Community Academic Profiles - Faculty & Researchers

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

Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors Recruiting

This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

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18F-FSPG PET/CT for Cancer Patients on Therapy Not Recruiting

The goal of this phase 2 study trial is to evaluate the utility of the radiolabel 18F-FSPG used before and after treatment to diagnose, predict, and evaluate response to therapy in patients with a wide variety of metastatic cancers.

Stanford is currently not accepting patients for this trial. For more information, please contact Phuong Pham, 650-725-9810.

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A Phase II Trial to Evaluate the Efficacy of AZD6094 (HMPL-504) in Patients With Papillary Renal Cell Carcinoma (PRCC) Not Recruiting

This is an open-label, single-arm, multicentre, global, phase II study designed to evaluate the efficacy and safety of AZD6094 in patients with papillary renal cell carcinoma (PRCC) who are treatment na�ve or previously treated. An independent central pathology review of tumour samples will be used to confirm the diagnosis of PRCC of all patients enrolling. However, locally available pathology results confirming PRCC will be allowed for timely study entry.

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer Not Recruiting

The purpose of this study is to evaluate the efficacy and safety of apalutamide in adult men with high-risk non-metastatic castration-resistant prostate cancer.

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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A Study of Atezolizumab in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer (Cohort 2) Not Recruiting

This Phase II, single-arm study is designed to evaluate the effect of atezolizumab treatment in participants with locally advanced or metastatic urothelial bladder cancer. Participants will be enrolled into 1 of 2 cohorts. Cohort 1 will consist of participants who are treatment-na�ve and ineligible for cisplatin-containing chemotherapy. The results of Cohort 1 are reported separately (NCT02951767). Cohort 2 (reported here) will contain participants who have progressed during or following a prior platinum-based chemotherapy regimen. Participants in both cohorts will be given a 1200 milligrams (mg) intravenous (IV) dose of atezolizumab on Day 1 of 21-day cycles. Treatment of participants in Cohort 1 will continue until disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) or unmanageable toxicity. Treatment of participants in Cohort 2 will continue until loss of clinical benefit or unmanageable toxicity.

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection Not Recruiting

This Phase III, open-label, randomized, multicenter study is to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with observation in participants with muscle-invasive UC who are at high risk for recurrence following resection. Eligible participants were randomized by a 1:1 ratio into atezolizumab group or control group.

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4 Not Recruiting

The purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab vedotin as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.

Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients Not Recruiting

The purpose of this trial is to determine if adjuvant therapy with axitinib will prevent or delay the recurrence of renal cell cancer after surgery to remove the primary tumor in high risk patients.

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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An Efficacy and Safety Study of Erdafitinib (JNJ-42756493) in Participants With Urothelial Cancer Not Recruiting

The purpose of this study is to evaluate the objective response rate (complete response [CR]+ partial response [PR]) of the selected dose regimen in participants with metastatic or surgically unresectable urothelial cancers that harbor specific FGFR genomic alterations.

Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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An Expanded Access Study of Atezolizumab in Participants With Locally Advanced or Metastatic Urothelial Carcinoma After Failure With Platinum-Containing Chemotherapy Not Recruiting

This is an open-label, multicenter, single-arm, expanded access program (EAP) designed to provide atezolizumab access to participants with locally advanced or metastatic urothelial carcinoma that has progressed on, or is intolerant to, a platinum-containing chemotherapy regimen.

Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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CANTATA: CB-839 With Cabozantinib vs. Cabozantinib With Placebo in Patients With Metastatic Renal Cell Carcinoma Not Recruiting

This clinical trial is a randomized Phase 2 evaluation of CB-839 (telaglenastat) in combination with cabozantinib versus placebo with cabozantinib in patients with advanced or metastatic Renal Cell Carcinoma with a clear cell component.

Stanford is currently not accepting patients for this trial. For more information, please contact Carleen Tabari, 650-725-9180.

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ENTRATA: CB-839 With Everolimus vs. Placebo With Everolimus in Patients With RCC Not Recruiting

Phase 2 Study Comparing CB-839 in Combination with Everolimus (CBE) vs. Placebo with Everolimus (PboE) in Patients with Advanced or Metastatic RCC

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Metastatic Castrate-Resistant Prostate Cancer Not Recruiting

The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of ipatasertib plus abiraterone and prednisone/prednisolone compared with placebo plus abiraterone and prednisone/prednisolone in participants with metastatic castrate-resistant prostate cancer (mCRPC).

Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma Not Recruiting

This is a multicenter, randomized, open-label, Phase 3 study to compare the efficacy and safety of lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) versus sunitinib (Arm C) as first-line treatment in participants with advanced renal cell carcinoma.

Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214) Not Recruiting

The purpose of this study is to compare the objective response rate, progression free survival and the overall survival of Nivolumab combined with Ipilimumab to Sunitinib monotherapy in patients with previously untreated Renal Cell Cancer.

