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What makes some cancers metastasize and spread or become resistant to treatment?

Researchers at MD Anderson developed a model to predict when renal cell carcinoma (RCC), the most common type of kidney cancer, might become metastatic and stop responding to treatment based on the loss of a specific cluster of genes in the cancer cell chromosomes. The study was published recently in the journal Nature Cancer.

“Until now, there haven’t been effective experimental models for metastatic renal cancer progression, but we introduced specific mutations that closely mimic the early stages of human cancers to see how tumors evolve and metastasize,” said one of the primary investigators Dr. Giannicola Genovese, professor of Genitourinary Medical Oncology at MD Anderson in a press release.

“These tumors become extremely genomically unstable, and, to tolerate this instability, they tend to lose genetic material at a specific site where the interferon genes are located. These insights can help clinicians identify tumors that have the genomic potential to become aggressive.”

About a third of people with RCC will experience aggressive disease progression despite effective surgical and drug treatment strategies, including breakthrough new immunotherapy combinations.

Genovese and colleagues found that a cluster of interferon receptor (IFNR) genes were consistently missing from chromosomes in aggressive RCC. These genes normally act as tumor suppressors and control cancerous growth.

IFNR genes also contribute to the body’s immune response. Lacking these genes, RCC cells may more easily evade the targeted, elevated immune response that is the hallmark of immunotherapy.

This research was funded by a 2018 research grant awarded to Dr. Pavlos Msaouel, a clinician and cancer biologist in the Department of Genitourinary Medical Oncology at MD Anderson, in addition to other funding support.

At that time, Msaouel and his research group were interested in developing new therapies for patients with rare, aggressive kidney cancers, specifically renal medullary carcinoma (RMC). In the process, Msaouel and his group developed cell lines, animal models, and tissue biobanks that helped in the discovery and validation phases.

A large portion of what they sought to understand were how, why, and when aggressive kidney cancers were resistant to treatment.

“Rare kidney cancers in many ways are ‘Rosetta Stones’ for cancer biology,” Msaouel said. “Our research is driven by the understanding that rare kidney cancers such as RMC are orphan diseases but what drives them are not orphan principles. Studying them gives us fundamental insights that can help patients with these rare diseases, who are in dire need for better options, but can also be of service to those with more common kidney cancers. I find that to be one of the most exciting and fulfilling aspects of studying rare tumors. Everyone gains from this.”

Masouel received an initial research award in 2017 and went on to receive a$500,000 Advanced Discovery Award from the KCA in 2021 supporting a project to identify whether patients will to immunotherapy, which could spare patients unnecessary treatment exposure.

Building on these findings, further exploration of the INFR pathway could reveal it as a predictive biomarker of metastatic RCC and lead the way to improved treatments for a variety of people with RCC.

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