Clinical Focus

  • Cancer > Urologic Oncology
  • Medical Oncology
  • Urologic Neoplasms
  • Kidney Cancer
  • Translational Research, Biomedical
  • Molecular Targeted Therapy
  • Nano-proteomics
  • Clinical Trials as Topic

Academic Appointments

Administrative Appointments

  • Director, "Frontiers in Cancer Clinical Translation" Seminar Series, Division of Oncology, Stanford School of Medicine (2020 - Present)
  • co-Director, Translational Investigator Program, Department of Medicine, Stanford School of Medicine (2022 - Present)
  • Research Mentor, Canary Cancer Research Education Summer Training (CREST) Program (2019 - Present)
  • Member, Stanford BioX Program (2016 - Present)
  • Faculty Fellow, ChemH [Chemistry, Engineering & Medicine for Human Health Institute] (2018 - Present)
  • Faculty Member, Canary Center, Stanford Radiology (2017 - Present)
  • Member, Stanford Kidney Cancer Research Group (2011 - Present)
  • Inteviewer, Stanford School of Medicine Internal Medicine Residency (2011 - Present)
  • Research Mentor, NIH/NIDDK Short term education program for under-represented persons (2011 - 2011)
  • Clinical Mentor, Stanford Molecular Imaging Scholars Program (2010 - Present)
  • Associate Member, Stanford Cancer Institute Translational Oncology Program (2008 - Present)
  • Founding Advisor, Stanford Association for Multidisciplinary Medicine and Science (2008 - 2013)
  • Member, Stanford Lymphoma Disease Management Group (2005 - 2013)

Honors & Awards

  • Early Detection of Hereditary Renal Cancer (RCC) Pilot Grant, International Alliance for Cancer Early Detection (June 2020-May 2021)
  • Career Development Award, ConquerCancer/ASCO (2016-2019)
  • K23 Career Development Award, NIH/NCI (July 2010-June 2015)
  • R21: Analysis of CTCs for Early Prediction of Response to Treatment in RCC, NIH/NCI (2014-2016)
  • Innovation Award, Stanford Cancer Institute (2014-2016)
  • Center for Cancer Nanotechnology Excellence: leader of the Clinical Translational Core, NIH/NCI (2015-2020)
  • R21: Nanoscale proteomic profiles of hypoxia pathways to develop biomarkers of renal cell carcinoma, NIH/NCI (August 2012-July 2014)
  • Developmental Cancer Research Award, Stanford Cancer Institute (September 2011-August 2012)
  • TRAM Renewal Grant: Development of blood biomarkers for diagnosis and monitoring of kidney cancer, Stanford Department of Medicine (October 2012-August 2013)
  • Translational Research and Applied Medicine Program (TRAM) Pilot Grant, Stanford Department of Medicine (October 2011-September 2012)
  • Special Fellow in Clinical Research, Leukemia and Lymphoma Society (July 2006-June 2009)
  • Research Fellowship, Lymphoma Research Foundation (July 2004-June 2006)
  • Dean's Fellowship, Stanford School of Medicine (April 2004- March 2005)

Professional Education

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

Community and International Work

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


    2004 Australia/New Zealand Concerts, 2008 China Concerts

    Partnering Organization(s)

    Stanford Symphony Orchestra

    Populations Served




    Ongoing Project


    Opportunities for Student Involvement


  • Violinist, Stanford Hosptial Bing Music Series, Stanford Hospital


    Chamber Music



    Ongoing Project


    Opportunities for Student Involvement


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


    Helping adult patients and families



    Ongoing Project


    Opportunities for Student Involvement


  • Outreach Speaker, Chinese Community Clinical Trials Forum


    Bay Area

    Ongoing Project


    Opportunities for Student Involvement


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


    Novel Therapeutics in Lymphoma

    Populations Served

    Aboriginal and Local Taiwanese populations



    Ongoing Project


    Opportunities for Student Involvement



  • Alice Fan, Dean Felsher. "United States Patent 10145851 Discovery and validation of cancer biomarkers using a protein analysis methodology to analyze specimens", Leland Stanford Junior University, Dec 4, 2018

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

  • Pilot Study for Black Men With Prostate Cancer: Optimization Of Mental and Heart Health, the BOOM-Heart Study Recruiting

    Pilot study to determine the feasibility of providing psychosocial and cardiac rehabilitation services to address socioeconomic health disparities and improve wellbeing for black men with prostate cancer.

