Early in his tenure as a physician-scientist at Dana-Farber, Srinivas Viswanathan, MD, PhD, had two young patients with a rare form of kidney cancer called translocation renal cell carcinoma (tRCC). Both at that time in 2019 and still today, there are no effective treatments for this disease.
“I realized what a clear unmet need we have to understand this rare form of kidney cancer,” says Viswanathan. “Gaining that understanding and determining how to act on it therapeutically is a motivation for our lab.”
That motivation led to a study published in February 2025 in Nature Metabolism, in which Viswanathan and team identify how tRCC growth is fueled. That mechanism turns out to run counter to the way a much more common form of kidney cancer is fueled, explaining why go-to treatments for common forms of kidney cancer may not work as well in tRCC.
Understanding what drives tRCC growth also helped Viswanathan and his team pinpoint a possible target for blocking that growth. The work could lead to the development of a targeted therapy specifically for tRCC.
A Rare Disease
The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), makes up about 75% of adult cases. In contrast, tRCC affects only 1-3% of adult patients. It also makes up about 50% of childhood cases of renal cell carcinoma, which are extremely rare.
The disease is caused when a gene called TFE3 fuses, or translocates, with another and ends up turned on all the time. The only way to definitively diagnose tRCC is with genetic testing to identify the fusion, which can be done using Dana-Farber’s OncoPanel test. But in community cancer centers, genetic testing of kidney cancer is not always done, so it is possible that tRCC is more common than what is currently observed.
Scientists have known about this fusion for decades, but exactly how it drives cancer has been mysterious. In this recent study, Viswanathan and his team have found that the TFE3 fusion flips the metabolic switch that determines how cells get their energy. In tRCC, the switch directs the cancer cells to rely on an extremely efficient metabolic pathway called oxidative phosphorylation, or OXPHOS. This metabolic pathway utilizes the mitochondria – a tiny organelle within the cell that generates energy in the presence of oxygen – and is completely different from the one used to fuel ccRCC, which relies on fermenting sugar to lactate and bypassing the mitochondria even in the absence of oxygen, a process called aerobic glycolysis or the “Warburg effect.”
“Translocation renal cell cancer doesn’t just use oxidative phosphorylation, but appears to hyper-activate it,” says Viswanathan, “In that sense, it is essentially the metabolic opposite of ccRCC.”
Unbiased Approaches
To make these discoveries, Viswanathan took an unbiased approach to studying tRCC samples in the lab. He used both genomic and functional screening that look across the entire genome for clues that explain how the cells grow and behave.
“These types of tools can be very powerful because you go into it with no preordained hypothesis about what the connection is going to be,” says Viswanathan.
Once the team understood how this fusion gene was driving cancer growth, they were able to look for genes involved in the OXPHOS growth program that might be suitable as therapeutic targets. Working in collaboration with the lab of co-senior author Liron Bar-Peled, PhD, at Massachusetts General Hospital, they found a gene called EGLN1.
The EGLN1 protein is involved in degrading proteins in the HIF family. These genes respond to low oxygen levels by amping up glycolysis. In many cancers, including ccRCC, an abundance of HIF proteins drives tumor growth.
Now that we know that this enzyme can be drugged, we want to determine if it is possible to use this as a potential targeted therapeutic strategy for this specific type of cancer.”
Srinivas Viswanathan, MD, PhD
In these cases, a protein like EGLN1 that degrades HIF proteins would be considered a good thing. In fact, a medicine called belzutifan was recently approved to treat ccRCC by inhibiting a HIF protein; its mechanism is based on Nobel Prize-winning research done by Dana-Farber’s William Kaelin, MD.
But in tRCC, inhibiting EGLN1 could slow tumor growth by keeping HIF proteins stable. The presence of more HIF proteins can flip a tRCC cell’s metabolic switch away from OXPHOS, which is driving tumor growth in this type of cancer, and toward glycolysis.
“If you inhibit EGLN1 in clear cell kidney cancer, it has no effect at all or in some cancers it might make them grow faster,” says Viswanathan. “But in the case of translocation kidney cancer, EGLN1 is a vulnerability.”
The team has identified several existing inhibitors of the EGLN family of proteins that are currently used in patients for the treatment of anemia or for patients on dialysis. The team is now focused on learning more about their effects in models of tRCC cancers.
“Now that we know that this enzyme can be drugged, we want to determine if it is possible to use this as a potential targeted therapeutic strategy for this specific type of cancer,” says Viswanathan.