Validating HIF-2 as a target for ccrcc

Transcription

1 COI: Patent HIF2 biomarker Research funding Peloton Therapeutics Development of a HIF2 inhibitor (HIF2I) Validating HIF2 as a target for ccrcc HighThroughput Screen Scheuermann et al. Nat Chem Biol 2013 HIF2I Scheuermann et al. PNAS 2009 HIF2 B B HIF1 HIF2 HIF1 PT2399 A A >100 lines HRE (DNA) HRE (DNA) PaviaJimenez et al., Nat Protoc

2 Validating HIF2 as a target HIF2I (PT2399) is active against human ccrcc transplants in mice Vehicle Human tumors in mice do they reproduce: Histological appearance? Gene expression? Unsupervised Mutations? hierarchical clustering of gene expression shows similarities between tumors and corresponding tumorgrafts DNA copy number alterations? Treatment responsiveness? Tumor volume (mm 3 ) Days Sunitinib HIF2I Sivanand et al., Sci Transl Med 2012 Adapted from Sivanand et al., Sci Transl Med 2012 Intermed. Sensitive HIF2I is active in 50% of ccrcc Vehicle Sunitinib HIF2I HIF2I (PT2399) has greater activity than sunitinib and is better tolerated Resistant 267 mice from 22 independently derived TG lines (18 ccrcc) 2

3 HIF2I (PT2399) inhibits proliferation & angiogenesis in sensitive ccrcc HIF2I (PT2399) suppresses VEGF only in the tumor XP169 XP490 XP164 XP373 vehicle HIF2 I V4237 V4236 V4234 V4241 V3290 V3294 V3287 V3281 V3212 V3224 V3210 V3214 XP373 Ki67 CD31 H&E XP373 XP144 veh HIF2I veh HIF2I Circulating Human VEGF (tumor) Circulating Mouse VEGF (host) V5239 V5229 P5231 P5240 HIF2I (PT2399) dissociates HIF2 in both sensitive & resistant tumors HIF2I (PT2399) is a highly specific inhibitor Sensitive Resistant Veh v HIF2I Veh v HIF2I Up RESISTANT SENSITIVE Relative mrna expression Relative mrna expression hvegf SERPINE1 IGFBP3 CCND1 TGFA SLC2A1 Vehicle HIF2I Sunitinib Down Total Differential Gene Expression Sensitive Resistant Veh HIF2I Veh HIF2I 3

4 Higher HIF2 in sensitive tumors Identification of biomarkers of HIF2dependency HIF2α HIF1α HIF2α HIF1α RNAseq XP374 XP469 XP164 XP530 XP462 XP490 HIF2 Percentage positive cells Tumor Volume (mm 3 ) Acquired resistance? XP164 V3286 P IP HIF1 Forward 3283 HIF2I Sunitinib Veh V1849 P Reverse Forward Reverse G323E (HIF2 ) F446L (HIF1 ) HIF2 and HIF1 mutants preserve HIF complexes despite HIF2I (PT2399) FLAGHIF1 FLAGHIF1 (F466L) HAHIF2 HAHIF2 (G323E) Input IP FLAG Vehicle PT2399 Vehicle PT2399 HA Input postresistance preresistance vehicle HIF2I FLAG V3290 V3294 V3298 P3297 P3283 P3288 V3290 V3294 V3298 P3297 P3283 P3288 Tubulin HIF 2 HIF 1 Tubulin HIF1 HIF2 4

5 Baseline Characteristics Pharmacokinetics & Pharmacodynamics Toxicity Targeted C min of 280 ng/ml exceeded at 400 mg b.i.d. Increased exposure up to 800 mg b.i.d. (no further increase beyond 800 mg b.i.d.) 5

6 Duration of Treatment Prolonged stable disease in heavily pretreated patient (7 prior lines) PT Days Liver Kidney Pelvis Higher exposure correlates with antitumor activity 6

7 Second generation inhibitor, PT2977 greater potency in preclinical models PT2977 Phase I PT2977 Phase I Pharmacokinetics PT2977 Pharmacodynamics PT2385 Slide 13 7