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer Not Recruiting

The purpose of the study is to assess the efficacy and safety of BAY1841788 (darolutamide (ODM-201)) in combination with standard androgen deprivation therapy (ADT) and docetaxel in patients with metastatic hormone sensitive prostate cancer.

Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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Perfusion CT Monitoring to Predict Treatment Efficacy in Renal Cell Carcinoma Not Recruiting

This pilot clinical trial studies perfusion computed tomography (CT) in predicting response to treatment in patients with advanced kidney cancer. Comparing results of diagnostic procedures done before, during, and after targeted therapy may help doctors predict a patient's response to treatment and help plan the best treatment.

Stanford is currently not accepting patients for this trial. For more information, please contact Yoriko Imae, 650-498-5186.

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Phase 2 Study of Atorvastatin Safety and Antitumor Effects in Non-Hodgkin's Lymphoma Not Recruiting

This is an approach which can inflict significant toxicity. An alternative is to block expression of oncogenes which are over-expressed only in cancer cells, a therapeutic approach which could reduce toxicity to the host while maximizing destruction of the oncogene-dependent malignant cells.

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

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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.

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S1314, Co-expression Extrapolation (COXEN) Program to Predict Chemotherapy Response in Patients With Bladder Cancer Not Recruiting

The primary focus of this study is to see if looking at tumor biomarkers using a program called coexpression extrapolation or "COXEN" may predict a patient's response to chemotherapy before surgery.

Stanford is currently not accepting patients for this trial. For more information, please contact Preeti Chavan, 650-723-5957.

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Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors Not Recruiting

Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.

Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Dauriac, 650-736-0697.

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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. The extension portion of the study will allow active subjects to continue to receive ABT-263 for up to 9 years after the last subject transitions with quarterly study evaluations.

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

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Serial Ultrasound in Metastatic Renal Cell Carcinoma (mRCC) Not Recruiting

To assess whether changes in quantitative tumor perfusion parameters after 3 weeks of treatment, as measured by power doppler ultrasound, can predict initial objective response, defined by current standard-of-care, to therapy at 12 weeks after start of treatment

Stanford is currently not accepting patients for this trial. For more information, please contact Christian Hoerner, PhD, 650-721-3206.

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Study CB-839 in Combination With Nivolumab in Patients With Melanoma, ccRCC and NSCLC Not Recruiting

This study is an open-label Phase 1/ 2 evaluation of CB-839 in combination with nivolumab in patients with clear cell renal cell carcinoma, melanoma, and non-small cell lung cancer.

Stanford is currently not accepting patients for this trial.

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Study of Dalantercept and Axitinib in Patients With Advanced Renal Cell Carcinoma Not Recruiting

The purpose of Part 1 of this study is to evaluate the safety and tolerability of dalantercept in combination with axitinib in patients with advanced renal cell carcinoma (RCC) to determine the recommended dose level of dalantercept in combination with axitinib for Part 2. The purpose of Part 2 of this study is to determine whether treatment with dalantercept in combination with axitinib prolongs progression free survival (PFS) compared to axitinib alone in patients with advanced renal cell carcinoma (RCC).

Stanford is currently not accepting patients for this trial. For more information, please contact Denise Haas, 650-736-1252.

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Study of MEDI4736 Monotherapy and in Combination With Tremelimumab Versus Standard of Care Therapy in Patients With Head and Neck Cancer Not Recruiting

This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy versus SoC therapy in the target patient population.

Stanford is currently not accepting patients for this trial. For more information, please contact Mary (Tookie) May, 650-721-4079.

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Study of the Glutaminase Inhibitor CB-839 in Solid Tumors Not Recruiting

Many tumor cells, in contrast to normal cells, have been shown to require the amino acid glutamine to produce energy for growth and survival. To exploit the dependence of tumors on glutamine, CB-839, a potent and selective inhibitor of the first enzyme in glutamine utilization, glutaminase, will be tested in this Phase 1 study in patients with solid tumors. This study is an open-label Phase 1 evaluation of CB-839 in patients with advanced solid tumors. The study will be conducted in 2 parts. Part 1 is a dose escalation study enrolling patients with locally-advanced, metastatic and/or refractory solid tumors to receive CB-839 capsules orally twice or three times daily. In Part 2, patients with each of the following diseases will be enrolled: A) Triple-Negative Breast Cancer, B) Non-Small Cell Lung Cancer (adenocarcinoma), C) Renal Cell Cancer, D) Mesothelioma, E) Fumarate hydratase (FH)-deficient tumors, F) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), G) SDH-deficient non-GIST tumors, H) tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) or IDH2, and I) cMyc mutation tumors. As an extension of Parts 1 & 2, patients will be treated with CB-839 in combination with standard chemotherapy. Combination groups include: Pac-CB, CBE, CB-Erl, CBD, and CB-Cabo. Pac-CB: patients with locally-advanced or metastatic TNBC will be treated with paclitaxel and CB-839. CBE: patients with advanced clear cell RCC or papillary RCC will be treated with everolimus in combination with CB-839. CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. CBD: patients with NSCLC harboring KRAS mutation will be treated with docetaxel and CB-839. CB-Cabo: patients with histologically confirmed diagnosis of locally-advanced, inoperable or metastatic RCC treated with cabozantinib in combination with CB-839. All patients will be assessed for safety, pharmacokinetics (plasma concentration of drug), pharmacodynamics (inhibition of glutaminase), biomarkers (biochemical markers that may predict responsiveness in later studies), and tumor response.

