Unmet Needs VHL Gene and Protein Data Models of Basic Science On - PowerPoint PPT Presentation

A Clinical and Research Perspective Eric Jonasch, MD Coming Up With A Cure: Many Layers of Knowledge are Needed! The Past, Present, and Future of Identification of the VHL VHL: A Clinical and Research Gene Perspective Description of VHL Detection Protein Function Eric Jonasch, MD Follow up Professor of Medicine Treatment Identifying and Characterizing Additional UT MD Anderson Cancer Center Genes Disrupted in VHL Disease Generate Real-World Patient Databases Development of Relevant Model Systems Unmet Needs VHL Gene and Protein Data Models of Basic Science • On chromosome 3p25 Collection Disease • 213 amino acid protein • Binds to Elongin C/B a • Forms “ VBC complex ” Screening Imaging New Elongin C (15kDa) Tools Technology Therapies Elongin B (18kDa) Cul 2 Modified from Stebbins and Pavletich, Science, Vol 284, 16 April 1999 VHL Alliance, 2017 Tampa, FL

A Clinical and Research Perspective Eric Jonasch, MD VHL Mutation Increases Production VHL- A Regulatory Hub of Growth Factors, like VEGF b a Elongin C HIF- b Elongin B HIF- a Cul 2 VHL Nucleus Transcription of: Regulates how the cell Controls the sees its surroundings primary cilium VEGF Impacts blood Regulates vessel formation Other angiogenic factors p53 Pugh et al Narture Medicine 2003 Ohh et al, Mol Cell, Vol 1, 959-968, 1998 Thoma et al Nature Cell Biology Aug 2009 Roe and Youn Mol Cell May 2006 Kerbel NEJM May 2008 Kuehn et al Ca Res May 15, 2007 Kurban et al, Cancer Res 2006; 66: (3). VEGF = vascular endothelial growth factor; HIF = hypoxia-inducible factor. VHL Loss Results in Abnormal Production of Blood Vessels, Fueled by VEGF Can We Block The Consequences VEGF VEGF of VHL Loss? VEGF VEGF Stromal cells VHL-/- Tumor cells VHL-/- VEGF VHL-/- VHL Alliance, 2017 Tampa, FL

