Renal cell carcinoma of clear cell type (ccRCC), the most common type, is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which is observed in >85% of tumors. Because no other gene is mutated at a similar frequency, and VHL mutations are a known initiating event, VHL loss is regarded as the governing event in ccRCC development. Loss of VHL activates HIF-2, which is sufficient to reconstitute tumor development in ccRCC cell lines restored with VHL. Arguably, HIF-2 is the most attractive target for drug development in ccRCC. HIF-2 is implicated in cell survival, proliferation, pluripotency and angiogenesis. Among these pathways, only angiogenesis is targeted clinically, today. Targeting HIF-2 would disrupt multiple pro-oncogenic pathways simultaneously, but as a transcription factor, HIF-2 is considered undruggable. HIF- 2 is an obligatory heterodimer of a constitutive HIF-1? subunit?and a regulated HIF-2? subunit, which was discovered at UT Southwestern Medical Center (UTSW). Detailed structural studies of HIF-2??at UTSW identified a 2803 cavity within the PAS-B domain, a domain implicated in heterodimerization. Despite the fact that this cavity is buried, UTSW investigators determined that it was accessible and hypothesized that it may provide a foothold for a small molecule. Such a molecule may induce conformational changes transmitted to the surface of the domain disrupting the interaction with HI F-1? and antagonizing HIF-2 function. Proof-of-principle experiments confirmed this idea and an ingenious high-throughput screen involving 200,000 compounds led to the identification of small-molecule inhibitors of HIF-2 heterodimerization. The lead compound was optimized through medicinal chemistry efforts at UTSW and was subsequently licensed to Peloton Therapeutics, Inc., a company founded by UTSW investigators and located in the UTSW BioCenter. Peloton has developed this compound into a highly-potent and selective inhibitor of HIF-2 (HIF2-I) with appropriate pharmacokinetic properties and oral bioavailability. This drug induces regression of established ccRCC cell line xenografts, and preliminary experiments show remarkable activity in some patient-derived xenografts (PDX)/tumorgraft models. However, not every ccRCC tumorgraft responds.
The aims of this project are: (i) to identify a biomarker of HIF-2 dependency in ccRCC, (ii) to anticipate mechanisms of acquired resistance to HIF2-I, and (iii) to evaluate multiparametric MR imaging as a pharmacodynamic biomarker in a first-in-human phase I clinical trial of this first-in-class HIF2-I in metastatic ccRCC patients. The successful development of an inhibitor against HIF-2 serves as a paradigm for innovation. To our knowledge, this is the first isoform-specific inhibitor of a transcription factor of the non- nuclear hormone receptor family. This illustrates how ground-breaking basic science discoveries can be translated into innovative drugs through successful academic-industry partnerships.

Public Health Relevance

Arguably, the most important driver of kidney cancer development is the HIF-2? protein, which heretofore has been considered ?undruggable.? HIF-2?, discovered and characterized at the atomic level by UT Southwestern scientists, was found to have a structural feature that could be exploited to develop a drug. Through ingenuity and perseverance a highly potent first-in-class drug was developed that will be evaluated for its activity against renal cancer in mice and humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA196516-03
Application #
9537556
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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