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  • Serial Ultrasound of Solid Tumor Lesions to Detect Early Response to Cancer Immunotherapy Recruiting

    Primary objective is to assess whether changes in quantitative tumor perfusion parameters after 3 weeks of treatment, as measured by CEUS, can predict initial objective response to therapy, defined by current standard-of-care Secondary objectives are to evaluate if there is an optimal ultrasound imaging modality (CEUS or conventional power Doppler or LEAD ultrasound) or optimal time point to predict initial objective response and to assess the correlation of tumor perfusion parameters with change in overall tumor burden, change in diameter on a per-lesion basis, and with 12-month progression-free survival (PFS).

    View full details

  • 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 naïve 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.

    View full details

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

    Tthe primary objective of this study is to compare blinded Independent Radiology Committee (IRC)-adjudicated progression free survival (PFS) of patients treated with CB-839 + cabozantinib (CB-Cabo) versus placebo + cabozantinib (Pbo-Cabo) for advanced or metastatic clear-cell RCC (ccRCC).

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

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  • Darolutamide in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Metastatic Hormone-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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  • 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.

    View full details

  • Lenvatinib (LEN) in Combination With Pembrolizumab (KEYtruda) in Subjects With Locally Advanced or Metastatic Non-clear Cell Renal Cell Carcinoma (The LENKYN Trial) Not Recruiting

    This is a single-arm, multicenter, phase 2 study of lenvatinib in combination with pembrolizumab (lenvatinib 20 mg/day + pembrolizumab 200mg q3weeks) in subjects with unresectable advanced or metastatic non-clear cell renal carcinoma who have not received any chemotherapy for advanced disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alice Fan, M.D., 650-498-6000.

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

    The primary purpose of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review \[IIR\] using Response Evaluation Criteria in Solid Tumors \[RECIST 1.1\]) as first-line treatment in participants with advanced renal cell carcinoma (RCC).

    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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  • 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 participants with CD20-positive lymphoproliferative disorders. The extension portion of the study will allow active participants to continue to receive ABT-263 for up to 14 years after the last participant 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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  • Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors Not 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.

    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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  • Study CB-839 in Combination With Nivolumab in Patients With Melanoma, Clear Cell Renal Cell Carcinoma (ccRCC) and Non-Small Cell Lung Cancer (NSCLC) Not Recruiting

    This study is an open-label Phase 1/2 evaluation of CB-839 in combination with nivolumab in participants 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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  • Tolerability/Palatability of TalityTM Synthetic Meal Replacement in Prostate Cancer Not Recruiting

    This study will find out if a meal replacement of this type is satisfying and tolerable for men with prostate cancer. Participants will receive meal replacements of TalityTM as their expected sole source of nutrition for 4 weeks. The purpose of the study is to test whether TalityTM Synthetic Meal Replacements are suitable to be used in larger studies of patients with prostate or other types of cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Deirdre Crommie, 650-387-7797.

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Graduate and Fellowship Programs

All Publications

  • In Search of Clinical Biomarkers of Response to Checkpoint Inhibitor Therapy in Renal Cell Carcinoma. JAMA network open Fan, A. C., Leppert, J. T. 2021; 4 (1): e2035120

    View details for DOI 10.1001/jamanetworkopen.2020.35120

    View details for PubMedID 33496791

  • 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)
  • 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


    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


    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. n., Agrawal, P. n., Zhang, C. A., Xie, L. n., Gong, C. L., Hoerner, C. R., Srinivas, S. n., Oermann, E. K., Fan, A. C. 2019; 11 (7)


    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

  • 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

    View details for DOI 10.3233/KCA-180043

    View details for Web of Science ID 000664211400003

  • 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


    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

  • 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


    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

  • 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


    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


    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)


