMedID 23796475

  • Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer. Expert opinion on investigational drugs Fan, A. C., O'Rourke, J. J., Praharaj, D. R., Felsher, D. W. 2013; 22 (11): 1495-1509

    Abstract

    Rigosertib (ON01910.Na), is a targeted therapeutic that inhibits multiple kinases, including PI3K and PIk-1. Rigosertib has been found to induce the proliferative arrest and apoptosis of myeloblasts but not of other normal hematopoietic cells. Rigosertib has significant clinical activity as a therapy for patients with high-risk myelodysplastic syndrome who are otherwise refractory to DNA methyltransferase inhibitors. Moreover, rigosertib has potential clinical activity in a multitude of solid tumors.The objective of this review is to evaluate the mechanism of activity, efficacy and dosing of rigosertib. Furthermore, the challenge in the clinical development of rigosertib, to identify the specific patients that are most likely to benefit from this therapeutic agent, is discussed. A PubMed search was performed using the following key words: rigosertib and ON01910.Na.We describe the application of a novel nanoscale proteomic assay, the nanoimmunoassay, a tractable approach for measuring the activity and predicting the efficacy of rigosertib, in real-time, using limited human clinical specimens. Our strategy suggests a possible paradigm where proteomic analysis during the pre-clinical and clinical development of a therapy can be used to uncover biomarkers for the analysis and prediction of efficacy in human patients.

    View details for DOI 10.1517/13543784.2013.829453

    View details for PubMedID 23937225

  • BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells. Blood Beurlet, S., Omidvar, N., Gorombei, P., Krief, P., Le Pogam, C., Setterblad, N., de la Grange, P., Leboeuf, C., Janin, A., Noguera, M., Hervatin, F., Sarda-Mantel, L., Konopleva, M., Andreeff, M., Tu, A. W., Fan, A. C., Felsher, D. W., Whetton, A., Pla, M., West, R., Fenaux, P., Chomienne, C., Padua, R. A. 2013; 122 (16): 2864-2876

    Abstract

    Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.

    View details for DOI 10.1182/blood-2012-07-445635

    View details for PubMedID 23943652

    View details for PubMedCentralID PMC3799000

  • A c-Myc Activation Sensor-Based High-Throughput Drug Screening Identifies an Antineoplastic Effect of Nitazoxanide. Molecular cancer therapeutics Fan-Minogue, H., Bodapati, S., Solow-Cordero, D., Fan, A., Paulmurugan, R., Massoud, T. F., Felsher, D. W., Gambhir, S. S. 2013; 12 (9): 1896-1905

    Abstract

    Deregulation of c-Myc plays a central role in the tumorigenesis of many human cancers. Yet, the development of drugs regulating c-Myc activity has been challenging. To facilitate the identification of c-Myc inhibitors, we developed a molecular imaging sensor based high throughput-screening (HTS) system. This system uses a cell-based assay to detect c-Myc activation in a HTS format, which is established from a pure clone of a stable breast cancer cell line that constitutively expresses a c-Myc activation sensor. Optimization of the assay performance in the HTS format resulted in uniform and robust signals at the baseline. Using this system, we performed a quantitative HTS against approximately 5,000 existing bioactive compounds from five different libraries. Thirty-nine potential hits were identified, including currently known c-Myc inhibitors. There are a few among the top potent hits that are not known for anti-c-Myc activity. One of these hits is nitazoxanide (NTZ), a thiazolide for treating human protozoal infections. Validation of NTZ in different cancer cell lines revealed a high potency for c-Myc inhibition with IC50 ranging between 10 - 500nM. Oral administration of NTZ in breast cancer xenograft mouse models significantly suppressed tumor growth by inhibition of c-Myc and induction of apoptosis. These findings suggest a potential of NTZ to be repurposed as a new anti-tumor agent for inhibition of c-Myc associated neoplasia. Our work also demonstrated the unique advantage of molecular imaging in accelerating discovery of drugs for c-Myc targeted cancer therapy.

    View details for DOI 10.1158/1535-7163.MCT-12-1243

    View details for PubMedID 23825064

  • A tumor-immune mathematical model of CD4+ T helper cell dependent tumor regression by oncogene inactivation. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference Nwabugwu, C. I., Rakhra, K., Felsher, D. W., Paik, D. S. 2013; 2013: 4529-4532

    Abstract

    Understanding the complex dynamics between the tumor cells and the host immune system will be key to improved therapeutic strategies against cancer. We propose an ODE-based mathematical model of both the tumor and immune system and how they respond to inactivation of the driving oncogene. Our model supports experimental results showing that cellular senescence of tumor cells is dependent on CD4+ T helper cells, leading to relapse of tumors in immunocompromised hosts.

    View details for DOI 10.1109/EMBC.2013.6610554

    View details for PubMedID 24110741

  • Characterization of MYC-Induced Tumorigenesis by in Situ Lipid Profiling ANALYTICAL CHEMISTRY Perry, R. H., Bellovin, D. I., Shroff, E. H., Ismail, A. I., Zabuawala, T., Felsher, D. W., Zare, R. N. 2013; 85 (9): 4259-4262

    Abstract

    We apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to provide an in situ lipidomic profile of genetically modified tissues from a conditional transgenic mouse model of MYC-induced hepatocellular carcinoma (HCC). This unique, label-free approach of combining DESI-MSI with the ability to turn specific genes on and off has led to the discovery of highly specific lipid molecules associated with MYC-induced tumor onset. We are able to distinguish normal from MYC-induced malignant cells. Our approach provides a strategy to define a precise molecular picture at a resolution of about 200 μm that may be useful in identifying lipid molecules that define how the MYC oncogene initiates and maintains tumorigenesis.