Stanford is currently not accepting patients for this trial. For more information, please contact Pei-Jen Chang, 650-725-0866.

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All Publications

Postmarketing Analysis of Sipuleucel-T-The Importance of Real-World Data. JAMA network open Fan, A. C., Leppert, J. T. 2019; 2 (8): e199233
View details for DOI 10.1001/jamanetworkopen.2019.9233

View details for PubMedID 31411706
Early Changes in CT Perfusion Parameters: Primary Renal Carcinoma Versus Metastases After Treatment with Targeted Therapy CANCERS Fan, A. C., Sundaram, V., Kino, A., Schmiedeskamp, H., Metzner, T. J., Kamaya, A. 2019; 11 (5)
View details for DOI 10.3390/cancers11050608

View details for Web of Science ID 000472738300021
18F-FPPRGD2 PET/CT in patients with metastatic renal cell cancer. European journal of nuclear medicine and molecular imaging Toriihara, A., Duan, H., Thompson, H. M., Park, S., Hatami, N., Baratto, L., Fan, A. C., Iagaru, A. 2019
Abstract

PURPOSE: The usefulness of positron emission tomography/computed tomography (PET/CT) using (18F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid peptide [PEG3-E{c(RGDyk)}2] (18F-FPPRGD2) in patients with metastatic renal cell cancer (mRCC) has not been evaluated; therefore, we were prompted to conduct this pilot study.METHODS: Seven patients with mRCC were enrolled in this prospective study. 18F-FPPRGD2 and 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/CT images were evaluated in a per-lesion analysis. Maximum standardized uptake value (SUVmax) and tumor-to-background ratio (T/B) were measured for all detected lesions, both before and after starting antiangiogenic therapy.RESULTS: Sixty lesions in total were detected in this cohort. SUVmax from 18F-FPPRGD2 PET/CT was lower than that from 18F-FDG PET/CT (4.4�2.9 vs 7.8�5.6, P<0.001). Both SUVmax and T/B from 18F-FPPRGD2 PET/CT decreased after starting antiangiogenic therapy (SUVmax, 4.2�3.2 vs 2.6�1.4, P=0.003; T/B, 3.7�3.2 vs 1.5�0.8, P<0.001). Average changes in SUVmax and T/B were-29.3�23.6% and-48.1�28.3%, respectively.CONCLUSIONS: 18F-FPPRGD2 PET/CT may be an useful tool for monitoring early response to antiangiogenic therapy in patients with mRCC. These preliminary results need to be confirmed in larger cohorts.

View details for PubMedID 30850872
The 'Achilles Heel' of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy. Kidney cancer Hoerner, C. R., Chen, V. J., Fan, A. C. 2019; 3 (1): 15?29
Abstract

An important hallmark of cancer is 'metabolic reprogramming' or the rewiring of cellular metabolism to support rapid cell proliferation [1-5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [6, 7]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.

View details for PubMedID 30854496
Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma. Cancers Chen, V. J., Hernandez-Meza, G., Agrawal, P., Zhang, C. A., Xie, L., Gong, C. L., Hoerner, C. R., Srinivas, S., Oermann, E. K., Fan, A. C. 2019; 11 (7)
Abstract

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, "clinical benefit" was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

View details for DOI 10.3390/cancers11071000

View details for PubMedID 31319594
Multiregion Quantification of Extracellular Signal-regulated Kinase Activity in Renal Cell Carcinoma. European urology oncology Hoerner, C. R., Massoudi, R., Metzner, T. J., Stell, L., O'Rourke, J. J., Kong, C. S., Liliental, J. E., Brooks, J. D., Sabatti, C., Leppert, J. T., Fan, A. C. 2018
Abstract