    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

  • Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer. JCO oncology practice Gensheimer, M. F., Gupta, D., Patel, M. I., Fardeen, T., Hildebrand, R., Teuteberg, W., Seevaratnam, B., Asuncion, M. K., Alves, N., Rogers, B., Hansen, J., DeNofrio, J., Shah, N. H., Parikh, D., Neal, J., Fan, A. C., Moore, K., Ruiz, S., Li, C., Khaki, A. R., Pagtama, J., Chien, J., Brown, T., Tisch, A. H., Das, M., Srinivas, S., Roy, M., Wakelee, H., Myall, N. J., Huang, J., Shah, S., Lee, H., Ramchandran, K. 2022: OP2200128


    Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures.In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis.In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04).Combining a computer prognosis model with care coaches increased ACP documentation.

    View details for DOI 10.1200/OP.22.00128

    View details for PubMedID 36395436

  • Personalised risk prediction in hereditary breast and ovarian cancer: A protocol for a multi-centre randomised controlled trial Fennell, N., Colvin, E., Laquindanum, R., Mills, M., Dennis, R., Donoso, F., Gold, R., Fan, A., Downes, K., Ford, J., Antoniou, A., Kurian, A., Evans, G., Tischkowitz, M., Archer, S. WILEY. 2022: 17
  • Personalised Risk Prediction in Hereditary Breast and Ovarian Cancer: A Protocol for a Multi-Centre Randomised Controlled Trial. Cancers Archer, S., Fennell, N., Colvin, E., Laquindanum, R., Mills, M., Dennis, R., Stutzin Donoso, F., Gold, R., Fan, A., Downes, K., Ford, J., Antoniou, A. C., Kurian, A. W., Evans, D. G., Tischkowitz, M. 2022; 14 (11)


    Women who test positive for an inherited pathogenic/likely pathogenic gene variant in BRCA1, BRCA2, PALB2, CHEK2 and ATM are at an increased risk of developing certain types of cancer-specifically breast (all) and epithelial ovarian cancer (only BRCA1, BRCA2, PALB2). Women receive broad cancer risk figures that are not personalised (e.g., 44-63% lifetime risk of breast cancer for those with PALB2). Broad, non-personalised risk estimates may be problematic for women when they are considering how to manage their risk. Multifactorial-risk-prediction tools have the potential to deliver personalised risk estimates. These may be useful in the patient's decision-making process and impact uptake of risk-management options. This randomised control trial (registration number to follow), based in genetic centres in the UK and US, will randomise participants on a 1:1 basis to either receive conventional cancer risk estimates, as per routine clinical practice, or to receive a personalised risk estimate. This personalised risk estimate will be calculated using the CanRisk risk prediction tool, which combines the patient's genetic result, family history and polygenic risk score (PRS), along with hormonal and lifestyle factors. Women's decision-making around risk management will be monitored using questionnaires, completed at baseline (pre-appointment) and follow-up (one, three and twelve months after receiving their risk assessment). The primary outcome for this study is the type and timing of risk management options (surveillance, chemoprevention, surgery) taken up over the course of the study (i.e., 12 months). The type of risk-management options planned to be taken up in the future (i.e., beyond the end of the study) and the potential impact of personalised risk estimates on women's psychosocial health will be collected as secondary-outcome measures. This study will also assess the acceptability, feasibility and cost-effectiveness of using personalised risk estimates in clinical care.