    View details for DOI 10.1021/ac400479j

    View details for Web of Science ID 000318756100008

    View details for PubMedID 23560736

  • [F-18]CAIP a smart PET tracer for imaging caspase-3 induced Apoptosis Shen Bin, B., Jeon, J., Palner, M., Tong Ling, L., Felsher, D., Gambhir, S. S., Chin, F. T., Rao Jianghong, J. H. WILEY-BLACKWELL. 2013: S6–S6
  • Role of MYCN in retinoblastoma LANCET ONCOLOGY Felsher, D. W. 2013; 14 (4): 270-271
  • Noncanonical roles of the immune system in eliciting oncogene addiction. Current opinion in immunology Casey, S. C., Bellovin, D. I., Felsher, D. W. 2013; 25 (2): 246-258

    Abstract

    Cancer is highly complex. The magnitude of this complexity makes it highly surprising that even the brief suppression of an oncogene can sometimes result in rapid and sustained tumor regression, illustrating that cancers can be 'oncogene addicted' [1-10]. The essential implication is that oncogenes may not only fuel the initiation of tumorigenesis, but in some cases must be excessively activated to maintain a neoplastic state [11]. Oncogene suppression acutely restores normal physiological programs that effectively overrides secondary genetic events and a cancer collapses [12,13]. Oncogene addiction is the description of the dramatic and sustained regression of some cancers upon the specific inactivation of a single oncogene [1-13,14(••),15,16(••)], that can occur through tumor intrinsic [1,2,4,12], but also host immune mechanisms [17-23]. Notably, oncogene inactivation elicits a host immune response that involves specific immune effectors and cytokines that facilitate a remodeling of the tumor microenvironment including the shut down of angiogenesis and the induction of cellular senescence of tumor cells [16(••)]. Hence, immune effectors are not only critically involved in tumor prevention, initiation [17-19], and progression [20], but also appear to be essential to tumor regression upon oncogene inactivation [21,22(••),23(••)]. Understanding how the inactivation of an oncogene elicits a systemic signal in the host that prompts a deconstruction of a tumor could have important implications. The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both robust tumor intrinsic and immunological responses, effectively leading to sustained tumor regression.

    View details for DOI 10.1016/j.coi.2013.02.003

    View details for PubMedID 23571026

  • Metabolic changes in cancer cells upon suppression of MYC. Cancer & metabolism Anso, E., Mullen, A. R., Felsher, D. W., Matés, J. M., DeBerardinis, R. J., Chandel, N. S. 2013; 1 (1): 7-?

    Abstract

    Cancer cells engage in aerobic glycolysis and glutaminolysis to fulfill their biosynthetic and energetic demands in part by activating MYC. Previous reports have characterized metabolic changes in proliferating cells upon MYC loss or gain of function. However, metabolic differences between MYC-dependent cancer cells and their isogenic differentiated counterparts have not been characterized upon MYC suppression in vitro.Here we report metabolic changes between MYC-dependent mouse osteogenic sarcomas and differentiated osteoid cells induced upon MYC suppression. While osteogenic sarcoma cells increased oxygen consumption and spare respiratory capacity upon MYC suppression, they displayed minimal changes in glucose and glutamine consumption as well as their respective contribution to the citrate pool. However, glutamine significantly induced oxygen consumption in the presence of MYC which was dependent on aminotransferases. Furthermore, inhibition of aminotransferases selectively diminished cell proliferation and survival of osteogenic sarcoma MYC-expressing cells. There were minimal changes in ROS levels and cell death sensitivity to reactive oxygen species (ROS)-inducing agents between osteoid cells and osteogenic sarcoma cells. Nevertheless, the mitochondrial-targeted antioxidant Mito-Vitamin E still diminished proliferation of MYC-dependent osteogenic sarcoma cells.These data highlight that aminotransferases and mitochondrial ROS might be attractive targets for cancer therapy in MYC-driven tumors.

    View details for DOI 10.1186/2049-3002-1-7

    View details for PubMedID 24280108

  • Dissection of the role of the tumor microenvironment in oncogene addiction by ex vivo and in situ imaging AACR/SNMMI Joint Conference on State-of-the-Art Molecular Imaging in Cancer Biology and Therapy Tong, L., Jeon, J., Shen, B., Jianghong, R., Chin, F., Gambhir, S., Felsher, D. SOC NUCLEAR MEDICINE INC. 2013: 25–25
  • CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Science translational medicine Das, B., Kashino, S. S., Pulu, I., Kalita, D., Swami, V., Yeger, H., Felsher, D. W., Campos-Neto, A. 2013; 5 (170): 170ra13-?

