DALLAS – November 29, 2021 – Funded by a Specialized Program of Research Excellence (SPORE) Award from the National Cancer Institute (NCI), the Kidney Cancer Program (KCP) at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern reports on the largest and most diverse catalog of kidney cancer tumor models to date.
Roy Elias, MD
Kidney cancer is the eighth most diagnosed cancer in the US Despite the development of new drugs to treat kidney cancer, it remains largely incurable if metastasized. Most of the drugs approved by the Food and Drug Administration are designed to treat clear cell renal cell carcinoma, the most common type of kidney cancer, but there are more than a dozen other types. The development of drugs for less common types has been limited by the lack of animal models suitable for preclinical studies.
Described in an article recently published in Cell Reports, the KCP platform encompasses a wide range of models for the scientific community. Over a decade, KCP researchers transplanted tumors from 926 ethnically diverse patients at UT Southwestern Medical Center and the affiliated Parkland Memorial Hospital into mice, creating a library of 172 tumor graft lines.
By directly transplanting into intact, preservative-free tumor samples from patients taken from the operating room within an hour or two of surgery, KCP researchers can create tumors very similar to human kidney cancer.
Vanina Tcheuyap, MS
KCP researchers previously showed that tumors in mice preserve the characteristics of the cancer in patients. Patient tumors can be identified by a unique gene expression signature that the tumors perpetuate in mice. “It’s like they remember where they came from. Tumors in mice are more similar to the donor patient than two tumors from two different patients, ”said co-lead author Roy Elias, MD, a former researcher in the lab of James Brugarolas, MD, Ph.D., Professor of Internal Medicine, Department of Hematology and Oncology and director of the KCP. “Tumors in mice also preserve the response to treatment for kidney cancer in patients,” he added.
The majority of tumor models were characterized by next-generation sequencing and showed both frequent and rarer cancer mutations.
“This platform skips conventional models to models that accurately replicate the spectrum of human kidney cancer,” said Kimryn Rathmell, MD, Ph.D., former chair of the integration committee for the Department of Defense Kidney Cancer Research Program, the largest kidney cancer research funder in the world.
“This resource also provides an opportunity to offer patients more precise, personalized treatment,” said Vanina Tcheuyap, MS, co-lead author and research fellow at the Brugarolas laboratory who oversees the platform.
UTSW Kidney Cancer Program tumor graft platform
KCP researchers have previously used this resource to advance precision medicine. In an article published in Nature in 2016, they used the platform to test a new type of kidney cancer drug, HIF-2α inhibitors, that was recently approved by the FDA. Using the same platform, the researchers also predicted HIF-2ɑ resistance mutations, which they later confirmed in patients.
“This resource will help accelerate the discovery and advancement of transformative concepts,” said Dr. Rathmell, who is also the chairman of the medical school at Vanderbilt University Medical Center in Nashville, Tennessee.
The same resource was used by KCP researchers to advance precision diagnostics and support two IND approvals by the FDA. “We used these tumor graft models to validate the radiotracers we developed for the non-invasive assessment of PD-L1 and HIF-2α,” said Dr. Xiankai Sun, Ph.D., Professor of Radiology and Director of the UTSW Cyclotron and Radiochemistry Program.
PD-L1 and its related PD-1 are the target of most FDA-approved immunotherapies. “By visualizing PD-L1 in patient tumors using positron emission tomography (PET), we may be able to predict who is most likely to respond to treatment,” said Dr. Sun.
HIF-2α levels can similarly predict that patients are likely to respond to HIF-2α-targeted drugs. Two ongoing clinical studies on KCP (NCT04006522, NCT04989959) are currently evaluating these concepts.
Researchers are also using the platform to develop second-generation HIF-2α drugs and see if FDA-approved anticancer drugs for other types of tumors can work against kidney cancer with certain mutations that may make them vulnerable.
“Many of these mutations are rare and we can only do this type of research because of the size of the resource,” said Ms. Tcheuyap.
The Tumorgraft Platform builds on the KCP’s commitment to advancing novel therapeutics, from drug discovery to the design of novel clinical trials.
“This resource would not have been possible without our patients, who are committed partners and eager to advance research toward a cure,” said Dr. Brugarolas. “By making this catalog available to the broader scientific community, we are enhancing the impact of your donations.” He added, “Developing and maintaining such a platform requires significant dedication, and I am with our funding agencies NCI, the American Cancer Society and the Cancer Prevention and Research Institute of Texas (CPRIT) as well as Ms. Tcheuyap and the cadres of researchers who have maintained and expanded this platform over the past ten years. “
Dr. Brugarolas holds the Sherry Wigley Crow Cancer Research Endowed Chair in honor of Robert Lewis Kirby. Dr. Sun holds the Dr. Jack Krohmer Professorship for Radiation Physics.
UT Southwestern co-authors include: Akash Kaushik, Nirmish Singla, Ming Gao, Oscar Torras, Alana Christie, Aditi Mulgaonkar, Layton Woolford, Christina Stevens, Kavitha Kettimuthu, Andrea Pavia-Jimenez, Lindsey Boroughs, Allison Joyce, Marianna Dakanali , Hollis Notgrass, Vitaly Margulis, Jeffrey Cadeddu, Ivan Pedrosa, Noelle Williams, Ralph DeBerardinis, Orhan Oz, Hua Zhong, Zora Modrusan, Brandi Cantarel and Payal Kapur.
This work was supported by grants from the American Cancer Society (115739), the National Institutes of Health (P50CA196516, R35CA22044901), CPRIT (RP170638, RP110771), and the Simmons Cancer Center (P30CA142543). Genomic studies were mainly funded by Genentech / Roche. Authors’ statements are contained in the manuscripts referenced in this press release. UTSW retains a financial interest in approvals and first-time sales of some HIF-2ɑ inhibitors.
Via the UT Southwestern Medical Center
UT Southwestern, one of the leading academic medical centers in the country, integrates groundbreaking biomedical research with exceptional clinical care and training. The institution’s faculty has won six Nobel Prizes and includes 25 members from the National Academy of Sciences, 16 members from the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty, with more than 2,800 employees, is responsible for breakthrough medical advances and is committed to quickly translating science-based research into new clinical treatments. UT Southwestern doctors care for more than 117,000 hospital patients, more than 360,000 emergency rooms in approximately 80 specialties, and oversee nearly 3 million outpatient visits per year.