Bio

Clinical Focus


  • Kidney Cancer
  • Clinical Trials as Topic
  • Molecular Targeted Therapy
  • Medical Oncology
  • Cancer > Lymphoma
  • Nano-proteomics
  • Translational Medical Research

Academic Appointments


Administrative Appointments


  • Member, Stanford Lymphoma Disease Management Group (2005 - Present)
  • Founding Advisor, Stanford Association for Multidisciplinary Medicine and Science (2008 - Present)
  • Co-Director, Stanford Nanopro1000 Instrument for Nano-scale protein detection (2008 - Present)
  • Associate Member, Stanford Cancer Institute Molecular Therapeutics Program (2008 - Present)
  • Clinical Mentor, Stanford Molecular Imaging Scholars Program (2010 - Present)
  • Research Mentor, NIH/NIDDK Short term education program for under-represented persons (2011 - 2011)
  • Inteviewer, Stanford School of Medicine Internal Medicine Residency (2011 - Present)
  • Member, Stanford Kidney Cancer Research Group (2011 - Present)

Honors & Awards


  • R21: Nanoscale proteomic profiles of hypoxia pathways to develop biomarkers of renal cell carcinoma, NIH/NCI (August 2012-July 2014)
  • K23 Career Development Award, NIH/NCI (July 2010-June 2015)
  • TRAM Renewal Grant: Development of blood biomarkers for diagnosis and monitoring of kidney cancer, Stanford Department of Medicine (October 2012-August 2013)
  • Translational Research and Applied Medicine Program (TRAM) Pilot Grant, Stanford Department of Medicine (October 2011-September 2012)
  • Developmental Cancer Research Award, Stanford Cancer Institute (September 2011-August 2012)
  • Special Fellow in Clinical Research, Leukemia and Lymphoma Society (July 2006-June 2009)
  • Research Fellowship, Lymphoma Research Foundation (July 2004-June 2006)
  • Dean's Fellowship, Stanford School of Medicine (April 2004- March 2005)

Professional Education


  • Residency:Brown University - School of Medicine (2001) RI
  • Fellowship:Stanford University Medical Center (2006) CA
  • Board Certification: Medical Oncology, American Board of Internal Medicine (2004)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2001)
  • Internship:Brown University - School of Medicine (1999) RI
  • Medical Education:Albany Medical Center (1998) NY
  • B.A., Harvard College, Biophysics (1994)

Community and International Work


  • Student Travel Health, Stanford Orchestra Tour Physician, Australia, New Zealand, China

    Topic

    2004 Australia/New Zealand Concerts, 2008 China Concerts

    Partnering Organization(s)

    Stanford Symphony Orchestra

    Populations Served

    students

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Violinist, Stanford Hosptial Bing Music Series, Stanford Hospital

    Topic

    Chamber Music

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Founding member of non-profit organization, "Lemonaide", Stanford Cancer Center

    Topic

    Helping adult patients and families

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

  • Outreach Speaker, Chinese Community Clinical Trials Forum

    Location

    Bay Area

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Grand Rounds Speaker, Hualien Hospital serving aboriginal and local Taiwanese populations, Taiwan

    Topic

    Novel Therapeutics in Lymphoma

    Populations Served

    Aboriginal and Local Taiwanese populations

    Location

    International

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Dr. Fan studies how turning off oncogenes (cancer genes) can cause tumor regression in preclinical and clinical studies. Based on preclinical findings, she has initiated clinical trials studying how tyrosine kinase inhibitors impact the hypoxia pathway in kidney cancer and the use of atorvastatin for the treatment of patients with certain non-Hodgkin's lymphomas. In the laboratory, she also uses preclinical models of cancer to validate new nanotechnology strategies for tumor diagnosis and treatment. She has shown that a new nano-immunoassay (NIA) can be used to measure how well drugs work in tumor cells sampled from individual patients with leukemia, lymphoma and myelodysplastic syndrome taking novel targeted therapies (Fan et al. Nature Medicine 2009, Seetharam, Fan et al. Leukemia Research 2012, Fan et al Oncotarget 2012). She is currently expanding her translational research to include early diagnostics, therapeutic monitoring, and prediction of response to therapeutics in solid tumors such as kidney cancer and lung cancer, with the goal of helping to make personalized medicine possible.