    View details for DOI 10.3390/cancers14112716

    View details for PubMedID 35681696

  • Telaglenastat Plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 ENTRATA Trial. Clinical cancer research : an official journal of the American Association for Cancer Research Lee, C. H., Motzer, R., Emamekhoo, H., Matrana, M., Percent, I., Hsieh, J. J., Hussain, A., Vaishampayan, U., Liu, S., McCune, S., Patel, V., Shaheen, M., Bendell, J., Fan, A. C., Gartrell, B. A., Goodman, O. B., Nikolinakos, P. G., Kalebasty, A. R., Zakharia, Y., Zhang, Z., Parmar, H., Akella, L., Orford, K., Tannir, N. M. 2022


    Glutaminase is a key enzyme that supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects which translated to encouraging safety and efficacy findings in a phase 1 trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).Eligible patients with mRCC, previously treated with at least 2 prior lines of therapy (including {greater than or equal to}1 VEGFR-targeted tyrosine kinase inhibitor [TKI]) were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; 1-sided alpha <0.2).69 patients were randomized (46 TelaE, 23 PboE). Patients had a median 3 prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE vs 1.9 months for PboE (hazard ratio [HR]=0.64; 95% confidence interval [CI]: 0.34, 1.20; 1-sided P=0.079). One TelaE patient had a partial response (PR) and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; Grade 3-4 events occurred in 74% TelaE patients vs. 61% PboE.TelaE was well tolerated and improved PFS vs PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.

    View details for DOI 10.1158/1078-0432.CCR-22-0061

    View details for PubMedID 35576438

  • Association of renal cell carcinoma (RCC) metastatic to pancreas with a distinct molecular profile and immune cell population. Chiang, R. S., Ashok, A., Mauer, E., Barrett, A., Hoerner, C. R., Khan, O. A., Kao, C., Shah, S., Srinivas, S., Fan, A. C., Khaki, A. LIPPINCOTT WILLIAMS & WILKINS. 2022
  • Utilizing the autoantibody immune response to tumor antigens for kidney cancer early detection. Hoerner, C. R., Jhatro, M., Waitz, R., Kamath, K., Zhang, M., Dhal, A., Shon, J., Fan, A. C. LIPPINCOTT WILLIAMS & WILKINS. 2022
  • The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity JACC: CardioOncology Huang, Y. V., Waliany, S., Lee, D., Galdos, F. X., Witteles, R. M., Neal, J. W., Fan, A. C., Maecker, H. T., Nguyen, P. K., Wu, S. M., Zhu, H. 2022; 4 (5): 629–634
  • Telaglenastat Plus Cabozantinib or Everolimus For Advanced or Metastatic Renal Cell Carcinoma: an Open-Label Phase 1 Trial. Clinical cancer research : an official journal of the American Association for Cancer Research Meric-Bernstam, F., Tannir, N. M., Lliopoulos, O., Lee, R. J., Telli, M. L., Fan, A. C., DeMichele, A., Haas, N. B., Patel, M. R., Harding, J. J., Voss, M. H., Owonikoko, T. K., Carthon, B., Srinivasan, R., Bendell, J. C., Jenkins, Y., Whiting, S. H., Orford, K., Bennett, M. K., Bauer, T. M. 2022


    Dual inhibition of glucose and glutamine metabolism results in synergistic anti-cancer effects in solid tumor models. Telaglenastat, an investigational, small molecule, glutaminase inhibitor, exhibits modest single agent activity in RCC patients. This phase 1b trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).mRCC patients received escalating doses of telaglenastat (400-800mg per os [PO] twice daily) in a 3+3 design, plus either everolimus (10mg daily PO; TelaE) or cabozantinib (60mg daily PO; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and anti-tumor activity.27 patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grade 1-2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No MTD was reached for either combination, leading to a recommended phase 2 dose of 800mg telaglenastat BID with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% (20/21, including 1 partial response [PR]) among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies (5/10 PRs as best response [3 confirmed] in clear cell).TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pre-treated mRCC patients.