To personalize treatment for renal cell carcinoma (RCC), it would be ideal to confirm the activity of druggable protein pathways within individual tumors. We have developed a high-resolution nanoimmunoassay (NIA) to measure protein activity with high precision in scant specimens (eg, fine needle aspirates [FNAs]). Here, we used NIA to determine whether protein activation varied in different regions of RCC tumors. Since most RCC therapies target angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) receptor, we quantified phosphorylation of extracellular signal-regulated kinase (ERK), a downstream effector of the VEGF signaling pathway. In 90 ex vivo FNA biopsies sampled from multiple regions of 38 primary clear cell RCC tumors, ERK phosphorylation differed among patients. In contrast, within individual patients, we found limited intratumoral heterogeneity of ERK phosphorylation. Our results suggest that measuring ERK in a single FNA may be representative of ERK activity in different regions of the same tumor. As diagnostic and therapeutic protein biomarkers are being sought, NIA measurements of protein signaling may increase the clinical utility of renal mass biopsy and allow for the application of precision oncology for patients with localized and advanced RCC. PATIENT SUMMARY: In this report, we applied a new approach to measure the activity of extracellular signal-regulated kinase (ERK), a key cancer signaling protein, in different areas within kidney cancers. We found that ERK activity varied between patients, but that different regions within individual kidney tumors showed similar ERK activity. This suggests that a single biopsy of renal cell carcinoma may be sufficient to measure protein signaling activity to aid in precision oncology approaches.

View details for DOI 10.1016/j.euo.2018.09.011

View details for PubMedID 31412000
Serum miR371a Quantitation for Assessing Tumor Burden in Testicular Germ Cell Tumors Kunder, C., Imae, Y., Srinivas, S., Fan, A. C. NATURE PUBLISHING GROUP. 2018: 703
View details for Web of Science ID 000429308604323
Phase 1 study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus (E) or cabozantinib (Cabo) in patients (pts) with clear cell (cc) and papillary (pap) metastatic renal cell cancer (mRCC). Tannir, N. M., Fan, A. C., Lee, R. J., Carthon, B., Iliopoulos, O., Mier, J., Patel, M. R., Meric-Bernstam, F., DeMichele, A., Voss, M., Harding, J. J., Srinivasan, R., Shapiro, G., Telli, M. L., Munster, P. N., Carvajal, R. D., Jenkins, Y., Whiting, S. H., Bendell, J. C., Bauer, T. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.603

View details for Web of Science ID 000436179500597
A phase 1/2 study of CB-839, a first-in-class glutaminase inhibitor, combined with nivolumab in patients with advanced melanoma (MEL), renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) Meric-Bernstam, F., Gordon, M., Tykodi, S., Lam, E., Vaishampayan, U., Chaves, J., Nikolinakos, P., Fan, A., Lee, R., McDermott, D., Shapiro, G., Gandhi, L., Tawbi, H., Bhatia, S., Muigai, L., Jenkins, Y., Whiting, S., Voss, M. BMC. 2017
View details for Web of Science ID 000465628700017
Consolidative Radiotherapy in Metastatic Urothelial Cancer. Clinical genitourinary cancer Shah, S., Zhang, C. A., Hancock, S., Fan, A., Skinner, E., Srinivas, S. 2017
Abstract

We report outcomes of a retrospective, single-institution experience with consolidative radiation after chemotherapy in metastatic urothelial cancer (MUC).From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with MUC who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. Overall survival (OS) was defined as time from start of chemotherapy to death or last follow-up.In the selected group of patients with MUC, the median age was 67 years; 59% had received previous cisplatin-based chemotherapy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases. Median survival from diagnosis to cystectomy was 48 months. Median PFS was 13 months and median OS was 29 months. Eight patients (36%) were alive and disease-free 6 years after radiation therapy. Patients who were rendered disease-free were those with nodal metastases and delivery of radiation to a single site of metastasis.In this highly selective cohort of patients with MUC treated with consolidative radiation after chemotherapy, 36% were rendered disease-free. This suggests that radiation is feasible and might contribute to long-term disease control. Further prospective studies are needed to better characterize the benefit of combined modality treatment.

View details for DOI 10.1016/j.clgc.2017.04.007

View details for PubMedID 28465049
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
Use of nano-immuno assay to generate rapid, quantitative nanoscale proteomic profiling of the hypoxia pathway in renal cell carcinoma clinical specimens. Fan, A. C., Banerjee, P., Leppert, J., Harshman, L., Sabatti, C., Brooks, J. D., Felsher, D. W. AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009801088
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 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 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 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 PubMedID 18461184
Targeting Metabolic Pathways in Kidney Cancer: Rationale and Therapeutic Opportunities. Cancer journal (Sudbury, Mass.) Hoerner, C. R., Miao, S. Y., Hsieh, J. J., Fan, A. C. ; 26 (5): 407?18
Abstract

Alterations in cellular sugar, amino acid and nucleic acid, and lipid metabolism, as well as in mitochondrial function, are a hallmark of renal cell carcinoma (RCC). The activation of oncogenes such as hypoxia-inducible factor and loss of the von Hippel-Lindau function and other tumor suppressors frequently occur early on during tumorigenesis and are the drivers for these changes, collectively known as "metabolic reprogramming," which promotes cellular growth, proliferation, and stress resilience. However, tumor cells can become addicted to reprogrammed metabolism. Here, we review the current knowledge of metabolic addictions in clear cell RCC, the most common form of RCC, and to what extent this has created therapeutic opportunities to interfere with such altered metabolic pathways to selectively target tumor cells. We highlight preclinical and emerging clinical data on novel therapeutics targeting metabolic traits in clear cell RCC to provide a comprehensive overview on current strategies to exploit metabolic reprogramming clinically.

