University of Texas Southwestern Medical Center SPORE in Kidney Cancer

Overall Summary
Particularly prevalent in Texas, renal cell carcinoma (RCC) is lethal when metastatic. To address this unmet
medical need, the UTSW Kidney Cancer SPORE has developed a comprehensive therapeutic program in proven
(targeted therapies and immunotherapy) and innovative (metabolism-directed) areas. Arguably, the most
important driver of RCC is HIF2α. Discovered at UTSW, and regarded as undruggable, structural studies
revealed a vulnerability that was exploited through a chemical screen leading to the founding of Peloton
Therapeutics in the UTSW BioCenter and the development of PT2385 and PT2977. During the previous funding
period, Project 1 investigators validated HIF2α as a target, identified putative biomarkers of dependency,
executed a phase 1 trial, identified resistance mutations, and established HIF2α as a core dependency.
Culminating the vertical collaboration and program success, Peloton was acquired by Merck, and PT2977 (also
called belzutifan) gained FDA approval. During the next period, an innovative siRNA-based, second-generation
inhibitor targeting both wild-type and resistant mutant HIF2α will be co-developed together with a ground-
breaking imaging radiotracer enabling HIF2α evaluation in patients. Project 2 investigators exploit a profound
link between RCC and metabolism. Using pioneering isotope-labeled nutrient infusions, Project 3 investigators
established during years 1-5 that glutamine is a key nutrient fueling RCC growth in patients. In years 7-12, they
will deploy the authenticated In Vivo Metabolism Lab to target glutamine bypass pathways, likely explaining
the recent failure of glutaminase inhibitors. Finally, by leveraging Breakthrough Prize-recognized research at
UTSW leading to a new innate immune system-activating drug, Project 3 investigators propose a paradigm shift
in immunotherapy development involving the coordinated activation of the adaptive and innate arms (as it occurs
physiologically). Together with previously commended development and career-enhancing programs, SPORE
investigators are supported by four Cores. A forward-looking Administrative Core (Core A) serves as a hub. A
Pathology Core (Core B) brings to bear one of the largest and most sophisticated RCC tumor banks and
expertise supporting national efforts. A Data Analytics Core (Core C) assists with statistical support,
bioinformatics, and data management with an avant-garde tool that automatically extracts information from the
electronic medical record, self-updates, and links this information to experimental genomics and the tumor bank.
An Imaging Core (Core D) delivers enabling technologies, including IND-holding innovative tracers, and
unqualified expertise. Building upon the Simmons Comprehensive Cancer Center Kidney Cancer Program and
its history of collaborative, interdisciplinary cancer research, SPORE Projects and Cores provide an engine of
discovery, innovation, and translation supporting national and international efforts to advance patient care,
research, and education.

Grant Number: 5P50CA196516-09
NIH Institute/Center: NIH
Principal Investigator: James Brugarolas