SPORE-funded Kidney Cancer Program at UT Southwestern Reports Wide Range of Tumor Models to Date

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Funded by a National Cancer Institute (NCI) Specialized Program of Research Excellence (SPORE) award, the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern’s Kidney Cancer Program (KCP) features the largest and most diverse catalog of kidney cancer tumor models. nowadays.

Kidney cancer is the eighth most commonly diagnosed cancer in the United States. Despite the development of new drugs to treat kidney cancer, it remains largely incurable when it is metastatic. Most of the drugs approved by the Food and Drug Administration were developed to treat clear cell renal cell carcinoma, the most common form of kidney cancer, but there are more than a dozen other types. The development of drugs for less common types has been limited by a lack of animal models suitable for preclinical studies.

Described in an article published this week in Cell reports, the KCP platform includes a wide range of models for the scientific community. Over a decade, KCP researchers transplanted tumors from 926 patients of various ethnic origins at UT Southwestern Medical Center and its affiliate Parkland Memorial Hospital into mice, generating a library of 172 tumor graft lines.

By transplanting tumor samples from intact, preservative-free patients taken in the operating room directly into mouse kidneys within an hour or two of surgery, KCP researchers are able to generate tumors closely mirroring the human kidney cancer.

KCP researchers have previously shown that tumors in mice preserved characteristics of cancer in patients. Patients’ tumors can be identified by a unique gene expression signature, which tumors in mice maintain. “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, former researcher from the laboratory of James Brugarolas, MD, Ph.D., professor of internal medicine, division of hematology and oncology, and director of the KCP. “Tumors in mice also preserve responsiveness to treating kidney cancer in patients,” he added.

The majority of tumor models have been characterized by next-generation sequencing and have been found to have both frequent and rarer cancer mutations.

“This platform goes beyond conventional models to become models that closely mimic the range of human kidney cancers,” said Kimryn Rathmell, MD, Ph.D., former chair of the Cancer Research Program Integration Group Kidney Fund from the Department of Defense, the largest funder of kidney cancer research in the world.

“This resource also helps provide more precise and personalized treatment to patients,” said Vanina Tcheuyap, MS, co-lead author and research associate at the Brugarolas laboratory who oversees the platform.

KCP researchers have previously deployed 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, recently approved by the FDA. Using the same platform, the researchers also predicted HIF-2ɑ resistance mutations, which they then confirmed in patients.

This resource will help accelerate the discovery and advancement of transformative concepts. “

Dr Rathmell, Chairman of the Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

The same resource has been used by KCP investigators to advance precision diagnostics and has supported two FDA approvals of new investigational drugs (INDs). “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 Cyclotron and Radiochemistry program at UTSW.

PD-L1 and associated PD-1 are the targets of most FDA approved immunotherapies. “By visualizing PD-L1 in patients’ tumors using positron emission tomography (PET) imaging, we might be able to predict who is most likely to respond to treatment,” said the Dr Sun.

HIF-2α levels can also predict patients likely to respond to drugs targeting HIF-2α. Two ongoing KCP clinical trials (NCT04006522, NCT04989959) are currently evaluating these concepts.

The researchers are also deploying the platform to develop second-generation HIF-2α drugs, as well as to determine whether anti-cancer drugs approved by the FDA for other tumor types may work against kidney cancers with particular mutations that can make them vulnerable.

“Many of these mutations are infrequent, and we can only do this type of research because of the vastness of the resource,” said Tcheuyap.

The tumor transplant platform builds on KCP’s commitment to advancing new therapies, from drug discovery to the design of new clinical trials.

“This resource would not have been possible without our patients, who are committed partners and keen to advance research towards a cure,” said Dr Brugarolas. “By making this catalog available to the scientific community at large, we are amplifying the impact of their donations.” He added: “Developing and sustaining such a platform requires a substantial commitment, and I am grateful to our funding agencies, the NCI, the American Cancer Society, and the Cancer Prevention and Research Institute of Texas ( CPRIT), as well as to Ms. Tcheuyap and the research staff who have maintained and developed this platform over the past decade. ”

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UT Southwestern Medical Center


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