Kidney tumorgraft platform for precision medicine

Kidney cancer is the eighth most frequently diagnosed cancer in the U.S. Despite the development of new drugs to treat kidney cancer, it remains largely incurable when metastatic. Most Food and Drug Administration-approved drugs 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. Drug development for less frequent types has been limited by a lack of animal models suitable for preclinical studies. 

Described in a paper published in Cell Reports, the KCP platform includes a wide array of models for the scientific community. Over a decade, KCP researchers transplanted into mice tumors from 926 ethnically diverse patients generating a library of 172 tumorgraft lines.

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

KCP investigators previously showed that tumors in mice preserve the features of the cancer in patients. Patient tumors can be identified by a unique gene expression signature, which the tumors in mice maintain. “It is as if they remember from where they came. Tumors in mice are more similar to the donor patient than any two tumors from two different patients,” said co-lead author. “Tumors in mice also preserve the treatment responsiveness of kidney cancer in patients,” the author added.

The majority of the tumor models were characterized through next-generation sequencing and found to have both frequent as well as rarer cancer mutations.

PD-L1 and the related PD-1 are the target of most FDA-approved immunotherapies. “By visualizing PD-L1 in patient tumors using positron emission tomography (PET) imaging, we may be able to predict who is most likely to respond to treatment,” said the author.  

HIF-2α levels may similarly predict patients likely to respond to HIF-2α-targeting drugs. Two ongoing KCP clinical trials (NCT04006522NCT04989959) are currently evaluating these concepts.  

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

“Many of these mutations are infrequent, and we are only able to conduct this type of research because of the vastness of the resource,” said the author.

The tumorgraft platform builds upon 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 invested partners and are eager to advance research toward a cure,” said the author. “By making this catalog available to the broad scientific community, we are amplifying the impact of their giving.