Roughly one in four people with kidney cancer have a type that does not respond to targeted therapy drugs, leaving no proven treatment options for those whose tumors have started to spread.

“It’s very much an unmet need,” says George Thomas, M.D., whose research team has discovered a potential way to stop these cancers by combining two different targeted agents. Individually, neither drug has much impact. Working together, they suppress a key cancer signaling pathway and shrink tumors in animal models of the cancer, called non-clear cell renal cell carcinoma. The journal Cell Reports Medicine published the findings online today.

“Our goal is to find options for these patients who haven’t benefited from the newer, targeted therapies,” Thomas says. He is a professor of pathology in the OHSU School of Medicine and the Knight Cancer Institute.

^{Image: Embryonic kidney with proliferating cells by Lydia Michael and Linda Sharp (CC BY 4.0)}

The most common type of kidney cancer is called clear cell renal cell carcinoma because the tumor cells have a clear appearance. The tumor cells also have DNA errors that wipe out an important tumor-suppressor gene. Loss of that gene triggers a cascade of activity by other genes, which then drives tumor cells to multiply and spread primarily by making new blood vessels. A variety of drugs can block targets along these signaling pathways and suppress these cancers.

“With non-clear cell renal carcinoma, the tumors don’t have the same gene loss and that’s why they won’t respond much to these drugs,” Thomas says.

‘This work has opened up new avenues for drug combinations we would not have thought about before’

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The team centered their search on an existing drug called dasatinib. It’s an inhibitor that targets an enzyme, called SRC, that plays an important role in driving non-clear cell tumors. In fact, it’s one of the earliest tumor-causing genes discovered. But as a single agent therapy, dasatinib has been disappointing.

“It has some effect, but no major effect,” Thomas says. “But since SRC acts like a messaging hub for multiple cancers, we thought it still made a lot of sense if you could simultaneously target one of its signaling partners.”

The scientists set up a systematic way to test drugs given in combination with dasatinib. They screened nearly 300 compounds with help from the Oregon Translational Research and Development Institute for robotic, high-throughput drug screening. They narrowed the field down in a series of steps, based on how effectively each combination inhibited cancer cells grown in the lab.

Twenty-eight drugs made the cut for deeper screening, including testing in five different cell lines grown from human renal cell carcinomas. Cabozantinib emerged as the overall most active drug used in combination with dasatinib. Together, the two drugs produced a combined effect greater than the sum of their separate effects.

The combo held up in animal tests. The researchers tested the safety and effectiveness of cotreatment in two animal models in which kidney cancer cells are grafted into mice. Dasatinib and cabozantinib not only inhibited tumor growth, the combo also caused tumor regression in the mouse models – validating the soundness of the researchers’ screening strategy. The animals appeared to tolerate the combination with no weight loss recorded.

A deep statistical analysis of gene activity and protein expression data revealed how the combination might be achieving its synergistic effect: suppression of MAPK signaling, a key pathway in cell proliferation and differentiation.

“MAPK wasn’t on my radar,” Thomas says. He credits the contribution of co-author Laura Heiser, Ph.D., an associate professor of biomedical engineering in the OHSU School of Medicine whose lab uses experimental and computational approaches to understand the complexity of cancer.

Follow-up experiments with renal cell carcinoma cells showed that dasatinib or cabozantinib given alone had minimal effect on MAPK activity. But the combination markedly suppressed MAPK signaling. The researchers said the MAPK findings suggest that combining dasatinib or cabozantinib with MEK inhibitors could potentially be an alternate combination against non-clear cell kidney cancer.

“This work has opened up new avenues for drug combinations we would not have thought about before,” Thomas says. He and co-author Christopher Ryan, M.D., an oncologist and professor in the OHSU School of Medicine, are making plans to choose the best drug combination to begin testing in a phase 1 clinical trial.

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Further reading:

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma by Hui-wen Lue, Daniel S. Derrick, Soumya Rao, Ahna Van Gaest, Larry Cheng, Jennifer Podolak, Samantha Lawson, Changhui Xue, Devin Garg, Ralph White III, Christopher W. Ryan, Justin M. Drake, Anna Ritz, Laura M. Heiser, and George V. Thomas. Cell Reports Medicine (May 7, 2021)