Notre Dame researchers developing a new treatment for kidney cancer

The original article was written by Deanna Csomo Ferrell.

A team of researchers that included Xin Lu, the John M. and Mary Jo Boler Collegiate Professor and associate chair in Notre Dame’s Department of Biological Sciences, recently discovered a genetic vulnerability in the most aggressive form of kidney cancer. Their findings could point toward a new combination therapy that effectively causes cancer cells to self-destruct.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is usually caused by the loss or mutation of a tumor-suppressing gene known as VHL.

One treatment, belzutifan, targets a protein called HIF-2-alpha that becomes overactive when VHL is lost. The drug has proven effective for some patients, but its impact is limited because some tumors are resistant to it from the outset and others develop resistance over time.

Lu and his collaborators discovered a potential way to overcome that resistance.

The researchers found that the loss of VHL sets off a chain reaction inside cancer cells. Without VHL, HIF-2-alpha becomes overactive and causes the cells to produce high levels of a protein called TRAIL. Normally, TRAIL helps trigger apoptosis—the natural process through which damaged or unwanted cells self-destruct—by binding to “death receptors” on the surface of a cell.

In ccRCC cells, however, excessive amounts of TRAIL have the opposite effect. They cause those death receptors to retreat inside the cell, where treatments cannot reach them. At the same time, the excess TRAIL accelerates cell division, helping tumors grow.

The researchers discovered that belzutifan can help reverse this process. By suppressing HIF-2-alpha, the drug reduces the amount of TRAIL produced inside the cancer cell. This slows the cancer cell’s proliferation while allowing its hidden death receptors to return to the cell’s surface.

The researchers can then introduce a laboratory-produced form of TRAIL, which binds to the newly exposed receptors and triggers apoptosis—the process through which the cancer cell self-destructs.

“This is really kind of magical, because when you reduce TRAIL, you can reduce cell division, cell proliferation, and make the cell more vulnerable to apoptosis,” Lu said. “You really kind of force the cells into this corner where they can’t divide well.”

In laboratory tests and mouse models, combining belzutifan with recombinant TRAIL significantly increased cancer cell death compared with either treatment alone.

The findings are particularly promising because belzutifan, sold under the name Welireg, is already FDA-approved, while therapies designed to activate TRAIL are being evaluated in clinical trials. That could provide researchers with a potential path toward translating the discovery into a new treatment for patients with ccRCC.

When Lu presented the research at a major urology conference, he said physicians immediately recognized its potential.

“The physicians, they’re excited about this,” Lu said. “They all know this belzutifan resistance is something they have to overcome.”

The research brought together collaborators from Notre Dame and the University of Galway in Ireland. Support for the project came from the Boler Family Foundation, the Naughton Faculty Research Accelerator Program, and the VHL Alliance.

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Discoveries like this demonstrate what is possible when researchers across disciplines unite around some of medicine’s most difficult challenges. Generous benefactors help make the next breakthrough possible by supporting the Institute for Rare Diseases, Berthiaume Institute for Precision Health, and Harper Cancer Research Institute. This generosity gives Notre Dame researchers the resources to pursue bold ideas, advance discovery, and improve lives.