    View details for DOI 10.1158/1078-0432.CCR-21-2972

    View details for PubMedID 35140121

  • Use of a computer model and care coaches to increase advance care planning conversations for patients with metastatic cancer Gupta, D., Fardeen, T., Teuteberg, W., Seevaratnam, B., Asuncion, M., Alves, N., Rogers, B., Neal, J. W., Fan, A. C., Parikh, D., Patel, M. I., Shah, S., Srinivas, S., Huang, J. E., Reddy, S. A., Ganjoo, K. N., Bui, N., Hansen, J., Gensheimer, M. F., Ramchandran, K. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer. Journal of patient-reported outcomes Generalova, O., Roy, M., Hall, E., Shah, S. A., Cunanan, K., Fardeen, T., Velazquez, B., Chu, G., Bruzzone, B., Cabot, A., Fisher, G. A., Srinivas, S., Fan, A. C., Haraldsdottir, S., Wakelee, H. A., Neal, J. W., Padda, S. K., Johnson, T., Heestand, G. M., Hsieh, R. W., Ramchandran, K. 2021; 5 (1): 91


    BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center.METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care.RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages.CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

    View details for DOI 10.1186/s41687-021-00358-2

    View details for PubMedID 34524558

  • Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC. CardioOncology Waliany, S., Neal, J. W., Reddy, S., Wakelee, H., Shah, S. A., Srinivas, S., Padda, S. K., Fan, A. C., Colevas, A. D., Wu, S. M., Witteles, R. M., Zhu, H. 2021; 3 (1): 137–39

    View details for DOI 10.1016/j.jaccao.2021.01.004

    View details for PubMedID 33796869

  • Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS). Urologic oncology Velaer, K., Thomas, I. C., Yang, J., Kapphahn, K., Metzner, T. J., Golla, A., Hoerner, C. R., Fan, A. C., Master, V., Chertow, G. M., Brooks, J. D., Patel, C. J., Desai, M., Leppert, J. T. 2021


    Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous ("high-low") cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC.We used laboratory data for 3,385 patients diagnosed with mRCC from 2002 to 2017. We developed a LWAS framework, to examine the association with 53 common clinical laboratory tests results (641,712 measurements) and overall survival. We employed false-discovery rate to test the association of multiple laboratory tests with survival, and validated these results using 3 separate cohorts to generate a standardized hazard ratio (sHR), reported for a 1 standard deviation unit change in each laboratory test.The LWAS approach confirmed the association of laboratory values currently used in prognostic models with survival, including calcium (HR 1.35, 95%CI 1.24-1.48), leukocyte count (HR 1.40, 95%CI 1.30-1.51), platelet count (HR 1.36, 95%CI 1.27-1.51), and hemoglobin (HR 0.79, 95%CI 0.72-0.86). Use of these tests as continuous variables improved model performance. LWAS also identified acute phase reactants associated with survival not typically included in prognostic models, including serum albumin (HR 0.66, 95%CI 0.61-0.72), ferritin (HR 1.25, 95%CI 1.08-1.45), alkaline phosphatase (HR 1.31, 95%CI 1.23-1.40), and C-reactive protein (HR 1.70, 95%CI 1.14-2.53).Routinely measured laboratory tests can refine current prognostic models, facilitate comparisons across clinical trial cohorts, and match patients with specific systemic therapies.

    View details for DOI 10.1016/j.urolonc.2021.08.011

    View details for PubMedID 34580027

  • Return of individual research results: What do participants prefer and expect? PloS one Sayeed, S., Califf, R., Green, R., Wong, C., Mahaffey, K., Gambhir, S. S., Mega, J., Patrick-Lake, B., Frazier, K., Pignone, M., Hernandez, A., Shah, S. H., Fan, A. C., Krug, S., Shaack, T., Shore, S., Spielman, S., Eckstrand, J., Wong, C. A., Project Baseline Health Study Research Group 2021; 16 (7): e0254153


