Unmet Needs. The Past, Present, and Future of. A Clinical and Research Perspective. VHL Gene and Protein

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1 The Past, Present, and Future of : A Clinical and Research Perspective Professor of Medicine UT MD Anderson Cancer Center Coming Up With A Cure: Many Layers of Knowledge are Needed! Generate Real-World Patient bases Identification of the Gene Description of Protein Function Identifying and Characterizing Additional Genes Disrupted in Development of Relevant Model Systems Detection Follow up Treatment Unmet Needs Gene and Protein Basic Science On chromosome p25 2 amino acid protein Binds to Elongin C/B Forms VBC complex a Screening Tools Imaging Technology Elongin C (5kDa) Elongin B (8kDa) Cul 2 Modified from Stebbins and Pavletich, Science, Vol 28, 6 April 999

2 - A Regulatory Hub Mutation Increases Production of Growth Factors, like b a Elongin C Elongin B Cul 2 Regulates how the cell sees its surroundings Regulates p5 Controls the primary cilium Impacts blood vessel formation Transcription of: Other angiogenic factors Ohh et al, Mol Cell, Vol, , 998 Kurban et al, Cancer Res 26; 66: (). Roe and Youn Mol Cell May 26 Thoma et al Nature Cell Biology Aug 29 Kuehn et al Ca Res May 5, 27 Pugh et al Narture Medicine 2 Kerbel NEJM May 28 = vascular endothelial growth factor; HIF = hypoxia-inducible factor. Loss Results in Abnormal Production of Blood Vessels, Fueled by Can We Block The Consequences of Loss? Stromal cells -/- -/- Tumor cells -/-

3 A Clinical and Research Perspective Agents Exist or Are in Development That Block or Receptors Pazopanib Study: American Society of Clinical Oncology 27 Phase II Study of Pazopanib in Patients with von Hippel Lindau Sunitinib Pazopanib Axitinib Bevacizumab Eric Jonasch, Daniel Gombos2, Steven G. Waguespack, Valerie Marcott, Diane Liu5, Justin Weldon, Shelly Bird, Christine Robichaux, Nizar Tannir Ashley Woodson6, Gregory N. Fuller7, Ian E. Mccutcheon8 and Surena Matin9 Departments of Genitourinary Medical Oncology, Ophthalmology2, Endocrinology, Investigational Therapeutics, Biostatistics5, Cancer Genetics6, Pathology7, Neurosurgery8 and Urology9 at the UT M. D. Anderson Cancer Center, Houston, TX RESULTS PATIENT PATIENT CHARACTERISTICS INTRODUCTION Swimmers plot of response by organ site RESULTS RESULTS Examples of organ specific response Dosing and reason for treatment discontinuation von Hippel Lindau disease () is an autosomal dominant disorder. Affected individuals develop vascular neoplastic lesions in multiple sites including the eye, brain, pancreas, adrenal and kidney. Standards of care includes surveillance imaging and surgical intervention. We hypothesized that treatment of related lesions with an antiangiogenic agent would result in shrinkage of all lesion types. We chose the multikinase inhibitor pazopanib to test this hypothesis. Stromal cells Tumor cells -/- Number of patients (%) (2) 8 (58) Total evaluable CR PR SD PD Inevaluable Best response by organ site Renal (%) Lesion Number CR 59 2 () CNS(%) Pancreas (%) 7 9 PR 29 (5) 2 () 9 (5) SD 28 (7) 7 (96) 8 (7) PD Pazopanib: Tumor Response Time to response per organ site and duration of treatment per patient. Median duration of treatment was six months. Diarrhea Fatigue Aspartate aminotransferase increased Alanine aminotransferase increased Skin hyperpigmentation Hypertension Nausea Dysgeusia Proteinuria Mucositis Leukopenia Alopecia Vomiting Platelet count decreased Hair pigment change Rash Anemia Alkaline phosphatase increased Creatinine increased Depression Epistaxis Hyperglycemia Hyperthyroidism Hypoalbuminemia Hypernatremia Hypocalcemia Hypokalemia Max Grade Max Grade 2 Max Grade N 2 6 Reason off therapy Transaminitis Other toxicities Progression Patient choice Ongoing treatment Death Patients treated with an alternate sunitinib schedule d CONCLUSIONS Max Grade This is the largest prospective disease specific therapeutic study presented to date. Pazopanib resulted in significant and sustained disease control for the majority of patients enrolled on the study, with shrinkage or stabilization in the kidney, pancreas and CNS, along with an acceptable safety profile. A number of patients remain on therapy, with continued response. This agent may be considered as an alternative to surgical intervention in patients with disease. If Is Broken, Cells Don t Control HIF Adverse Event Overall response rate -/- -/- Treatment emergent toxicities seen in at least percent of patients RESULTS METHODS Patients with clinical features or genetic confirmation of disease, with measurable lesions were treated with pazopanib 8mg PO daily for two 2-week cycles. Efficacy was determined by modified RECIST after two cycles, with overall response the primary endpoint. Patients had the option to continue therapy beyond 2 weeks. Continuous monitoring for any lesion progression and drug discontinuation due to toxicity during the whole period of the treatment was planned. Dosing 8mg 6mg mg No dose received

4 If Is Broken, Cells Don t Control HIF If Is Broken, Cells Don t Control HIF If Is Broken, Cells Don t Control HIF Peloton HIF 2 Alpha Blocker Can we block HIF? 2977

5 Peloton HIF 2 Alpha Blocker Peloton HIF 2 Alpha Blocker A clinical trial is being developed to test 2977 in patients! Peloton HIF 2 Alpha Blocker 2977 is a next-generation HIF2a blocker that is administered in pill form. A study will be launched in 28 to test the effect of 2977 on kidney and other manifestations in individuals with. Alliance Research Funding Primary goal of study will be to see whether kidney tumors shrink- will also assess impact in other sites.