Clinical Trials


  • Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts Not Recruiting

    The primary objective of this study is to compare overall survival (OS) in patients receiving ON 01910.Na + best supportive care (BSC) to OS of patients receiving BSC in a population of patients with myelodysplastic syndrome (MDS) with excess blasts (5% to 30% bone marrow blasts) who have failed azacitidine or decitabine treatment. This patient population has no available therapy and a short life expectancy (approximately 4 months). The high level of bone marrow activity of ON 01910.Na documented in Phase 1 and 2 studies has the potential to delay substantially the transition of MDS to Acute Myeloid Leukemia(AML), a very significant and severe complication, which shortens survival of these MDS patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact Savita Kamble, (650) 723 - 8594.

    View full details

  • Phase II Study of Atorvastatin Safety and Antitumor Effects in Non-Hodgkin's Lymphoma Not Recruiting

    The purpose of this study is to: 1. Determine changes in levels of tumor bioactivity upon treatment with atorvastatin. Secondary objective: 2. Determine validity of tumor bioactivity as a biologic endpoint by correlation with clinical response. 3. Determine whether administration of atorvastatin is tolerable and safe in low grade NHL patients. We do not anticipate any significant toxicity since this dose of atorvastatin has been FDA approved for patients with hypercholesterolemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alice Fan, 650-736-1285.

    View full details

  • Safety Study of ABT-263 in Combination With Rituximab in Lymphoid Cancers Not Recruiting

    This is a Phase 1 study evaluating the safety of ABT-263 administered in combination with rituximab in subjects with CD20-positive lymphoproliferative disorders.

    Stanford is currently not accepting patients for this trial. For more information, please contact Euodia Jonathan, (650) 725 - 6432.

    View full details

Teaching

Graduate and Fellowship Programs


Publications

Journal Articles


  • 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 Web of Science ID 000298149100035

    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 Web of Science ID 000303914000009

    View details for PubMedID 22308267

  • Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens NATURE MEDICINE Fan, A. C., Deb-Basu, D., Orban, M. W., Gotlib, J. R., Natkunam, Y., O'Neill, R., Padua, R., Xu, L., Taketa, D., Shirer, A. E., Beer, S., Yee, A. X., Voehringer, D. W., Felsher, D. W. 2009; 15 (5): 566-571

    Abstract

    Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.

    View details for DOI 10.1038/nm.1903

    View details for Web of Science ID 000265889300036

    View details for PubMedID 19363496

  • Supramolecular Stacking of Doxorubicin on Carbon Nanotubes for In Vivo Cancer Therapy ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Liu, Z., Fan, A. C., Rakhra, K., Sherlock, S., Goodwin, A., Chen, X., Yang, Q., Felsher, D. W., Dai, H. 2009; 48 (41): 7668-7672

    View details for DOI 10.1002/anie.200902612

    View details for Web of Science ID 000270436900037

    View details for PubMedID 19760685

  • A quantitative PCR method to detect blood microRNAs associated with tumorigenesis in transgenic mice MOLECULAR CANCER Fan, A. C., Goldrick, M. M., Ho, J., Liang, Y., Bachireddy, P., Felsher, D. W. 2008; 7

    Abstract

    MicroRNA (miRNA) dysregulation frequently occurs in cancer. Analysis of whole blood miRNA in tumor models has not been widely reported, but could potentially lead to novel assays for early detection and monitoring of cancer. To determine whether miRNAs associated with malignancy could be detected in the peripheral blood, we used real-time reverse transcriptase-PCR to determine miRNA profiles in whole blood obtained from transgenic mice with c-MYC-induced lymphoma, hepatocellular carcinoma and osteosarcoma. The PCR-based assays used in our studies require only 10 nanograms of total RNA, allowing serial mini-profiles (20 - 30 miRNAs) to be carried out on individual animals over time. Blood miRNAs were measured from mice at different stages of MYC-induced lymphomagenesis and regression. Unsupervised hierarchical clustering of the data identified specific miRNA expression profiles that correlated with tumor type and stage. The miRNAs found to be altered in the blood of mice with tumors frequently reverted to normal levels upon tumor regression. Our results suggest that specific changes in blood miRNA can be detected during tumorigenesis and tumor regression.