8 Response Duration Responses in ccrcc PT2977 VHL pts RCC University of Colorado Cancer Center June 6, 2018 Aurora, Colorado, United States, Yale Cancer Center New Haven, Connecticut, United States, National Institutes of Health Clinical Center Recruiting Bethesda, Maryland, United States, Massachusetts General Hospital Recruiting Boston, Massachusetts, United States, University of Michigan Recruiting Ann Arbor, Michigan, United States, Memorial Sloan Kettering Cancer Center New York, New York, United States, Wake Forest Winston Salem, North Carolina, United States, University of Pennsylvania Medical Center Philadelphia, Pennsylvania, United States, University of Pittsburgh Medical Center Inclusion Pittsburgh, Criteria: Pennsylvania, United States, von Vanderbilt Hippel Medical Center Lindau disease Recruiting with a germline VHL Nashville, Tennessee, United States, mut. UT Southwestern Medical Center Dallas, Texas, United States, At least 1 measurable solid RCC tumor MD Anderson Cancer Center Recruiting (diagnosis Houston, Texas, United of States, RCC can be radiologic). Huntsman Cancer Institute Recruiting VHL Salt Lake diseaseassociated City, Utah, United States, tumors in other organ Aarhus University Hospital systems. Aarhus, Denmark Exclusion Hospital Georges Criteria: Pompidou Paris, France Prior University systemic Medical Center Utrecht anticancer Not yet therapy recruiting (includes anti Utrecht, Netherlands VEGF therapy and investigational agents). Cambridge University Hospitals Immediate Cambridge, United Kingdom need for surgical intervention for tumor Guy's and St. Thomas' Hospitals treatment. London, United Kingdom Christie NHS Foundation Trust Metastatic disease. Manchester, United Kingdom Conclusions HIF2 is a valid target in ccrcc. Inhibition of the HIF2 transcription factor abrogates tumor growth in >50% of human ccrcc tumors implanted in mice, including tumors resistant to sunitinib. HIF2I effectively (and specifically) dissociates HIF2 from HIF1 in human ccrcc implanted in mice. HIF2 inhibition results in the downregulation of HIF2 target genes and decreased circulating levels of tumorproduced VEGF. HIF2 inhibitors are more effective and better tolerated than sunitinib in TG models. Primary resistance occurs despite dissociation of the HIF2 complex in tumors. Sensitive and resistant tumors can be distinguished by HIF2 levels and gene expression. Resistance develops in sensitive tumors due to binding site and secondsite suppressor mutations. A Phase I clinical trial of PT2385 showed that HIF2 inhibitors are safe and may benefit a subset of patients, but resistance develops. Second generation inhibitors (PT2799) have greater potency. HIF2 inhibitors are well tolerated and associated with anemia. Close monitoring for hypoxia is needed (which can be severe). Photo, courtesy of Brian Coats 8

9 Brugarolas Lab Alana Christie Roy Elias Adrien Jump Eric Ma Renee McKay Tiffani McKenzie Oreoluwa Onabolu Gopinath Prakasam Nirmish Singla Christina Stevens Vanina Toffessi Layton Woolford Juan Yang Hui Ye Xiaolin Zhu Wenfang Chen Shannon Cohn Yifeng Gu Haley Hill Allison Joyce Blanka Kucejova Andrea PaviaJimenez Samuel PeñaLlopis Sharanya Sivanand Tram Anh Tran Silvia VegaRubin de Celis Shanshan Wang Nick Wolff Toshinari Yamasaki Anum Yousuf Avery Anderson Megan Dougherty Debbie Harvey Marieshia Hicks Chey Reynolds Illumina Inc. Mark Ross David Bentley Mayo Clinic Richard W. Joseph Daniel J. Serie Jeanette EckelPassow Thai Ho John C. Cheville Alexander Parker Genentech Anwesha Dey Steffen Durinck Eric W. Stawiski Zora Modrusan Sekar Seshagiri NCI Laura Schmidt Marston Linehan Other Collaborators Kevin Jones Brian Rini UTSW Collaborators Laura Banaszynski Tom Carroll Ralph DeBerardinis Bob Hammer Lisa Kinch Sri Malladi Josh Mendell Bruce Posner Noelle Williams Jin Ye Yonghao Yu Kidney Cancer Program Urology Aditya Bagrodia Jeff Cadeddu Jeff Gahan Yair Lotan Vitaly Margulis Ganesh Raj Arthur Sagalowsky Medical Oncology Yull Arriaga Alex Bowman Kevin Courtney Eugene Frenkel Hans Hammers Radiation Oncology Neil Desai Michael Folkert Raquibul Hannan Robert Timmerman Zabi Wardak Pathology Payal Kapur Dinesh Rakheja Radiology Alberto Diaz de Leon Ananth Madhuranthakam Ivan Pedrosa Xiankai Sun Lori Watumull Phase 1 Trial (PT2385) Kevin Courtney Jeffrey Infante Elaine Lam Robert Figlin Brian Rini Naseem Zojwalla Keshi Wang Eli Wallace John Josey Toni Choueiri Bioinformatics Min Kim Satwik Rajaram Phillip Reeder Tao Wang Jason Xie Guanghua Xiao Yang Xie He Zhang Clinical Coordinators Jenny Chang Dendra Von Merveldt Funding Virginia Murchison Linthicum Endowment Cancer Prevention and Research Institute of Texas NIH, National Cancer Institute Peloton Therapeutics, Inc 9