    Newer data platforms offer increased opportunity to share multidimensional health data with research participants, but the preferences of participants for which data to receive and how is evolving. Our objective is to describe the preferences and expectations of participants for the return of individual research results within Project Baseline Health Study (PBHS). The PBHS is an ongoing, multicenter, longitudinal cohort study with data from four initial enrollment sites. PBHS participants are recruited from the general population along with groups enriched for heart disease and cancer disease risk. Cross-sectional data on return of results were collected in 2017-2018 from an (1) in-person enrollment survey (n = 1,890), (2) benchmark online survey (n = 1,059), and (3) participant interviews (n = 21). The main outcomes included (1) preferences for type of information to be added next to returned results, (2) participant plans for sharing returned results with a non-study clinician, and (3) choice to opt-out of receiving genetic results. Results were compared by sociodemographic characteristics. Enrollment and benchmark survey respondents were 57.1% and 53.5% female, and 60.0% and 66.2% white, respectively. Participants preferred the following data types be added to returned results in the future: genetics (29.9%), heart imaging, (16.4%), study watch (15.8%), and microbiome (13.3%). Older adults (OR 0.60, 95% CI: 0.41-0.87) were less likely to want their genetic results returned next. Forty percent of participants reported that they would not share all returned results with their non-study clinicians. Black (OR 0.64, 95% CI 0.43-0.95) and Asian (OR 0.47, 95% CI 0.30-0.73) participants were less likely, and older participants more likely (OR 1.45-1.61), to plan to share all results with their clinician than their counterparts. At enrollment, 5.8% of participants opted out of receiving their genetics results. The study showed that substantial heterogeneity existed in participant's preferences and expectations for return of results, and variations were related to sociodemographic characteristics.

    View details for DOI 10.1371/journal.pone.0254153

    View details for PubMedID 34324495

  • Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring. Clinical chemistry Nesvet, J. C., Antilla, K. A., Pancirer, D. S., Lozano, A. X., Preiss, J. S., Ma, W. n., Fu, A. n., Park, S. M., Gambhir, S. S., Fan, A. C., Neal, J. W., Padda, S. K., Das, M. n., Li, T. n., Wakelee, H. A., Wang, S. X. 2021


    Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.

    View details for DOI 10.1093/clinchem/hvaa307

    View details for PubMedID 33393992

  • 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. n., Rich, T. A., Sartor, O. n., Yen, J. n., Hardin, A. n., Nance, T. n., Lilly, M. B., Nezami, M. A., Patel, S. P., Carneiro, B. A., Fan, A. n., Brufksy, A. M., Parker, B. A., Bridges, B. B., Agarwal, N. n., Maughan, B. L., Raymond, V. M., Fairclough, S. R., Lanman, R. B., Bardia, A. n., Cristofanilli, M. n. 2020


    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

  • Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma. Journal of the American Academy of Dermatology Hirotsu, K. E., Rana, J. n., Wang, J. Y., Raghavan, S. S., Rieger, K. E., Srinivas, S. n., Fan, A. C., Kwong, B. Y., Novoa, R. A., Zaba, L. n. 2020

    View details for DOI 10.1016/j.jaad.2020.11.067

    View details for PubMedID 33301805

  • 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
  • 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


    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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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., Tüzel, E., Demirci, U. 2017; 1 (9)


    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 DOI 10.1002/smtd.201700193

    View details for PubMedID 30740513

    View details for PubMedCentralID PMC6364993

  • 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
  • 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
  • Consolidative Radiotherapy in Metastatic Urothelial Cancer. Clinical genitourinary cancer Shah, S., Zhang, C. A., Hancock, S., Fan, A., Skinner, E., Srinivas, S. 2017


    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

  • 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
  • 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., Holmström, A., Matsa, E., Zhang, Y., Kumar, A., Fan, A. C., Del Álamo, J. C., Wu, S. M., Moslehi, J. J., Mercola, M., Wu, J. C. 2017; 9 (377)


    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

  • 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


    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


    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

  • 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
  • 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
  • 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


    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

  • 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


    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 PubMedID 27095570

  • Consolidative radiotherapy in metastatic urothelial cancer (MUC) Srinivas, S., Narayanan, S., Fan, A. C., Hancock, S., Skinner, E. C. AMER SOC CLINICAL ONCOLOGY. 2016
  • 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
  • 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


    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-?


    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


    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


    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
  • 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
  • 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
  • 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
  • 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
  • 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


    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


    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


    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
  • 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


    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

  • 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
  • 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
  • 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


    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
  • 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


    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
  • 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
  • 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


    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


    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
  • 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
  • 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


    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
  • 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
  • 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
  • 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
  • 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
  • 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


    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
  • 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


    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

  • 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


    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