6 Alliance Research Funding Preproposal Requests (May-June) Over million dollars given for research! Review committee consisting of world leaders in research. Strong emphasis on translational research which will benefit patients sooner rather than later. Invitation for Full Review (July) Full Proposal Submission (August) Peer Review and Selection Vetted by internationally recognized experts 2 Full Project Awardee Basic Science Models and Novel Therapeutics Screening Tools Imaging Technology Othon Iliopoulos Dept. Oncology Massachusetts General Hospital, Boston MA

7 Zebrafish are tiny fish that can be genetically modified. mutation in zebrafish can represent aspects of human biology. Dr. Iliopoulos used zebrafish to discover new drugs that may rescue consequences of mutation. Work is almost complete and will be published soon. 25 Pilot Project Awardee Salivary, plasma metanephrines and anxiety levels in pheochromocytomas (STRESS) A.N.A van der Horst-Schrivers Department of Endocrinology University Medical Center Groningen Screening Tools Approach and Significance Screening Tools 25 Full Project Awardee Models The team will assess salivary metanephrine levels and compare to blood levels to determine accuracy If measurement of salivary metanephrines is just as accurate as blood metanephrines, then this approach will be more time and cost effective for patients/germline mutation carriers and for the treating medical team. Using a novel mouse model of ccrcc to investigate Hif-α and Hif-2α inhibition for cancer prevention and therapy Prof. Dr. Ian J. Frew Institute of Physiology, University of Zurich

8 Rationale Approach and Significance Clear cell renal cell carcinomas (ccrcc) that arise frequently in patients with von Hippel-Lindau () disease. The generation of mouse models has been a powerful tool used by scientists to not only understand the genetic causes and biological behaviour of tumors but also to test new therapies that can guide subsequent drug trials in human patients. Dr. Frew and his team have recently generated a very good mouse model of ccrcc, possibly the first that truly represents what happens in patients. They will use mouse ccrcc model to determine whether drug treatment can prevent the formation of new tumors and efficiently treat existing tumors. They will test available compounds that block HIF. If successful, this will allow us to more rapidly screen for new drugs that can treat kidney cancer. 26 Pilot Project Awardee IT Sharing International Consortium (VISIon) Raymond Kim PI University of Toronto Rationale We lack consolidated databases that aggregate information on genotypephenotype correlations. By creating such a database, it will advance our ability understand why we see specific patterns of manifestations in patients.

9 Approach and Significance Dr. Kim will develop an interactive database to collect genotypic and phenotypic data on patients worldwide. 26 Full Project Awardee ips model for Retinal Hemangioma Pathogenesis By performing this work, Dr. Kim s team will create a template that will allow more rapid collection of genotypes and phenotypes, and will contribute to our understanding of how mutations affects patients. Michael Gorin, MD, PhD UCLA Rationale Significance No good models currently exist for hemangioblastomas. Induced progenitor stem cells are cells that can be modulated to develop specific cell types, including those from the eye. Knockout of the Vhl gene in specific regions of a mouse is possible using specific gene modulating techniques. If successful, this model will provide a representative model of abnormal retinal cells in. This model will allow the Gorin team to test how retinal hemangiomas influence blood vessels in the eye, and to screen for potential strategies that will overcome blood vessel formation.

10 Origins Patient Natural History Study A patient-driven databank dedicated to finding a cure for, BHD, HLRCC, SDH, and related disorders Outcome of th International Medical Symposium (Houston, 22) A Research Council Collaborative effort includes National Organization of Rare Disorders (NORD) NORD = Software Provider A = bank Owner A Complementary Effort Joint effort between A and heath care professionals Complementary to existing institutional databanks Information best answered by patients, i.e. Lifestyle (diet, exercise, sleep, nutritional supplements, mood, altitude, oral health) De-identified data available to researchers Match participants within a specific research criteria Provide baseline data for clinical trial Goals Further understand natural history Longitudinal International study Wide range of genotype Study geographical differences Comprehensive patient-driven data Impact of lifestyle on disease progression and/or tumor growth rate Learn from all experimentation Learn from commonalities and differences between disorders

11 Features Privacy and Confidentiality: Primary concerns and factor built into CGIP Confidential/Secure IRB Approved curation process incorporated Online: no geographic limitations Language = English No age limitations Challenges Global support and participation by researchers Increased awareness among patients, BHD, HLRCC, SDH, etc. Increasing participation Patient follow-through Surveys Medical information 27 Grant Cycle Past Present and Future Basic Science Identification of the Gene Screening Tools Imaging Technology Determining how deficiency affect patients Developing new ways to treat disease