In 2021, a novel drug called belzutifan was approved by the U.S. Food and Drug Administration (FDA) to treat clear cell renal cell carcinoma, a form of kidney cancer. Since then, Dana-Farber clinical investigator Panos Konstantinopoulos, MD, PhD, has wanted to launch a clinical trial of the drug for clear cell ovarian cancer.
That vision has finally become reality. Konstantinopoulos recently launched a clinical trial of his own design, with funding from Merck, the maker of the drug, for patients with this difficult-to-treat form of ovarian cancer.
“I have been hoping to bring this agent to our patients with clear cell ovarian cancer for the last three years,” says Konstantinopoulos, who is also a gynecologic oncologist. “We want to see how effective this drug is for our patients because we want to be able to offer more treatment options.”
About 1 in 10 cases of ovarian cancer are diagnosed as clear cell ovarian cancer, which is a particularly aggressive form of the disease. It is also difficult to treat. The types of chemotherapy used to treat other types of ovarian cancer are less effective for clear cell ovarian cancer.
“In patients with advanced stage disease, the cancer often comes back, and treatment options after that are limited,” explains Konstantinopoulos.

Konstantinopoulos’ desire to test belzutifan in clear cell ovarian cancer stems from the disease’s commonalities with clear cell renal cell cancer. The most obvious similarity — the name “clear cell” — is a term pathologists use to describe how they characterize the cells.
Both cancers resist treatment with chemotherapy and also appear to respond to immunotherapy. For clear cell ovarian cancer, however, signs that immunotherapy might be effective are only just beginning to emerge in clinical trials.
“The similarities run even deeper, down to the molecular level,” adds Konstantinopoulos.
All cells function by turning genes into proteins that carry out the cell’s work. This process, called gene expression, can be likened to the way an orchestra turns notes on a musical score into a symphony. Each cell type plays a unique song, but clear cell renal cell cancer cells and clear cell ovarian cancer cells play strikingly similar tunes.
“This is truly remarkable,” says Konstantinopoulos. “Clear cell ovarian cancer cells look more like clear cell renal cancer than like another type of ovarian cancer when it comes to gene expression levels.”
Further, one common note in those gene expression scores is an overabundance of a protein called HIF-2α. The 2019 Nobel-prize winning research of Dana-Farber researcher William G. Kaelin, Jr., MD, revealed that this protein acts as an oxygen sensor in cells and enables them to survive low oxygen conditions.
Kaelin’s research also linked overexpressed HIF-2α to renal cell cancer and carried out the foundational research that led to the development and FDA approval of belzutifan, the first HIf-2α inhibitor for clear cell renal cell cancer. Konstantinopoulos wants to know if belzutifan might also help patients with clear cell ovarian cancer, a disease in which HIF-2α levels are elevated very early on in the disease process.
In 2023, Merck, the makers of belzutifan, called for proposals for novel trials of this promising medicine. After a competitive review process, Konstantinopoulos was awarded medicine and funding for his investigator-initiated trial to treat up to 29 patients.
In addition, Konstantinopoulos will research the molecular changes that occur in clear cell ovarian cancer cells in response to treatment. These studies will continue to build an understanding of the disease and its response to treatments that will help investigators like Konstantinopoulos devise and test the next wave of ovarian cancer treatments.