    Abstract

    Mycobacterium tuberculosis (Mtb) can persist in hostile intracellular microenvironments evading immune cells and drug treatment. However, the protective cellular niches where Mtb persists remain unclear. We report that Mtb may maintain long-term intracellular viability in a human bone marrow (BM)-derived CD271(+)/CD45(-) mesenchymal stem cell (BM-MSC) population in vitro. We also report that Mtb resides in an equivalent population of BM-MSCs in a mouse model of dormant tuberculosis infection. Viable Mtb was detected in CD271(+)/CD45(-) BM-MSCs isolated from individuals who had successfully completed months of anti-Mtb drug treatment. These results suggest that CD271(+) BM-MSCs may provide a long-term protective intracellular niche in the host in which dormant Mtb can reside.

    View details for DOI 10.1126/scitranslmed.3004912

    View details for PubMedID 23363977

    View details for PubMedCentralID PMC3616630

  • CD271(+) Bone Marrow Mesenchymal Stem Cells May Provide a Niche for Dormant Mycobacterium tuberculosis SCIENCE TRANSLATIONAL MEDICINE Das, B., Kashino, S. S., Pulu, I., Kalita, D., Swami, V., Yeger, H., Felsher, D. W., Campos-Neto, A. 2013; 5 (170)

    View details for DOI 10.1126/scitranslmed.3004912

    View details for Web of Science ID 000314343100003

    View details for PubMedID 23363977

  • Tumor dormancy, oncogene addiction, cellular senescence, and self-renewal programs. Advances in experimental medicine and biology Bellovin, D. I., Das, B., Felsher, D. W. 2013; 734: 91-107

    Abstract

    Cancers are frequently addicted to initiating oncogenes that elicit aberrant cellular proliferation, self-renewal, and apoptosis. Restoration of oncogenes to normal physiologic regulation can elicit dramatic reversal of the neoplastic phenotype, including reduced proliferation and increased apoptosis of tumor cells (Science 297(5578):63-64, 2002). In some cases, oncogene inactivation is associated with compete elimination of a tumor. However, in other cases, oncogene inactivation induces a conversion of tumor cells to a dormant state that is associated with cellular differentiation and/or loss of the ability to self-replicate. Importantly, this dormant state is reversible, with tumor cells regaining the ability to self-renew upon oncogene reactivation. Thus, understanding the mechanism of oncogene inactivation-induced dormancy may be crucial for predicting therapeutic outcome of targeted therapy. One important mechanistic insight into tumor dormancy is that oncogene addiction might involve regulation of a decision between self-renewal and cellular senescence. Recent evidence suggests that this decision is regulated by multiple mechanisms that include tumor cell-intrinsic, cell-autonomous mechanisms and host-dependent, tumor cell-non-autonomous programs (Mol Cell 4(2):199-207, 1999; Science 297(5578):102-104, 2002; Nature 431(7012):1112-1117, 2004; Proc Natl Acad Sci U S A 104(32):13028-13033, 2007). In particular, the tumor microenvironment, which is known to be critical during tumor initiation (Cancer Cell 7(5):411-423, 2005; J Clin Invest 121(6):2436-2446, 2011), prevention (Nature 410(6832):1107-1111, 2001), and progression (Cytokine Growth Factor Rev 21(1):3-10, 2010), also appears to dictate when oncogene inactivation elicits the permanent loss of self-renewal through induction of cellular senescence (Nat Rev Clin Oncol 8(3):151-160, 2011; Science 313(5795):1960-1964, 2006; N Engl J Med 351(21):2159-21569, 2004). Thus, oncogene addiction may be best modeled as a consequence of the interplay amongst cell-autonomous and host-dependent programs that define when a therapy will result in tumor dormancy.

    View details for DOI 10.1007/978-1-4614-1445-2_6

    View details for PubMedID 23143977

  • Generation of a Tetracycline Regulated Mouse Model of MYC-Induced T-Cell Acute Lymphoblastic Leukemia. Methods in molecular biology (Clifton, N.J.) Rakhra, K., Felsher, D. W. 2013; 1012: 221-235

    Abstract

    The tetracycline regulatory system provides a tractable strategy to interrogate the role of oncogenes in the initiation and maintenance of tumorigenesis through both spatial and temporal control of expression. This approach has several potential advantages over conventional methods to generate genetically engineered mouse models. First, continuous constitutive overexpression of an oncogene can be lethal to the host impeding further study. Second, constitutive overexpression fails to model adult onset of disease. Third, constitutive deletion does not permit, whereas conditional overexpression of an oncogene enables the study of the consequences of restoring expression of an oncogene back to endogenous levels. Fourth, the conditional activation of oncogenes enables examination of specific and/or developmental state-specific consequences.Hence, by allowing precise control of when and where a gene is expressed, the tetracycline regulatory system provides an ideal approach for the study of putative oncogenes in both the initiation and maintenance of tumorigenesis. In this protocol, we describe the methods involved in the development of a conditional mouse model of MYC-induced T-cell acute lymphoblastic leukemia.

    View details for DOI 10.1007/978-1-62703-429-6_15

    View details for PubMedID 24006068

  • In vivo imaging-based mathematical modeling techniques that enhance the understanding of oncogene addiction in relation to tumor growth. Computational and mathematical methods in medicine Nwabugwu, C., Rakhra, K., Felsher, D., Paik, D. 2013; 2013: 802512-?

    Abstract

    The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor's multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma.

