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Last Updated: 09/08/21

Kidney Cancer SPORE

University of Texas Southwestern

Principal Investigator(s):

James Brugarolas, MD, PhD
James Brugarolas, MD, PhD

Principal Investigator(s) Contact Information

James Brugarolas, MD, PhD
Professor
Department of Internal Medicine, Oncology Division
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, TX 75390-8852
Tel: (214) 648-4059
Fax: (214) 648-1955

Overview

Kidney cancer continues to be a significant problem for adults and children. There are an estimated 400,000 people in the U.S. living with kidney cancer and many more worldwide. Over 60,000 new cases of kidney cancer are expected in the U.S. in 2016. Kidney cancer is one of the 10 most common tumor types in men and women and, for reasons that are poorly understood, is particularly prevalent in Texas. Despite remarkable advances leading to the approval by the FDA of multiple treatments since 2005, metastatic kidney cancer remains largely incurable. In children, kidney cancer (Wilms tumor) is curable in the majority of patients, but the treatment involves chemotherapy and often leaves lifelong debilitating effects.

The UTSW kidney cancer SPORE, one of two SPORE awards for kidney cancer in the U.S., leverages discoveries and technological innovation at UTSW to improve the treatment and diagnosis of kidney cancer.

Project 1: Evaluation of a promising new drug to treat kidney cancer

Project Co-Leaders:
James Brugarolas, MD, PhD
Kevin Courtney, MD, PhD
Ivan Pedrosa, MD, PhD

Project 1 evaluates a novel drug that blocks, arguably, the main driver of kidney cancer, the HIF-2a protein. HIF-2a is activated by mutations in VHL, which occur frequently in both sporadic and familial kidney cancer. HIF-2a was originally discovered at UTSW. Atomic studies, also performed at UTSW, found a vulnerability in the HIF-2a structure. Chemicals were identified that exploited this vulnerability. They were licensed to Peloton Therapeutics Inc., a company founded by UTSW scientists in the UTSW BioCenter, which developed several drugs (PT2385 and PT2977). Peloton was acquired by Merck and in 2021, the FDA approved Belzutifan (PT2977), a first-in-class HIF-2a inhibitor. Belzutifan was approved for the treatment of kidney and other tumors in patients with germline mutations in VHL (VHL syndrome patients).

Project 2: Identification of new subtypes of kidney cancer

Project Co-Leaders:
Payal Kapur, MD
Thomas Carroll, PhD
Yonghao Yu, PhD

Discoveries at UTSW using next-generation sequencing led to the identification of a gene, BAP1, that is frequently mutated in kidney cancer. Subsequent studies, also performed at UTSW, showed that BAP1 loss is an important event in kidney cancer development. Furthermore, BAP1-deficient tumors are particularly aggressive and associated with poor prognosis. This project aims to understand how BAP1 inactivation causes kidney cancer and seeks to identify vulnerabilities that can lead to new treatments.

Project 3: Applying new technologies to determine the malignant potential of small kidney tumors

Project Co-Leaders:
Ralph DeBerardinis, MD, PhD
Ivan Pedrosa, MD, PhD
Vitaly Margulis, MD

The majority of small kidney tumors tend to grow slowly and may never impact patients' health. However, some tumors can be deadly and our ability to recognize them is poor. Project 3 evaluates an innovative platform developed at UTSW to identify aggressive tumors. The methodology exploits the observation that aggressive tumors have higher needs for nutrients to sustain their growth. Understanding how nutrients are used by aggressive tumors may, in addition, expose weaknesses that can be targeted with novel approaches.

Project 4: Investigating a new subtype of childhood kidney cancer

Project Co-Leaders:
James Amatruda, MD, PhD
Joshua Mendell, MD, PhD

Using next-generation sequencing technologies, UTSW investigators discovered a new subtype of childhood kidney cancer characterized by mutations in the DROSHA gene. Project 4 focuses on understanding how these mutations turn a normal kidney cell into a tumor cell and the identification of new, less toxic treatments.

Administrative Core

Core Directors:
James Brugarolas, MD, PhD
Arthur Sagalowsky, MD
Renée McKay, PhD

This is the organizing hub of the SPORE, providing both administrative support and scientific oversight. The administration works together with an outstanding External Advisory Board and a Patient Council.

Leveraging Biospecimen and Pathology Resources for Discovery and Innovation Core

Core Directors:
Payal Kapur, MD
Dinesh Rakheja, MD

This service coordinates the distribution of cancer specimens donated by patients. The facility characterizes these specimens through genomic and other analyses and generates reagents that can be used to probe kidney cancer biology. For instance, kidney cancer samples from patients are transplanted into the kidney of mice, where they grow to form human cancer in mice.

Data Analytics Support Core

Core Directors:
Yang Xie, PhD
Tao Wang, PhD

This facility offers a centralized research design and data analysis platform that brings together the required expertise in biostatistics, bioinformatics, clinical trials, and data management for the SPORE investigators. A centerpiece is Kidney Cancer Explorer, an online database that links cancer specimens to clinical and genomic information.

Imaging Innovations in Translational Research Core

Core Directors:
Ivan Pedrosa, MD, PhD
Robert Lenkinski, PhD

This Core provides imaging (radiology) services for the evaluation of kidney cancer in patients and animal models. It supports a web-based centralized archive for all projects.

Developmental Research Program

This program provides seed funds to support innovative, high-impact, translational kidney cancer research projects.

Career Enhancement Program

This program provides seed funding to nurture talented new investigators that may become the next generation of kidney cancer researchers.