    View details for DOI 10.1186/1476-4598-7-74

    View details for Web of Science ID 000260393800001

    View details for PubMedID 18826639

  • Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas PLOS ONE Tran, P. T., Fan, A. C., Bendapudi, P. K., Koh, S., Komatsubara, K., Chen, J., Horng, G., Bellovin, D. I., Giuriato, S., Wang, C. S., Whitsett, J. A., Felsher, D. W. 2008; 3 (5)

    Abstract

    Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as "oncogene-addiction." However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.To examine how the MYC and K-ras(G12D) oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras(G12D) to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras(G12D)- or MYC/K-ras(G12D)-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras(G12D)-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras(G12D) resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras(G12D) in maintenance of lung tumors, we found that the down-stream mediators of K-ras(G12D) signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras(G12D) but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras(G12D). Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas.

    View details for DOI 10.1371/journal.pone.0002125

    View details for Web of Science ID 000261642400046

    View details for PubMedID 18461184

  • 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

  • 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

  • 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

  • Definition of an Enhanced Immune Cell Therapy in Mice That Can Target Stem-Like Lymphoma Cells CANCER RESEARCH Contag, C. H., Sikorski, R., Negrin, R. S., Schmidt, T., Fan, A. C., Bachireddy, P., Felsher, D. W., Thorne, S. H. 2010; 70 (23): 9837-9845

    Abstract

    Current treatments of high-grade lymphoma often have curative potential, but unfortunately many patients relapse and develop therapeutic resistance. Thus, there remains a need for novel therapeutics that can target the residual cancer cells whose phenotypes are distinct from the bulk tumor and that are capable of reforming tumors from very few cells. Oncolytic viruses offer an approach to destroy tumors by multiple mechanisms, but they cannot effectively reach residual disease or micrometastases, especially within the lymphatic system. To address these limitations, we have generated immune cells infected with oncolytic viruses as a therapeutic strategy that can combine effective cellular delivery with synergistic tumor killing. In this study, we tested this approach against minimal disease states of lymphomas characterized by the persistence of cancer cells that display stem cell-like properties and resistance to conventional therapies. We found that the immune cells were capable of trafficking to and targeting residual cancer cells. The combination biotherapy used prevented relapse by creating a long-term, disease-free state, with acquired immunity to the tumor functioning as an essential mediator of this effect. Immune components necessary for this acquired immunity were identified. We further demonstrated that the dual biotherapy could be applied before or after conventional therapy. Our approach offers a potentially powerful new way to clear residual cancer cells, showing how restoring immune surveillance is critical for maintenance of a disease-free state.

    View details for DOI 10.1158/0008-5472.CAN-10-2650

    View details for Web of Science ID 000285045900033

    View details for PubMedID 20935221

  • CD4(+) T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation CANCER CELL Rakhra, K., Bachireddy, P., Zabuawala, T., Zeiser, R., Xu, L., Kopelman, A., Fan, A. C., Yang, Q., Braunstein, L., Crosby, E., Ryeom, S., Felsher, D. W. 2010; 18 (5): 485-498

    Abstract

    Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4(+) T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4(+) T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.

    View details for DOI 10.1016/j.ccr.2010.10.002

    View details for Web of Science ID 000284658600013

    View details for PubMedID 21035406

  • Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kampa, K. M., Acoba, J. D., Chen, D., Gay, J., Lee, H., Beemer, K., Padiernos, E., Boonmark, N., Zhu, Z., Fan, A. C., Bailey, A. S., Fleming, W. H., Corless, C., Felsher, D. W., Naumovski, L., Lopez, C. D. 2009; 106 (11): 4390-4395

    Abstract

    The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.

