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, offer hope to patients who develop this condition, which affects about 10% of patients with advanced kidney cancer and is associated with lower survival rates. Typically treated with drugs like bisphosphonates, hypercalcemia can cause confusion, muscle spasms, and seizures, with potential side effects like osteonecrosis of the jaw and fractures.
In a study led by researchers at UT Southwestern, including postdoctoral researcher Arijit Mal and Assistant Professor Bingqing Xie, along with senior investigator James Brugarolas, the potential of HIF-2α inhibitors to block hypercalcemia was evaluated. This condition is often caused by a hormone produced by kidney tumors called parathyroid hormone-related protein (PTHrP), which raises blood calcium levels. The study showed that HIF-2α blockers could effectively reduce hypercalcemia by preventing the production of PTHrP.
The development of HIF-2α inhibitors has been a significant journey at UT Southwestern, starting with the identification of HIF-2α in the 1990s by researchers like Steven McKnight and David Russell. This led to the founding of Peloton Therapeutics, which developed PT2399 for animal studies and PT2977/belzutifan, approved by the FDA in 2023 to treat kidney cancer. In the recent study, mice with human kidney tumors were treated with PT2399, leading to a significant reduction in calcium levels and associated symptoms.
Further investigations revealed that PT2399 works by preventing HIF-2α from binding to the gene responsible for producing PTHrP, thereby reducing its production and normalizing calcium levels. A case study involving a patient with advanced clear cell renal cell carcinoma showed promising results, with PT2977/belzutifan effectively lowering PTHrP levels and restoring normal calcium levels without the side effects seen with standard therapies.
Dr. Brugarolas emphasized the importance of evaluating HIF-2α inhibitors for kidney cancer patients with hypercalcemia based on the study’s outcomes. The research was funded by various organizations, including the NCI, Department of Defense, and Cancer Prevention and Research Institute of Texas. UT Southwestern and its researchers will receive financial compensation through prior agreements with Peloton related to belzutifan’s FDA approval.
UT Southwestern Medical Center, known for its pioneering biomedical research and exceptional clinical care, continues to make significant contributions to the field of medicine. With a faculty responsible for groundbreaking medical advances and a commitment to translating research into clinical treatments, UT Southwestern remains at the forefront of healthcare innovation.
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