Kidney cancer drug shows promise against dangerous calcium imbalance caused by tumors
Belzutifan, a drug developed by UTSW, may control life-threatening hypercalcemia
DALLAS – Oct. 09, 2025 – 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.
A full list of contributors can be found in the published study.
Dr. Brugarolas holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D., and is a member of the Cellular Networks in Cancer Research Program of the Simmons Cancer Center.
This study used kidney cancer tumor models developed by UTSW’s Kidney Cancer Program through a National Cancer Institute (NCI)-funded Specialized Program of Research Excellence award.
This study was funded by grants from the NCI (P50CA196516, R01CA245294, R01CA295997, P50CA196516, and P50CA070907), Department of Defense Congressionally Directed Medical Research Program’s Kidney Cancer Research Program (HT9425-25-1-0346), Cancer Prevention and Research Institute of Texas (RP230382, RP240516), National Institute of Diabetes and Digestive and Kidney Diseases through the UTSW Nutrition & Obesity Research Center (P30DK127984), and an NCI Cancer Center Support Grant (P30CA142543).
Disclosures: UT Southwestern and some of its researchers will receive financial compensation, through prior agreements with Peloton, based on belzutifan’s FDA approval.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 24 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.