View details for DOI 10.1097/PPO.0000000000000472

View details for PubMedID 32947309
Routine plasma-based genotyping to comprehensively detect germline, somatic, and reversion BRCA mutations among patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research Vidula, N., Rich, T. A., Sartor, O., Yen, J., Hardin, A., Nance, T., Lilly, M. B., Nezami, M. A., Patel, S. P., Carneiro, B. A., Fan, A., Brufksy, A. M., Parker, B. A., Bridges, B. B., Agarwal, N., Maughan, B. L., Raymond, V. M., Fairclough, S. R., Lanman, R. B., Bardia, A., Cristofanilli, M. 2020
Abstract

Poly ADP-ribose inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay which evaluates single nucleotide variants and insertion-deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.Among 828 patients, greater than or equal to 1 deleterious BRCA1/2 mutation was detected in 60 (7.2%) patients, including germline (n=42) and somatic (n=18) mutations. Common co-existing mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%) and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9/42 (21.4%) germline BRCA1/2 mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure which contributed to subsequent resistance to PARPi and platinum therapy.cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical application of these findings to guide precision medicine approaches for advanced malignancies.

View details for DOI 10.1158/1078-0432.CCR-19-2933

View details for PubMedID 32034076
Feasibility and design of a cloud-based digital platform in patients with advanced cancer. Roy, M., Hall, E., Velazquez, B., Shah, S., Fardeen, T., Cunanan, K., San Pedro-Salcedo, M., Wakelee, H. A., Neal, J. W., Padda, S., Das, M., Fan, A. C., Srinivas, S., Fisher, G. A., Haraldsdottir, S., Johnson, T., Chu, G., McMillan, A., Ramchandran, K. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.27_suppl.211

View details for Web of Science ID 000518223100208
A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-Deficient Renal Cell Carcinoma in 32 Patients. The American journal of surgical pathology Lau, H. D., Chan, E., Fan, A. C., Kunder, C. A., Williamson, S. R., Zhou, M., Idrees, M. T., Maclean, F. M., Gill, A. J., Kao, C. 2019
Abstract

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69y), and the M:F ratio was 2.2:1. Median tumor size was 6.5cm (range, 2.5 to 28cm), and 71% presented at stage ?pT3a. After a median follow-up of 16 months (range, 1 to 118mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.

View details for DOI 10.1097/PAS.0000000000001372

View details for PubMedID 31524643
Therapeutic benefit of empiric drug sequencing in metastatic renal cell carcinoma Chen, V., Gong, C., Hoerner, C. R., Zhang, C. A., Srinivas, S., Fan, A. C. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.e16569

View details for Web of Science ID 000442916005425
Landscape of BRCA1 and BRCA2 germline, somatic, and reversion alterations detectable by cell-free DNA testing among patients with metastatic breast, ovarian, pancreatic, or prostate cancer Bardia, A., Rich, T. A., Raymond, V. M., Fairclough, S. R., Sartor, A., Lilly, M. B., Nezami, M., Patel, S., Carneiro, B. A., Fan, A. C., Brufsky, A., Parker, B. A., Bridges, B. B., Agarwal, N., Maughan, B., Lanman, R. B., Cristofanilli, M. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.12097

View details for Web of Science ID 000442916004110
F-18-FPPRGD(2) PET/CT in patients with metastatic renal cell cancer Toriihara, A., Duan, H., Park, S., Hatami, N., Baratto, L., Fan, A., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2018
View details for Web of Science ID 000467489902164
Clinicopathologic Characteristics of Fumarate Hydratase-Deficient and Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Series of 10 Cases Lau, H., Williamson, S. R., Kunder, C., Fan, A. C., Kao, C. NATURE PUBLISHING GROUP. 2018: 358
View details for Web of Science ID 000429308602336
Clinicopathologic Characteristics of Fumarate Hydratase-Deficient and Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Series of 10 Cases Lau, H., Williamson, S. R., Kunder, C., Fan, A. C., Kao, C. NATURE PUBLISHING GROUP. 2018: 358
View details for Web of Science ID 000459341001466
Serum miR371a Quantitation for Assessing Tumor Burden in Testicular Germ Cell Tumors Kunder, C., Imae, Y., Srinivas, S., Fan, A. C. NATURE PUBLISHING GROUP. 2018: 703
View details for Web of Science ID 000459341003276
Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in BRCA2-Associated Prostate Cancer Resulting From Biallelic BRCA2 Reversion Mutations Restores Both Germline and Somatic Loss-of-Function Mutations JCO PRECISION ONCOLOGY Carneiro, B. A., Collier, K., Nagy, R. J., Pamarthy, S., Sagar, V., Fairclough, S., Odegaard, J., Lanman, R. B., Costa, R., Taxter, T., Kuzel, T. M., Fan, A., Chae, Y., Cristofanilli, M., Hussain, M. H., Abdulkadir, S. A., Giles, F. J. 2018; 2
View details for DOI 10.1200/PO.17.00176