    View details for DOI 10.1155/2013/802512

    View details for PubMedID 23573174

    View details for PubMedCentralID PMC3616361

  • In Vivo Imaging-Based Mathematical Modeling Techniques That Enhance the Understanding of Oncogene Addiction in relation to Tumor Growth COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE Nwabugwu, C., Rakhra, K., Felsher, D., Paik, D. 2013

    Abstract

    The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor's multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma.

    View details for DOI 10.1155/2013/802512

    View details for Web of Science ID 000316905000001

    View details for PubMedID 23573174

    View details for PubMedCentralID PMC3616361

  • SIRT1 and c-Myc Promote Liver Tumor Cell Survival and Predict Poor Survival of Human Hepatocellular Carcinomas PLOS ONE Jang, K. Y., Noh, S. J., Lehwald, N., Tao, G., Bellovin, D. I., Park, H. S., Moon, W. S., Felsher, D. W., Sylvester, K. G. 2012; 7 (9)

    Abstract

    The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.

    View details for DOI 10.1371/journal.pone.0045119

    View details for Web of Science ID 000308860100058

    View details for PubMedID 23024800

    View details for PubMedCentralID PMC3443243

  • HIF-2 alpha Suppresses p53 to Enhance the Stemness and Regenerative Potential of Human Embryonic Stem Cells STEM CELLS Das, B., Bayat-Mokhtari, R., Tsui, M., Lotfi, S., Tsuchida, R., Felsher, D. W., Yeger, H. 2012; 30 (8): 1685-1695

    Abstract

    Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the "enhanced stemness" state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration.

    View details for DOI 10.1002/stem.1142

    View details for Web of Science ID 000306684900011

    View details for PubMedID 22689594

    View details for PubMedCentralID PMC3584519

  • Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis PLOS GENETICS Tran, P. T., Shroff, E. H., Burns, T. F., Thiyagarajan, S., Das, S. T., Zabuawala, T., Chen, J., Cho, Y., Luong, R., Tamayo, P., Salih, T., Aziz, K., Adam, S. J., Vicent, S., Nielsen, C. H., Withofs, N., Sweet-Cordero, A., Gambhir, S. S., Rudin, C. M., Felsher, D. W. 2012; 8 (5)

    Abstract

    KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

    View details for DOI 10.1371/journal.pgen.1002650

    View details for Web of Science ID 000304864000004

    View details for PubMedID 22654667

    View details for PubMedCentralID PMC3360067

  • Immunology in the clinic review series; focus on cancer: multiple roles for the immune system in oncogene addiction CLINICAL AND EXPERIMENTAL IMMUNOLOGY Bachireddy, P., Rakhra, K., Felsher, D. W. 2012; 167 (2): 188-194

    Abstract

    Despite complex genomic and epigenetic abnormalities, many cancers are irrevocably dependent on an initiating oncogenic lesion whose restoration to a normal physiological activation can elicit a dramatic and sudden reversal of their neoplastic properties. This phenomenon of the reversal of tumorigenesis has been described as oncogene addiction. Oncogene addiction had been thought to occur largely through tumour cell-autonomous mechanisms such as proliferative arrest, apoptosis, differentiation and cellular senescence. However, the immune system plays an integral role in almost every aspect of tumorigenesis, including tumour initiation, prevention and progression as well as the response to therapeutics. Here we highlight more recent evidence suggesting that oncogene addiction may be integrally dependent upon host immune-mediated mechanisms, including specific immune effectors and cytokines that regulate tumour cell senescence and tumour-associated angiogenesis. Hence, the host immune system is essential to oncogene addiction.

    View details for DOI 10.1111/j.1365-2249.2011.04514.x

    View details for Web of Science ID 000299037700002

    View details for PubMedID 22235994

  • Mathematical Modeling of the Interactions between Cellular Programs in Response to Oncogene Inactivation 12th IEEE International Conference on BioInformatics and BioEngineering (BIBE) Nwabugwu, C., Rakhra, K., Felsher, D., Paik, D. IEEE. 2012: 454–459
  • Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na LEUKEMIA RESEARCH Seetharam, M., Fan, A. C., Tran, M., Xu, L., Renschler, J. P., Felsher, D. W., Sridhar, K., Wilhelm, F., Greenberg, P. L. 2012; 36 (1): 98-103

    Abstract

    In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients.

    View details for DOI 10.1016/j.leukres.2011.08.022

    View details for PubMedID 21924492

  • "Picolog," a Synthetically-Available Bryostatin Analog, Inhibits Growth of MYC-Induced Lymphoma In Vivo ONCOTARGET DeChristopher, B. A., Fan, A. C., Felsher, D. W., Wender, P. A. 2012; 3 (1): 58-66

    Abstract

    Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway. Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.

    View details for PubMedID 22308267

  • Cryptococcal osteomyelitis and meningitis in a patient with non-hodgkin's lymphoma treated with PEP-C. BMJ case reports To, C. A., Hsieh, R. W., McClellan, J. S., Howard, W., Fischbein, N. J., Brown, J. M., Felsher, D. W., Fan, A. C. 2012; 2012

    Abstract

    The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient's disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.

