Kidney cancer drug shows promise against dangerous calcium imbalance caused by tumors

Elevated calcium levels in the blood—a complication of kidney cancers known as hypercalcemia—may be successfully treated with a class of medications called HIF-2α inhibitors developed by UT Southwestern Medical Center, a new study shows. The findings, published in Cancer Discovery by a team at UTSW, offer hope to patients who develop this condition.

About 10% of patients with advanced kidney cancer develop hypercalcemia, which can cause confusion, muscle spasms, and seizures and is associated with lower patient survival. It’s typically treated with drugs like bisphosphonates that reduce calcium release from bone; however, these drugs have side effects, including osteonecrosis of the jaw, fractures, and an opposing complication called hypocalcemia, when blood calcium levels become too low.

In their study, Arijit Mal, Ph.D., a postdoctoral researcher, and Bingqing Xie, Ph.D., Assistant Professor of Internal Medicine, along with senior investigator James Brugarolas, M.D., Ph.D., Professor of Internal Medicine in the Division of Hematology and Oncology and founding Director of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, evaluated the potential of HIF-2α inhibitors to block hypercalcemia at its root.

Hypercalcemia is frequently caused by a hormone produced by kidney tumors called parathyroid hormone-related protein (PTHrP), which raises blood calcium levels. A previous study by the Brugarolas Lab showed that PTHrP production in kidney cancer is regulated by HIF-2, which led the investigators to test the role of HIF-2α-blocking drugs in hypercalcemia.

HIF-2α-blocking drugs are the result of a long journey at UT Southwestern. In the 1990s, Steven McKnight, Ph.D., Professor of Biochemistry, and David Russell, Ph.D., Professor Emeritus of Molecular Genetics, identified HIF-2α, the key component of HIF-2. Subsequent studies by Richard Bruick, Ph.D., and Kevin Gardner, Ph.D., then at UTSW, identified a vulnerability in the structure that they exploited with a chemical obtained from the UTSW chemical library. These results led to the founding of Peloton Therapeutics, which developed a series of related HIF-2α inhibitors: PT2399 for animal studies and PT2977/belzutifan, which the Food and Drug Administration approved to treat kidney cancer in 2023.

To determine whether inhibiting HIF-2α could treat hypercalcemia, researchers leveraged mice transplanted with human kidney tumors. They treated tumor-bearing mice that developed hypercalcemia with PT2399. Interestingly, the majority of the mice responded. Calcium levels dropped within just a few days of treatment onset, and symptoms, including weight loss, fatigue, and calcium deposition, subsided.

Additional studies showed that PT2399 prevents HIF-2α from binding to the gene that produces PTHrP, decreasing the amount of PTHrP made and explaining PT2399’s effects on hypercalcemia.

In a subsequent case study, a 63-year-old man with advanced clear cell renal cell carcinoma and elevated calcium was treated with PT2977/belzutifan. After treatment, PTHrP levels dropped, and calcium returned to normal levels within a few days without the side effects seen with standard therapies.

“Our study supports the systematic evaluation of HIF-2α inhibitors for kidney cancer patients with hypercalcemia,” Dr. Brugarolas said.