View details for Web of Science ID 000462082000001
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
Economic burden of empiric drug utilization in metastatic renal cell carcinoma emphasizes the need for early biomarkers of response. Chen, V., Gong, C., Zhang, C. A., Srinivas, S., Lee, H. E., Fan, A. C. AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.e16072

View details for Web of Science ID 000411931702162
Pilot study of F-18-FSPG vs F-18-FDG PET imaging for response assessment in cancer Park, S., Hatami, N., Rutledge, O., Koglin, N., Loo, B., Fan, A., Mittra, E. SOC NUCLEAR MEDICINE INC. 2017
View details for Web of Science ID 000404949900118
INTRA-TUMOR HETEROGENEITY IN RENAL CELL CARCINOMA: IMPLICATIONS FOR PROTEOMIC ANALYSIS OF RENAL MASS BIOPSIES Massoudi, R., Hoerner, C., Metzner, T., O'Rourke, J., Curtis, R., Stell, L., Sabatti, C., Brooks, J., Fan, A., Leppert, J. ELSEVIER SCIENCE INC. 2017: E496?E497
View details for DOI 10.1016/j.juro.2017.02.1184

View details for Web of Science ID 000398276602070
High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Science translational medicine Sharma, A., Burridge, P. W., McKeithan, W. L., Serrano, R., Shukla, P., Sayed, N., Churko, J. M., Kitani, T., Wu, H., Holmstr�m, A., Matsa, E., Zhang, Y., Kumar, A., Fan, A. C., Del �lamo, J. C., Wu, S. M., Moslehi, J. J., Mercola, M., Wu, J. C. 2017; 9 (377)
Abstract

Tyrosine kinase inhibitors (TKIs), despite their efficacy as anticancer therapeutics, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen U.S. Food and Drug Administration-approved TKIs for cardiotoxicities by measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling. With these data, we generated a "cardiac safety index" to reflect the cardiotoxicities of existing TKIs. TKIs with low cardiac safety indices exhibit cardiotoxicity in patients. We also derived endothelial cells (hiPSC-ECs) and cardiac fibroblasts (hiPSC-CFs) to examine cell type-specific cardiotoxicities. Using high-throughput screening, we determined that vascular endothelial growth factor receptor 2 (VEGFR2)/platelet-derived growth factor receptor (PDGFR)-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. With phosphoprotein analysis, we determined that VEGFR2/PDGFR-inhibiting TKIs led to a compensatory increase in cardioprotective insulin and insulin-like growth factor (IGF) signaling in hiPSC-CMs. Up-regulating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during cotreatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anticancer TKIs, and the results correlate with clinical phenotypes. This approach provides unexpected insights, as illustrated by our finding that toxicity can be alleviated via cardioprotective insulin/IGF signaling.

View details for DOI 10.1126/scitranslmed.aaf2584

View details for PubMedID 28202772
Monitoring Neutropenia for Cancer Patients at the Point of Care Small Methods Inan, H., et al 2017
View details for DOI 10.1002/smtd.201700193
Monitoring Neutropenia for Cancer Patients at the Point of Care. Small methods Inan, H., Kingsley, J. L., Ozen, M. O., Tekin, H. C., Hoerner, C. R., Imae, Y., Metzner, T. J., Preiss, J. S., Durmus, N. G., Ozsoz, M., Wakelee, H., Fan, A. C., T�zel, E., Demirci, U. 2017; 1 (9)
Abstract

Neutrophils have a critical role in regulating the immune system. The immune system is compromised during chemotherapy, increasing infection risks and imposing a need for regular monitoring of neutrophil counts. Although commercial hematology analyzers are currently used in clinical practice for neutrophil counts, they are only available in clinics and hospitals, use large blood volumes, and are not available at the point of care (POC). Additionally, phlebotomy and blood processing require trained personnel, where patients are often admitted to hospitals when the infections are at late stage due to lack of frequent monitoring. Here, a reliable method is presented that selectively captures and quantifies white blood cells (WBCs) and neutrophils from a finger prick volume of whole blood by integrating microfluidics with high-resolution imaging algorithms. The platform is compact, portable, and easy to use. It captures and quantifies WBCs and neutrophils with high efficiency (>95%) and specificity (>95%) with an overall 4.2% bias compared to standard testing. The results from a small cohort of patients (N = 11 healthy, N = 5 lung and kidney cancer) present a unique disposable cell counter, demonstrating the ability of this tool to monitor neutrophil and WBC counts within clinical or in resource-constrained environments.