    View details for DOI 10.1136/bcr.08.2011.4578

    View details for PubMedID 22962380

  • High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation LAB ON A CHIP Wu, A. R., Kawahara, T. L., Rapicavoli, N. A., van Riggelen, J., Shroff, E. H., Xu, L., Felsher, D. W., Chang, H. Y., Quake, S. R. 2012; 12 (12): 2190-2198

    Abstract

    Chromatin immunoprecipitation (ChIP) is an assay for interrogating protein-DNA interactions that is increasingly being used for drug target discovery and screening applications. Currently the complexity of the protocol and the amount of hands-on time required for this assay limits its use to low throughput applications; furthermore, variability in antibody quality poses an additional obstacle in scaling up ChIP for large scale screening purposes. To address these challenges, we report HTChIP, an automated microfluidic-based platform for performing high-throughput ChIP screening measurements of 16 different targets simultaneously, with potential for further scale-up. From chromatin to analyzable PCR results only takes one day using HTChIP, as compared to several days up to one week for conventional protocols. HTChIP can also be used to test multiple antibodies and select the best performer for downstream ChIP applications, saving time and reagent costs of unsuccessful ChIP assays as a result of poor antibody quality. We performed a series of characterization assays to demonstrate that HTChIP can rapidly and accurately evaluate the epigenetic states of a cell, and that it is sensitive enough to detect the changes in the epigenetic state induced by a cytokine stimulant over a fine temporal resolution. With these results, we believe that HTChIP can introduce large improvements in routine ChIP, antibody screening, and drug screening efficiency, and further facilitate the use of ChIP as a valuable tool for research and discovery.

    View details for DOI 10.1039/c2lc21290k

    View details for PubMedID 22566096

  • Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis JOURNAL OF CLINICAL INVESTIGATION Hlady, R. A., Novakova, S., Opavska, J., Klinkebiel, D., Peters, S. L., Bies, J., Hannah, J., Iqbal, J., Anderson, K. M., Siebler, H. M., Smith, L. M., Greiner, T. C., Bastola, D., Joshi, S., Lockridge, O., Simpson, M. A., Felsher, D. W., Wagner, K., Chan, W. C., Christman, J. K., Opavsky, R. 2012; 122 (1): 163-177

    Abstract

    DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b-/- lymphomas, but not in Dnmt3b-/- pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt3b-/- lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b+/+ cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies.

    View details for DOI 10.1172/JCI57292

    View details for Web of Science ID 000298769400022

    View details for PubMedID 22133874

    View details for PubMedCentralID PMC3248285

  • Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas LEUKEMIA Dejean, E., Renalier, M. H., Foisseau, M., Agirre, X., Joseph, N., De Paiva, G. R., Al Saati, T., Soulier, J., Desjobert, C., Lamant, L., Prosper, F., Felsher, D. W., Cavaille, J., Prats, H., Delsol, G., Giuriato, S., Meggetto, F. 2011; 25 (12): 1882-1890

    Abstract

    The anaplastic lymphoma kinase (ALK), tyrosine kinase oncogene is implicated in a wide variety of cancers. In this study we used conditional onco-ALK (NPM-ALK and TPM3-ALK) mouse MEF cell lines (ALK+ fibroblasts) and transgenic models (ALK+ B-lymphoma) to investigate the involvement and regulation of angiogenesis in ALK tumor development. First, we observed that ALK expression leads to downregulation of miR-16 and increased Vascular Endothelial Growth Factor (VEGF) levels. Second, we found that modification of miR-16 levels in TPM3-ALK MEF cells greatly affected VEGF levels. Third, we demonstrated that miR-16 directly interacts with VEGF mRNA at the 3'-untranslated region and that the regulation of VEGF by miR-16 occurs at the translational level. Fourth, we showed that expression of both the ALK oncogene and hypoxia-induced factor 1α (HIF1α) is a prerequisite for miR-16 downregulation. Fifth, in vivo, miR-16 gain resulted in reduced angiogenesis and tumor growth. Finally, we highlighted an inverse correlation between the levels of miR-16 and VEGF in human NPM-ALK+ Anaplastic Large Cell Lymphomas (ALCL). Altogether, our results demonstrate, for the first time, the involvement of angiogenesis in ALK+ ALCL and strongly suggest an important role for hypoxia-miR-16 in regulating VEGF translation.

    View details for DOI 10.1038/leu.2011.168

    View details for Web of Science ID 000298405500012

    View details for PubMedID 21778999

  • A Novel Nano-Immunoassay (NIA) Reveals Inhibition of PI3K and MAPK Pathways in CD34+Bone Marrow Cells of Patients with Myelodysplastic Syndrome (MDS) Treated with the Multi-Kinase Inhibitor On 01910.Na (Rigosertib) 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Fan, A. C., Xu, L., Sridhar, K. J., Tran, M., Banerjee, P., Renschler, J. P., Tripuraneni, R., Wilhelm, F., Greenberg, P. L., Felsher, D. W. AMER SOC HEMATOLOGY. 2011: 1626–26
  • Lymphomas that recur after MYC suppression continue to exhibit oncogene addiction PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Choi, P. S., van Riggelen, J., Gentles, A. J., Bachireddy, P., Rakhra, K., Adam, S. J., Plevritis, S. K., Felsher, D. W. 2011; 108 (42): 17432-17437