A Clinical and Research Perspective Eric Jonasch, MD New Agents Exist or Are in Development That Pazopanib Study: American Society Therapies of Clinical Oncology 2017 Block VEGF or VEGF Receptors Phase II Study of Pazopanib in Patients with von Hippel Lindau Disease Sunitinib VEGF Pazopanib VEGF Eric Jonasch 1 , Daniel Gombos 2 , Steven G. Waguespack 3 , Valerie Marcott 4 , Diane Liu 5 , Justin Weldon 1 , Shelly Bird 1 , Christine Robichaux 1 , Nizar Tannir 1 Ashley Woodson 6 , Gregory N. Fuller 7 , Ian E. Mccutcheon 8 and Surena Matin 9 Axitinib VEGF Departments of Genitourinary Medical Oncology 1 , Ophthalmology 2 , Endocrinology 3 , Investigational Therapeutics 4 , Biostatistics 5 , Cancer Genetics 6 , Pathology 7 , Neurosurgery 8 and Urology 9 at the UT M. D. Anderson Cancer Center, Houston, TX Bevacizumab VEGF RESULTS RESULTS PATIENT PATIENT CHARACTERISTICS RESULTS INTRODUCTION Swimmers plot of response by organ site Examples of organ specific response Dosing and reason for treatment discontinuation � von Hippel Lindau disease (VHL) is an Dosing� � N� autosomal dominant disorder. Affected 800mg� 13� individuals develop vascular neoplastic lesions 600mg� 12� 400mg� 6� in multiple sites including the eye, brain, No� dose� received� 1� pancreas, adrenal and kidney. Standards of care � � includes surveillance imaging and surgical Reason� off� therapy � � Transaminitis� 4� intervention. We hypothesized that treatment of Other� toxicities� 3� VHL related lesions with an antiangiogenic Progression� 3� agent would result in shrinkage of all lesion Patient� choice� 11� Ongoing� treatment� 10� types. We chose the multikinase inhibitor Death� 1� pazopanib to test this hypothesis. � � Stromal cells � Treatment emergent toxicities seen in at least 10 RESULTS METHODS percent of patients Patients treated with an alternate sunitinib schedule d CONCLUSIONS Overall response rate Adverse� Event� Max� Grade� 1� Max� Grade� 2� Max� Grade� 3� Max� Grade� 4� Diarrhea� 14� 9� � � � � Fatigue� 11� 10� 1� � � Patients with clinical features or genetic Aspartate� This is the largest prospective VHL disease � Number� of� patients� (%) � aminotransferase� c onfi rmation of VHL disease, with speci fi c therapeutic study presented to date. Total� evaluable� 31� increased� 12� 5� 3� � � Alanine� aminotransferase� measurable lesions were treated with CR� 0� increased� 11� 4� 3� 1� VHL-/- PR� 13� (42)� Skin� hyperpigmentation� 18� � � � � � � pazopanib 800mg PO daily for two 12-week Hypertension� 4� 10� � � � � Pazopanib resulted in signi fi cant and sustained SD� 18� (58)� Nausea� 9� 3� � � � � cycles. E ffi cacy was determined by modi fi ed PD� 0� Dysgeusia� 7� 3� � � � � disease control for the majority of VHL Inevaluable� 1� Proteinuria� 7� 1� 1� � � RECIST after two cycles, with overall Mucositis� 5� 3� � � � � patients enrolled on the study, with shrinkage � � Leukopenia� 7� � � � � � � � � � � � � � � � � � � � � � � � 1� � � � � � response the primary endpoint. Patients had � Alopecia� 8� � � � � � � or stabilization in the kidney, pancreas and Best response by organ site Vomiting� 7� � � � � the option to continue therapy beyond 24 Platelet� count� decreased� 6� � � � � � � � CNS, along with an acceptable safety profi le. Tumor cells Hair� pigment� change� 6� � � � � � � weeks. Continuous monitoring for any lesion Rash� 4� 2� � � � � A number of patients remain on therapy, with � Renal� (%)� CNS(%)� Pancreas� (%)� Anemia� 5� � � � � � � progression and drug discontinuation due to Lesion� 59� 49� 17� Alkaline� phosphatase� continued response. increased� 4� � � � � � � Number� � VHL-/- toxicity during the whole period of the CR� 2� (3)� 0� � 0� Creatinine� increased� 4� � � � � � � Depression� 4� � � � � � � treatment was planned. PR� 29� (53)� 2� (4)� 9� (53)� Epistaxis� 4� � � � � � � This agent may be considered as an alternative Hyperglycemia� 4� � � � � � � SD� 28� (47)� 47� (96)� 8� � (47)� Hyperthyroidism� 4� � � � � � � to surgical intervention in patients with VHL Hypoalbuminemia� 4� � � � � � � PD� 0� 0� 0� Time to response per organ site and duration of treatment per Hypernatremia� 3� � � � � � � disease. � patient. Median duration of treatment was six months. Hypocalcemia� 3� � � � � � � VEGF Hypokalemia� 3� � � � � � � � VHL-/- If VHL Is Broken, Cells Don ’ t New Pazopanib: Tumor Response Control HIF Therapies HIF- b HIF- a PT VHL Nucleus VHL Alliance, 2017 Tampa, FL

A Clinical and Research Perspective Eric Jonasch, MD If VHL Is Broken, Cells Don ’ t If VHL Is Broken, Cells Don ’ t Control HIF Control HIF HIF- b HIF- b HIF- a HIF- a PT PT VHL VHL Nucleus Nucleus VEGF If VHL Is Broken, Cells Don ’ t New Peloton HIF 2 Alpha Blocker Control HIF Therapies HIF- b HIF- b Can we block HIF? HIF- a HIF- a PT2977 PT PT VHL VHL Nucleus Nucleus VEGF VEGF VHL Alliance, 2017 Tampa, FL

A Clinical and Research Perspective Eric Jonasch, MD New New Peloton HIF 2 Alpha Blocker Peloton HIF 2 Alpha Blocker Therapies Therapies HIF- b HIF- b HIF- a HIF- a PT2977 PT2977 PT PT A clinical trial is being developed to test PT2977 in VHL VHL Nucleus Nucleus VHL patients! VEGF VEGF New Peloton HIF 2 Alpha Blocker Therapies • PT2977 is a next-generation HIF2a blocker that is administered in pill form. VHL Alliance Research Funding • A study will be launched in 2018 to test the effect of PT2977 on kidney and other manifestations in individuals with VHL. • Primary goal of study will be to see whether kidney tumors shrink- will also assess impact in other sites. VHL Alliance, 2017 Tampa, FL

A Clinical and Research Perspective Eric Jonasch, MD VHL Alliance Research Funding Preproposal Requests (May-June) • Over 1 million dollars given for research! Invitation for Full Review (July) • Review committee consisting of world leaders in VHL research. Full Proposal Submission (August) • Strong emphasis on translational research which will benefit patients sooner rather than later. Vetted by internationally Peer Review and Selection recognized experts Models of 2014 Full Project Awardee Disease VHL Models and Novel Data Models of Therapeutics Basic Science Collection Disease Othon Iliopoulos Dept. Oncology Screening Imaging New Massachusetts General Hospital, Boston MA Tools Technology Therapies VHL Alliance, 2017 Tampa, FL