View details for PubMedID 30740513
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
Phase II Study of Pazopanib and Paclitaxel in Patients With Refractory Urothelial Cancer. Clinical genitourinary cancer Narayanan, S., Lam, A., Vaishampayan, U., Harshman, L., Fan, A., Pachynski, R., Poushnejad, S., Haas, D., Li, S., Srinivas, S. 2016; 14 (5): 432-437
Abstract

Currently, no standard treatments are available for relapsed or refractory urothelial carcinoma (UC). Paclitaxel has demonstrated efficacy in the treatment of UC when used alone or combined with other cytotoxic therapies. We designed a phase II trial combining paclitaxel with pazopanib, a commonly used antiangiogenic agent with significant antitumor activity in various solid tumors.We enrolled 32 patients with refractory UC who had demonstrated disease progression after 2 previous chemotherapeutic regimens. The patients received paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and oral pazopanib 800 mg daily. The primary endpoint was the overall response rate (ORR). The secondary endpoints included progression-free survival, overall survival, and a safety assessment of the combination.Of the 28 evaluable patients, a complete response was observed in 3 patients and a partial response in 12, with an ORR of 54% (95% confidence interval, 33.9-72.5). The median progression-free and overall survival was 6.2 and 10 months, respectively. The most frequent side effects noted (all grades) were fatigue (63%), diarrhea (44%), and nausea and vomiting (41%). Hematologic toxicities were common and included (all grades) anemia (69%), neutropenia (38%), and thrombocytopenia (47%). Growth factor support was required for 44% of the patients.The combination of paclitaxel and pazopanib resulted in a promising ORR of 54% in patients with advanced pretreated UC. This represents a greater response rate and median survival than found with other existing second-line regimens for UC and is worthy of further study.

View details for DOI 10.1016/j.clgc.2016.03.011

View details for PubMedID 27068017
Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), alone and in combination with everolimus (E) in patients (pts) with renal cell cancer (RCC) Meric-Bernstam, F., Tannir, N. M., Mier, J., DeMichele, A., Telli, M. L., Fan, A. C., Munster, P. N., Carvajal, R. D., Orford, K. W., Bennett, M. K., Iliopoulos, O., Owonikoko, T., Patel, M. R., McKay, R., Infante, J. R., Voss, M., Harding, J. J. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.4568

View details for Web of Science ID 000404665407141
Prognostic factors for pancreatic metastases in renal cell cancer. Chung, A., Li, S., Shah, S., Fan, A. C., Srinivas, S. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e16106

View details for Web of Science ID 000404711500073
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
Consolidative radiotherapy in metastatic urothelial cancer (MUC) Srinivas, S., Narayanan, S., Fan, A. C., Hancock, S., Skinner, E. C. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.2_suppl.406

View details for Web of Science ID 000378109100400
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
Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer. Srinivas, S., Narayanan, S., Harshman, L., Pachynski, R., Lam, A. P., Fan, A. C., Poushnejad, S., Haas, D., Vaishampayan, U. N. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.7_suppl.294

View details for Web of Science ID 000356886700294
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
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
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
NANO-SCALE PROTEOMIC PROFILING TO DEFINE DIAGNOSTIC SIGNATURES AND BIOMARKERS OF THERAPEUTIC ACTIVITY IN RCC Leppert, J., Fan, A., Liliental, J., Xu, L., Thong, A., Yost, C., Yaghi, A., Metzner, T., Brooks, J., Harshman, L., Sabatti, C., Srinivas, S., Felsher, D. ELSEVIER SCIENCE INC. 2013: E246?E247
View details for DOI 10.1016/j.juro.2013.02.154

View details for Web of Science ID 000320281600603
Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC Fan, A. C., Leppert, J., Liliental, J. E., Xu, L., Thong, A. E., Yost, C., Yaghi, A., Brooks, J. D., Harshman, L., Sabatti, C., Srinivas, S., Felsher, D. W. AMER SOC CLINICAL ONCOLOGY. 2013
View details for DOI 10.1200/jco.2013.31.6_suppl.432

View details for Web of Science ID 000333679600429
The Simple Western rapidly generates quantitative profiles of MAPK and PI3K proteins in clinical specimens Fan, A. C., Banerjee, P., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2012
View details for DOI 10.1158/1538-7445.AM2012-LB-443

View details for Web of Science ID 000209701600342
Nano-scale phospho-proteomic analysis to define diagnostic signatures and biomarkers of therapeutic activity in cancer Fan, A. C., Banerjee, P., Xu, L., Kong, C., Sabatti, C., Wilheim, F., Greenberg, P., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2012
View details for DOI 10.1158/1538-7445.AM2012-1280