    Abstract

    The suppression of oncogenic levels of MYC is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, and/or apoptosis, a phenomenon known as oncogene addiction. However, after prolonged inactivation of MYC in a conditional transgenic mouse model of Eμ-tTA/tetO-MYC T-cell acute lymphoblastic leukemia, some of the tumors recur, recapitulating what is frequently observed in human tumors in response to targeted therapies. Here we report that these recurring lymphomas express either transgenic or endogenous Myc, albeit in many cases at levels below those in the original tumor, suggesting that tumors continue to be addicted to MYC. Many of the recurring lymphomas (76%) harbored mutations in the tetracycline transactivator, resulting in expression of the MYC transgene even in the presence of doxycycline. Some of the remaining recurring tumors expressed high levels of endogenous Myc, which was associated with a genomic rearrangement of the endogenous Myc locus or activation of Notch1. By gene expression profiling, we confirmed that the primary and recurring tumors have highly similar transcriptomes. Importantly, shRNA-mediated suppression of the high levels of MYC in recurring tumors elicited both suppression of proliferation and increased apoptosis, confirming that these tumors remain oncogene addicted. These results suggest that tumors induced by MYC remain addicted to overexpression of this oncogene.

    View details for DOI 10.1073/pnas.1107303108

    View details for PubMedID 21969595

  • Survival and Death Signals Can Predict Tumor Response to Therapy After Oncogene Inactivation SCIENCE TRANSLATIONAL MEDICINE Tran, P. T., Bendapudi, P. K., Lin, H. J., Choi, P., Koh, S., Chen, J., Horng, G., Hughes, N. P., Schwartz, L. H., Miller, V. A., Kawashima, T., Kitamura, T., Paik, D., Felsher, D. W. 2011; 3 (103)

    Abstract

    Cancers can exhibit marked tumor regression after oncogene inhibition through a phenomenon called "oncogene addiction." The ability to predict when a tumor will exhibit oncogene addiction would be useful in the development of targeted therapeutics. Oncogene addiction is likely the consequence of many cellular programs. However, we reasoned that many of these inputs may converge on aggregate survival and death signals. To test this, we examined conditional transgenic models of K-ras(G12D)--or MYC-induced lung tumors and lymphoma combined with quantitative imaging and an in situ analysis of biomarkers of proliferation and apoptotic signaling. We then used computational modeling based on ordinary differential equations (ODEs) to show that oncogene addiction could be modeled as differential changes in survival and death intracellular signals. Our mathematical model could be generalized to different imaging methods (computed tomography and bioluminescence imaging), different oncogenes (K-ras(G12D) and MYC), and several tumor types (lung and lymphoma). Our ODE model could predict the differential dynamics of several putative prosurvival and prodeath signaling factors [phosphorylated extracellular signal-regulated kinase 1 and 2, Akt1, Stat3/5 (signal transducer and activator of transcription 3/5), and p38] that contribute to the aggregate survival and death signals after oncogene inactivation. Furthermore, we could predict the influence of specific genetic lesions (p53⁻/⁻, Stat3-d358L, and myr-Akt1) on tumor regression after oncogene inactivation. Then, using machine learning based on support vector machine, we applied quantitative imaging methods to human patients to predict both their EGFR genotype and their progression-free survival after treatment with the targeted therapeutic erlotinib. Hence, the consequences of oncogene inactivation can be accurately modeled on the basis of a relatively small number of parameters that may predict when targeted therapeutics will elicit oncogene addiction after oncogene inactivation and hence tumor regression.

    View details for DOI 10.1126/scitranslmed.3002018

    View details for PubMedID 21974937

  • Functional Interactions between Retinoblastoma and c-MYC in a Mouse Model of Hepatocellular Carcinoma PLOS ONE Saddic, L. A., Wirt, S., Vogel, H., Felsher, D. W., Sage, J. 2011; 6 (5)

    Abstract

    Inactivation of the RB tumor suppressor and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Loss of RB function and MYC activation are thought to control both overlapping and distinct cellular processes during cell cycle progression. However, how these two major cancer genes functionally interact during tumorigenesis is still unclear. Here, we sought to test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC), a deadly cancer type in which RB is frequently inactivated and c-MYC often activated. We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors. There was a trend for decreased survival in double mutant animals compared to mice developing c-MYC-induced tumors. Thus, loss of RB function does not provide a proliferative advantage to c-MYC-expressing HCC cells but the RB and c-MYC pathways may cooperate to control the polyploidy of mature hepatocytes.

    View details for DOI 10.1371/journal.pone.0019758

    View details for PubMedID 21573126

  • Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation JOURNAL OF BIOLOGICAL CHEMISTRY Huang, M., Whang, P., Chodaparambil, J. V., Pollyea, D. A., Kusler, B., Xu, L., Felsher, D. W., Mitchell, B. S. 2011; 286 (13): 11035-11046

    Abstract

    Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H(2)O(2)) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H(2)O(2) impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation of NS by ROS was validated in a murine lymphoma tumor model in which c-Myc is overexpressed and in CD34+ cells from patients with chronic myelogenous leukemia in blast crisis. In both instances, increased ROS levels were associated with markedly increased expression of NS protein and thiol-reversible oligomerization. Site-directed mutagenesis of critical cysteine-containing regions of nucleostemin altered both its intracellular localization and its stability. MG132, a potent proteasome inhibitor and activator of ROS, markedly decreased degradation and increased nucleolar retention of NS mutants, whereas N-acetyl-L-cysteine largely prevented the effects of MG132. These results indicate that NS is a highly redox-sensitive protein. Increased intracellular ROS levels, such as those that result from oncogenic transformation in hematopoietic malignancies, regulate the ability of NS to oligomerize, prevent its degradation, and may alter its ability to regulate cell proliferation.