    View details for DOI 10.1073/pnas.0809080106

    View details for Web of Science ID 000264278800061

    View details for PubMedID 19251665

  • Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis BLOOD Shachaf, C. M., Perez, O. D., Youssef, S., Fan, A. C., Elchuri, S., Goldstein, M. J., Shirer, A. E., Sharpe, O., Chen, J., Mitchell, D. J., Chang, M., Nolan, G. P., Steinman, L., Felsher, D. W. 2007; 110 (7): 2674-2684

    Abstract

    Statins are a class of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase, a critical enzyme in the mevalonate pathway. Several reports document that statins may prevent different human cancers. However, whether or not statins can prevent cancer is controversial due to discordant results. One possible explanation for these conflicting conclusions is that only some tumors or specific statins may be effective. Here, we demonstrate in an in vivo transgenic model in which atorvastatin reverses and prevents the onset of MYC-induced lymphomagenesis, but fails to reverse or prevent tumorigenesis in the presence of constitutively activated K-Ras (G12D). Using phosphoprotein fluorescence-activated cell sorter (FACS) analysis, atorvastatin treatment was found to result in the inactivation of the Ras and ERK1/2 signaling pathways associated with the dephosphorylation and inactivation of MYC. Correspondingly, tumors with a constitutively activated K-Ras (G12D) did not exhibit dephosphorylation of ERK1/2 and MYC. Atorvastatin's effects on MYC were specific to the inhibition of HMGcoA reductase, as treatment with mevalonate, the product of HMG-CoA reductase activity, abrogated these effects and inhibited the ability of atorvastatin to reverse or suppress tumorigenesis. Also, RNAi directed at HMGcoA reductase was sufficient to abrogate the neoplastic properties of MYC-induced tumors. Thus, atorvastatin, by inhibiting HMGcoA reductase, induces changes in phosphoprotein signaling that in turn prevent MYC-induced lymphomagenesis.

    View details for DOI 10.1182/blood-2006-09-048033

    View details for Web of Science ID 000249800900069

    View details for PubMedID 17622571

  • Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wu, C., van Riggelen, J., Yetil, A., Fan, A. C., Bachireddy, P., Felsher, D. W. 2007; 104 (32): 13028-13033

    Abstract

    Oncogene-induced senescence is an important mechanism by which normal cells are restrained from malignant transformation. Here we report that the suppression of the c-Myc (MYC) oncogene induces cellular senescence in diverse tumor types including lymphoma, osteosarcoma, and hepatocellular carcinoma. MYC inactivation was associated with prototypical markers of senescence, including acidic beta-gal staining, induction of p16INK4a, and p15INK4b expression. Moreover, MYC inactivation induced global changes in chromatin structure associated with the marked reduction of histone H4 acetylation and increased histone H3 K9 methylation. Osteosarcomas engineered to be deficient in p16INK4a or Rb exhibited impaired senescence and failed to exhibit sustained tumor regression upon MYC inactivation. Similarly, only after lymphomas were repaired for p53 expression did MYC inactivation induce robust senescence and sustained tumor regression. The pharmacologic inhibition of signaling pathways implicated in oncogene-induced senescence including ATM/ATR and MAPK did not prevent senescence associated with MYC inactivation. Our results suggest that cellular senescence programs remain latently functional, even in established tumors, and can become reactivated, serving as a critical mechanism of oncogene addiction associated with MYC inactivation.

    View details for DOI 10.1073/pnas.0701953104

    View details for Web of Science ID 000248650300015

    View details for PubMedID 17664422

  • Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Giuriato, S., Ryeom, S., Fan, A. C., Bachireddy, P., Lynch, R. C., Rioth, M. J., van Riggelen, J., Kopelman, A. M., Passegue, E., Tang, F., Folkman, J., Felsher, D. W. 2006; 103 (44): 16266-16271

