Research reveals key to understanding kidney cancer treatment variability

Fighting cancer can seem like a deadly game of chance. While some patients may respond well to certain treatments, others might not be as fortunate. Doctors and scientists have long struggled to explain why. Now, in new research from the Perelman School of Medicine at the University of Pennsylvania, Shelley Berger, PhD, the Daniel S. Och University Professor and Director of Penn's Epigentics Institute, and Katherine Alexander, PhD, currently an assistant professor at Cold Spring Harbor Laboratory have found a possible source of this variability in clear cell renal cell carcinoma (ccRCC)-;the most common kidney cancer diagnosed in adults. The findings of their study are published this week in Nature Cell Biology.

The research found that kidney tumors have two different patterns of cellular structures known as nuclear speckles. The research, conducted in Berger's lab at Penn, shows a potential correlation between speckle patterns and patient outcomes. Berger and Alexander collaborated with Celeste Simon, PhD, Arthur H. Rubenstein Professor of Cell and Developmental Biology and Scientific Director of the Abramson Family Cancer Research Institute at Penn.

"We found if a patient has a normal or abnormal speckle arrangement, they might be more responsive to one drug versus another. Of course, more research needs to be done," explained Alexander, who completed her postdoctoral fellowship in Berger's lab.

What is a nuclear speckle?

Discovered more than 100 years ago, nuclear speckles are tiny cellular structures that reside in the nucleus. These speckles intermingle with DNA and help regulate gene activity. This newly published research reveals that nuclear speckles have two different signatures in ccRCC: normal-like and aberrant. It's a matter of positioning. Normal speckles tend to congregate toward the center of the nucleus. Aberrant speckles are more dispersed. 

How these signatures affect patient outcomes remains a mystery for now. However, the search for answers may lead to more personalized treatments. This discovery offers a new starting point in ccRCC."

Shelley Berger, PhD, the Daniel S. Och University Professor and Director of Penn's Epigentics Institute

"It's the first suggestion that this would be potentially applicable to giving someone [diagnosed with ccRCC] one drug or another. That's huge because cancer therapy has a lot of horrible side effects," said Alexander. "To be able to tell a patient, 'Your tumor looks like this, so we think this drug will work better than this drug,' is something we really need." 

Further implications

The team didn't just look at kidney cancer. They analyzed speckles in over 20 different types of cancers, from melanomas to breast cancer. However, only ccRCC showed a correlation between speckle patterns and patient outcomes. What makes this cancer special? Alexander's findings point to HIF-2α, a protein typically overactive in ccRCC and target of the FDA approved drug Belzutifan used to treat patients with ccRCC. In her new lab at Cold Spring Harbor, Alexander aims to pursue this lead alongside other researchers at CSHL's Cancer Center.

The research was funded in part by the National Institutes of Health (RO1CA078831, R35CA263922, F32CA221010, R35CA220483) and U.S. Department of Defense (W81XWH-20-1-0856).