View details for Web of Science ID 000209701502383
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
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
"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
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
View details for Web of Science ID 000299597105536
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 PubMedID 20935221
Treatment of Higher Risk Myelodysplastic Syndrome Patients Unresponsive to Hypomethylating Agents with ON 01910.Na 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Seetharam, M., Tran, M., Fan, A. C., Xu, L., Renschler, J. P., Felsher, D. W., Sridhar, K., Wilhelm, F., Greenberg, P. L. AMER SOC HEMATOLOGY. 2010: 1635?35
View details for Web of Science ID 000289662204430
ABT-737 Targets Leukemic Stem Cells In Mouse Models of Mutant NRASD12/hBCL-2-Mediated Acute Myeloid Leukemia progression with Increased Survival 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Padua, R. A., Beurlet, S., Krief, P., Omidvar, N., Le Pogam, C., Auboeuf, D., de la Grange, P., Soulie, A., Janin, A., Noguera, M., Merlet, P., Sarda-Mantel, L., Fenaux, P., Konopleva, M., Andreeff, M., Tu, A., Yang, P., Fan, A. C., Kogan, S. C., Weissman, I. L., Felsher, D. W., Pla, M., West, R., Chomienne, C. AMER SOC HEMATOLOGY. 2010: 1355?56
View details for Web of Science ID 000289662203639
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 PubMedID 21035406
A rapid screening method for monitoring signaling changes in the monocyte cell line U937 Huang, Y., Shahijanian, F., Deb-Basu, D., Fan, A., Voehringer, D., Hirschberg, D. AMER ASSOC CANCER RESEARCH. 2009
View details for Web of Science ID 000209701803332
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 PubMedID 19251665
A nano-immunoassay system for monitoring changes in signaling upon oncogene inactivation in hematopoietic tumors Fan, A. C., Deb-Basu, D., Gotlib, J., Voehringer, D. W., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2007: 3610S
View details for Web of Science ID 000251969000837
A novel nano-immunoassay system capable of absolute protein measurements from 400 tumor-derived stem cells. Voehringer, D. W., Deb-Basu, D., Weissman, I., Fan, A., Nguyen, U., Bhamidipati, A., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2007: 3556S?3556S
View details for Web of Science ID 000251969000677
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 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 PubMedID 17664422
Nano-fluidic detection of oncoprotein signaling in preclinical and patient lymphoma samples. Fan, A. C., Deb-Basu, D., Horoschak, M., Shirer, A., Voehringer, D., O'Neill, R., Felsher, D. W. AMER SOC HEMATOLOGY. 2006: 715A
View details for Web of Science ID 000242440003317
ASPP2 haploinsufficiency promotes tumor formation in a mouse model. 48th Annual Meeting of the American-Society-of-Hematology Kampa, K. M., Acoba, J. D., Chen, D., Beemer, K., Gay, J., Zhu, Z., Padiernos, E., Fan, A., Felsher, D., Corless, C., Naumovski, L., Lopez, C. D. AMER SOC HEMATOLOGY. 2006: 162B?162B
View details for Web of Science ID 000242440401020
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 PubMedID 17056717
MYC or RAS, but not BCL2 expression induces reversible lymphomagenesis Fan, A. C., Giuriato, S., Karlsson, A., Bachireddy, P., Bendapudi, P., Rakhra, K., Padua, R., Felsher, D. AMER ASSOC CANCER RESEARCH. 2006
View details for Web of Science ID 000454606200593
MYC quantification in lymphoma fine needle aspirates using "Firefly," a novel nanofluidic protein analysis system Fan, A. C., Voehringer, D., Deb-Basu, D., Gossett, J., O'Neill, R., Felsher, D. AMER ASSOC CANCER RESEARCH. 2006
View details for Web of Science ID 000454608801268
Nanoliter-scale Western-blot-like BCL-2 analysis of lymphoma fine needle aspirates Fan, A. C., Voehringer, D., Deb-Basu, D., Gossett, J., O-Neill, R., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2006
View details for Web of Science ID 000454606200464
Two oncogenic hits are required to initiate lymphomagenesis in adult, but not neonatal hosts. Fan, A. C., Giuriato, S., Karlsson, A., Padua, R. A., Felsher, D. W. AMER SOC HEMATOLOGY. 2005: 732A
View details for Web of Science ID 000233426004451
Cooperation between MYC and BCL2 to induce lymphoma is uncovered in an adult context Fan, A. C., Giuriato, S., Feng, C., Padua, R. A., Felsher, D. AMER SOC HEMATOLOGY. 2004: 429A
View details for Web of Science ID 000225127501532
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 PubMedID 14757531
Defining the genetic contexts when MYC inactivation induces sustained regression of hematopoietic tumors. Giuriato, S., Passegue, E., Fan, A., Tang, F., Felsher, D. W. AMER SOC HEMATOLOGY. 2003: 586A
View details for Web of Science ID 000186536702158
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

Alice C.�Fan

Assistant Professor of Medicine (Oncology) and, by courtesy, of Urology at the Stanford University Medical Center

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