    View details for DOI 10.1074/jbc.M110.208470

    View details for PubMedID 21242306

  • MYC Phosphorylation, Activation, and Tumorigenic Potential in Hepatocellular Carcinoma Are Regulated by HMG-CoA Reductase CANCER RESEARCH Cao, Z., Fan-Minogue, H., Bellovin, D. I., Yevtodiyenko, A., Arzeno, J., Yang, Q., Gambhir, S. S., Felsher, D. W. 2011; 71 (6): 2286-2297

    Abstract

    MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors.

    View details for DOI 10.1158/0008-5472.CAN-10-3367

    View details for Web of Science ID 000288381300028

    View details for PubMedID 21262914

    View details for PubMedCentralID PMC3059327

  • TGFbeta-dependent gene expression shows that senescence correlates with abortive differentiation along several lineages in Myc-induced lymphomas CELL CYCLE Mueller, J., Samans, B., van Riggelen, J., Faga, G., Peh, R. K., Wei, C., Mueller, H., Amati, B., Felsher, D., Eilers, M. 2010; 9 (23): 4622-4626

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  1. Gouw AM, Margulis K, Liu NS, Raman SJ, Mancuso A, Toal GG, Tong L, Mosley A, Hsieh AL, Sullivan DK, Stine ZE, Altman BJ, Schulze A, Dang CV, Zare RN, Felsher DW. Cell Metab. 2019 Sep 3;30(3):556-572.e5. doi: 10.1016/j.cmet.2019.07.012. Epub 2019 Aug 22. PMID: 31447321
  2. Lipid nanoparticles that deliver IL-12 messenge RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma (accepted Journal for ImmunoTherapy of Cancer)
  3. Dhanasekaran R, Gabay-Ryan M, Baylot V, Lai I, Mosley A, Huang X, Zabludoff S, Li J, Kaimal V, Karmali P, Felsher DW. Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC). Oncotarget. 2017: 9:5517-5528. PMID: 29464015
  4. Hebb JPO, Mosley AR, Vences-Catalán F, Rajasekaran N, Rosén A, Ellmark P, Felsher DW. Administration of low-dose combination anti-CTLA4, anti-CD137, and anti-OX40 into murine tumor or proximal to the tumor draining lymph node induces systemic tumor regression. Cancer Immunol Immunother. 2017 Sep 13. doi: 10.1007/s00262-017-2059-y. [Epub ahead of print] PMID: 28905118
  5. Gouw AM, Eberlin LS, Margulis K, Sullivan DK, Toal GG, Tong L, Zare RN, Felsher DW.
    Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma. Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4300-4305. doi: 10.1073/pnas.1617709114. Epub 2017 Apr 11. PMID: 28400509
  6. Casey SC, Baylot V, Felsher DW. Trends Immunol. 2017 Apr;38(4):298-305. doi: 10.1016/j.it.2017.01.002. PMID: 28233639
  7. Li Y, Deutzmann A, Felsher DW. BIM-mediated apoptosis and oncogene addiction.  Aging (Albany NY). 2016 Sep 29;8(9):1834-1835. doi: 10.18632/aging.101072. PubMed PMID: 27688082.
  8. Felsher DW, Lowe L. Affordable Cancer Medications Are Within Reach but We Need a Different Approach. J Clin Oncol. 2016 Jun 20;34(18):2194-5. doi: 10.1200/JCO.2016.67.2436. PubMed PMID: 27161965.
  9. Li Y, Deutzmann A, Choi PS, Fan AC, Felsher DW. BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia. Oncotarget. 2016 May 10;7(19):26926-34. doi: 10.18632/oncotarget.8731. PubMed PMID: 27095570.
  10. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gütgemann I, Eilers M, Felsher DW. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016 Apr 8;352(6282):227-31. doi: 10.1126/science.aac9935. PubMed PMID: 26966191; PubMed Central PMCID: PMC4940030.
  11. Gouw AM, Toal GG, Felsher DW. Metabolic vulnerabilities of MYC-induced cancer. Oncotarget. 2016 May 24;7(21):29879-80. doi: 10.18632/oncotarget.7223. PubMed PMID: 26863454.
  12. Yetil A, Anchang B, Gouw AM, Adam SJ, Zabuawala T, Parameswaran R, van Riggelen J, Plevritis S, Felsher DW. p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia. Oncotarget. 2015 Feb 28;6(6):3563-77. PubMed PMID: 25784651; PubMed Central PMCID: PMC4414137.
  13. Li Y, Choi PS, Felsher DW. Oncogene addiction: resetting the safety switch? Oncotarget. 2014 Sep 30;5(18):7986-7. PubMed PMID: 25275297; PubMed Central PMCID: PMC4226662.
  14. Li Y, Casey SC, Choi PS, Felsher DW. miR-17-92 explains MYC oncogene addiction. Mol Cell Oncol. 2014 Dec 31;1(4):e970092. doi: 10.4161/23723548.2014.970092. PubMed PMID: 27308380; PubMed Central PMCID: PMC4905255.
