1 http://www.utsouthwestern.edu/kidneycancer COI: Patent HIF-2 biomarker Research funding – Peloton Therapeutics Scheuermann et al. PNAS 2009 B A B A HRE (DNA) HIF-2HIF-1HRE (DNA) HIF-1HIF-2Scheuermann et al. Nat Chem Biol 2013 High-Throughput Screen HIF2-I Development of a HIF-2 inhibitor (HIF2-I) PT2399 Validating HIF-2 as a target for ccRCC Pavia-Jimenez et al., Nat Protoc 2014 >100 lines
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COI: Patent HIF-2 biomarker Research funding –Peloton ... · COI: Patent HIF-2 biomarker Research funding –Peloton Therapeutics Scheuermann et al. PNAS 2009 B A B A HRE (DNA)
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VEGF therapy and investigational agents).• Immediate need for surgical intervention for tumor
treatment.• Metastatic disease.
University of Colorado Cancer Center Not yet recruitingAurora, Colorado, United States, 80045Yale Cancer Center Not yet recruitingNew Haven, Connecticut, United States, 06519National Institutes of Health Clinical Center RecruitingBethesda, Maryland, United States, 20892Massachusetts General Hospital RecruitingBoston, Massachusetts, United States, 02114University of Michigan RecruitingAnn Arbor, Michigan, United States, 48109Memorial Sloan Kettering Cancer Center Not yet recruitingNew York, New York, United States, 10065Wake Forest Not yet recruitingWinston‐Salem, North Carolina, United States, 27103University of Pennsylvania Medical Center Not yet recruitingPhiladelphia, Pennsylvania, United States, 19104University of Pittsburgh Medical Center Not yet recruitingPittsburgh, Pennsylvania, United States, 15232Vanderbilt Medical Center RecruitingNashville, Tennessee, United States, 37232UT Southwestern Medical Center Not yet recruitingDallas, Texas, United States, 75239MD Anderson Cancer Center RecruitingHouston, Texas, United States, 77030Huntsman Cancer Institute RecruitingSalt Lake City, Utah, United States, 84112Aarhus University Hospital Not yet recruitingAarhus, DenmarkHospital Georges Pompidou Not yet recruitingParis, FranceUniversity Medical Center Utrecht Not yet recruitingUtrecht, NetherlandsCambridge University Hospitals Not yet recruitingCambridge, United KingdomGuy's and St. Thomas' Hospitals Not yet recruitingLondon, United KingdomChristie NHS Foundation Trust Not yet recruitingManchester, United Kingdom
June 6, 2018
Photo, courtesy of Brian Coats
Conclusions HIF-2 is a valid target in ccRCC. Inhibition of the HIF-2 transcription factor abrogates tumor growth in >50% of human
ccRCC tumors implanted in mice, including tumors resistant to sunitinib. HIF2-I effectively (and specifically) dissociates HIF-2 from HIF-1 in human ccRCC
implanted in mice. HIF-2 inhibition results in the downregulation of HIF-2 target genes and decreased
circulating levels of tumor-produced VEGF. HIF-2 inhibitors are more effective and better tolerated than sunitinib in TG models. Primary resistance occurs despite dissociation of the HIF-2 complex in tumors. Sensitive and resistant tumors can be distinguished by HIF-2 levels and gene
expression. Resistance develops in sensitive tumors due to binding site and “second-site
suppressor mutations.” A Phase I clinical trial of PT2385 showed that HIF-2 inhibitors are safe and may benefit
a subset of patients, but resistance develops. Second generation inhibitors (PT2799) have greater potency. HIF-2 inhibitors are well tolerated and associated with anemia. Close monitoring for
hypoxia is needed (which can be severe).
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Brugarolas LabAlana Christie
Roy EliasAdrien Jump
Eric MaRenee McKay
Tiffani McKenzieOreoluwa OnaboluGopinath Prakasam
Nirmish Singla Christina Stevens Vanina Toffessi Layton Woolford
Juan YangHui Ye
Xiaolin Zhu
Wenfang ChenShannon Cohn
Yifeng GuHaley Hill
Allison JoyceBlanka Kucejova
Andrea Pavia-JimenezSamuel Peña-LlopisSharanya Sivanand
Tram Anh TranSilvia Vega-Rubin de Celis
Shanshan WangNick Wolff
Toshinari YamasakiAnum Yousuf
Avery Anderson Megan Dougherty
Debbie HarveyMarieshia HicksChey Reynolds
FundingVirginia Murchison Linthicum Endowment
Cancer Prevention and Research Institute of TexasNIH, National Cancer Institute
Peloton Therapeutics, Inc
Kidney Cancer ProgramUrology
Aditya Bagrodia Jeff CadedduJeff GahanYair Lotan
Vitaly MargulisGanesh Raj
Arthur Sagalowsky
Medical OncologyYull Arriaga
Alex BowmanKevin CourtneyEugene FrenkelHans Hammers
Radiation OncologyNeil Desai
Michael FolkertRaquibul Hannan
Robert TimmermanZabi Wardak
PathologyPayal Kapur
Dinesh Rakheja
RadiologyAlberto Diaz de Leon
Ananth Madhuranthakam Ivan PedrosaXiankai Sun
Lori Watumull
Illumina Inc. Mark Ross
David Bentley
Mayo ClinicRichard W. Joseph
Daniel J. SerieJeanette Eckel-Passow
Thai HoJohn C. ChevilleAlexander Parker
GenentechAnwesha Dey
Steffen DurinckEric W. StawiskiZora ModrusanSekar Seshagiri