    Abstract

    The targeted inactivation of oncogenes offers a rational therapeutic approach for the treatment of cancer. However, the therapeutic inactivation of a single oncogene has been associated with tumor recurrence. Therefore, it is necessary to develop strategies to override mechanisms of tumor escape from oncogene dependence. We report here that the targeted inactivation of MYC is sufficient to induce sustained regression of hematopoietic tumors in transgenic mice, except in tumors that had lost p53 function. p53 negative tumors were unable to be completely eliminated, as demonstrated by the kinetics of tumor cell elimination revealed by bioluminescence imaging. Histological examination revealed that upon MYC inactivation, the loss of p53 led to a deficiency in thrombospondin-1 (TSP-1) expression, a potent antiangiogenic protein, and the subsequent inability to shut off angiogenesis. Restoration of p53 expression in these tumors re-established TSP-1 expression. This permitted the suppression of angiogenesis and subsequent sustained tumor regression upon MYC inactivation. Similarly, the restoration of TSP-1 alone in p53 negative tumors resulted in the shut down of angiogenesis and led to sustained tumor regression upon MYC inactivation. Hence, the complete regression of tumor mass driven by inactivation of the MYC oncogene requires the p53-dependent induction of TSP-1 and the shut down of angiogenesis. Notably, overexpression of TSP-1 alone did not influence tumor growth. Therefore, the combined inactivation of oncogenes and angiogenesis may be a more clinically effective treatment of cancer. We conclude that angiogenesis is an essential component of oncogene addiction.

    View details for DOI 10.1073/pnas.0608017103

    View details for Web of Science ID 000241879500038

    View details for PubMedID 17056717

  • Conditional animal models: a strategy to define when oncogenes will be effective targets to treat cancer SEMINARS IN CANCER BIOLOGY Giuriato, S., Rabin, K., Fan, A. C., Shachaf, C. M., Felsher, D. W. 2004; 14 (1): 3-11

    Abstract

    The ability to model cancer in the mouse has provided a robust methodology to dissect the molecular etiology of cancer. These models serve as potentially powerful platforms to preclinically evaluate novel therapeutics. In particular, the recent development of strategies to conditionally induce the or knockout the function of genes in a tissue specific manner has enabled investigators to engineer mice to demonstrate that the targeted inactivation of specific oncogenes can be effective in inducing sustained regression of tumors. Thus, these animal models will be useful to define the specific genes that will be therapeutically useful to target for the treatment of particular human cancers.

    View details for DOI 10.1016/j.semcancer.2003.11.002

    View details for Web of Science ID 000189081200002

    View details for PubMedID 14757531

  • p53 mutations do not predict response to paclitaxel in metastatic nonsmall cell lung carcinoma CANCER King, T. C., Akerley, W., Fan, A. C., Moore, T., Mangray, S., Chen, M. H., Safran, H. 2000; 89 (4): 769-773

    Abstract

    In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function. The authors previously demonstrated that response to paclitaxel and concurrent radiation was not affected by p53 mutations in nonsmall cell lung carcinoma (NSCLC). We sought to determine whether p53 mutations affect response to paclitaxel alone in patients with metastatic NSCLC.Twenty-five patients with metastatic NSCLC who participated in Brown University Oncology Group protocols utilizing single-agent weekly paclitaxel had tumor tissue that was adequate for p53 analysis. Tumor tissue was evaluated for p53 gene mutations in exons 5 through 8 by single-strand conformation polymorphism analysis. Mutations were confirmed by direct sequencing of altered mobility polymerase chain reaction products.Mutations in p53 were found in 8 of 25 patients (32%). The response rates of 75% for patients with tumors with p53 mutations and 47% for patients with wild-type p53 do not differ significantly (P = 0.12). The 1-year survival rates for patients with and without p53 mutation after treatment with weekly paclitaxel were 63% (95% confidence interval [CI], 31-100%) and 53% (95% CI, 33-86%), respectively.p53 mutations do not adversely affect response to paclitaxel as a single agent in metastatic NSCLC. These results provide clinical support for in vitro observations that paclitaxel can bypass mutant p53 and lead to tumor cell death by alternate pathway(s). Paclitaxel should be considered as a component of treatment for patients with metastatic NSCLC with tumors that have p53 mutations.

    View details for Web of Science ID 000088753500008

    View details for PubMedID 10951339

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