  15. Li Y, Choi PS, Felsher DW. Oncogene addiction: resetting the safety switch? Oncotarget. 2014 Sep 20. [Epub ahead of print] PubMed PMID: 25275297.
  16. Li Y, Choi PS, Casey SC, Felsher DW. Activation of cre recombinase alone can induce complete tumor regression. PLoS One. 2014 Sep 10;9(9):e107589. doi: 10.1371/journal.pone.0107589. eCollection 2014. PubMed PMID: 25208064; PubMed Central PMCID: PMC4160265.
  17. Li Y, Choi PS, Casey SC, Dill DL, Felsher DW. MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. Cancer Cell. 2014 Aug 11;26(2):262-72. doi: 10.1016/j.ccr.2014.06.014. PubMed PMID: 25117713.
  18. Casey SC, Li Y, Fan AC, Felsher DW. Oncogene withdrawal engages the immune system to induce sustained cancer regression. J Immunother Cancer. 2014 Jul 15;2:24. doi: 10.1186/2051-1426-2-24. eCollection 2014. Review. PubMed PMID: 25089198; PubMed Central PMCID: PMC4118610.
  19. Choi PS, Li Y, Felsher DW. Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance. Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):E3316-24. doi: 10.1073/pnas.1406123111. Epub 2014 Jul 28. PubMed PMID: 25071175; PubMed Central PMCID: PMC4136575.
  20. Eberlin LS, Gabay M, Fan AC, Gouw AM, Tibshirani RJ, Felsher DW, Zare RN. Alteration of the lipid profile in lymphomas induced by MYC overexpression. Proc  Natl Acad Sci U S A. 2014 Jul 22;111(29):10450-5. doi: 10.1073/pnas.1409778111. Epub 2014 Jul 3. PubMed PMID: 24994904; PubMed Central PMCID: PMC4115527.
  21. Gabay M, Li Y, Felsher DW. MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb Perspect Med. 2014 Jun 2;4(6). pii: a014241. doi: 10.1101/cshperspect.a014241. PubMed PMID: 24890832.
  22. Ye D, Shuhendler AJ, Cui L, Tong L, Tee SS, Tikhomirov G, Felsher DW, Rao J. Bioorthogonal cyclization-mediated in situ self-assembly of small-molecule probes for imaging caspase activity in vivo. Nat Chem. 2014 Jun;6(6):519-26. doi: 10.1038/nchem.1920. Epub 2014 Apr 28. PubMed PMID: 24848238; PubMed Central PMCID: PMC4031611.
  23. Casey SC, Li Y, Felsher DW. An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. Immunol Res. 2014 May;58(2-3):282-91. doi: 10.1007/s12026-014-8503-6. PubMed PMID: 24791942.
  24. Li Y, Casey SC, Felsher DW. Inactivation of MYC reverses tumorigenesis. J Intern Med. 2014 Jul;276(1):52-60. doi: 10.1111/joim.12237. Review. PubMed PMID:  24645771; PubMed Central PMCID: PMC4065197.
  25. Cao Z, Ding BS, Guo P, Lee SB, Butler JM, Casey SC, Simons M, Tam W, Felsher  DW, Shido K, Rafii A, Scandura JM, Rafii S. Angiocrine factors deployed by tumor  vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell. 2014 Mar 17;25(3):350-65. doi: 10.1016/j.ccr.2014.02.005. PubMed PMID: 24651014; PubMed Central PMCID: PMC4017921.
  26. Nwabugwu CI, Rakhra K, Felsher DW, Paik DS. A tumor-immune mathematical model of CD4+ T helper cell dependent tumor regression by oncogene inactivation. Conf Proc IEEE Eng Med Biol Soc. 2013;2013:4529-32. doi: 10.1109/EMBC.2013.6610554. PubMed PMID: 24110741.
  27. Rakhra K, Felsher DW. Generation of a tetracycline regulated mouse model of MYC-induced T-cell acute lymphoblastic leukemia. Methods Mol Biol. 2013;1012:221-35. doi: 10.1007/978-1-62703-429-6_15. PubMed PMID: 24006068.
  28. Ansari C, Tikhomirov GA, Hong SH, Falconer RA, Loadman PM, Gill JH, Castaneda R, Hazard FK, Tong L, Lenkov OD, Felsher DW, Rao J, Daldrup-Link HE. Development  of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small. 2014 Feb 12;10(3):566-75, 417. doi: 10.1002/smll.201301456. Epub  2013 Aug 27. PubMed PMID: 24038954; PubMed Central PMCID: PMC3946335.
  29. Fan AC, O'Rourke JJ, Praharaj DR, Felsher DW. Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer. Expert Opin Investig Drugs. 2013 Nov;22(11):1495-509. doi: 10.1517/13543784.2013.829453. Epub 2013 Aug 12. Review. PubMed PMID: 23937225; PubMed Central PMCID: PMC4111569.
  30. Casey SC, Bellovin DI, Felsher DW. Noncanonical roles of the immune system in eliciting oncogene addiction. Curr Opin Immunol. 2013 Apr;25(2):246-58. doi: 10.1016/j.coi.2013.02.003. Epub 2013 Apr 6. Review. PubMed PMID: 23571026; PubMed Central PMCID: PMC3683588.

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