HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer.
• Paraneoplastic syndromes like hypercalcemia and cachexia are common in kidney cancer but poorly understood.
• Loss of the pVHL tumor suppressor protein and subsequent HIF2 upregulation are key events in ccRCC.

Purpose of the Study:

• To investigate the mechanisms linking pVHL loss, HIF2, and paraneoplastic syndromes in ccRCC.
• To identify the role of PTHLH in ccRCC-associated hypercalcemia and cachexia.
• To evaluate the efficacy of HIF2 inhibitors in treating these paraneoplastic syndromes.

Main Methods:

• Analysis of PTHLH as a direct HIF2 transcriptional target in ccRCC.
• Utilizing preclinical orthotopic cell line tumor models to assess the necessity and sufficiency of PTHLH.
• Clinical evaluation of HIF2 inhibitors (belzutifan and NKT2152) in ccRCC patients with hypercalcemia and cachexia.

Main Results:

• PTHLH is a direct HIF2 transcriptional target in ccRCC.
• Increased PTHLH expression is necessary and sufficient to induce hypercalcemia and cachexia in ccRCC models.
• HIF2 inhibitors rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, irrespective of tumor shrinkage.

Conclusions:

• HIF2-driven PTHLH expression is a key mechanism underlying paraneoplastic syndromes in ccRCC.
• Targeting HIF2 with inhibitors offers a therapeutic strategy for managing hypercalcemia and cachexia in kidney cancer patients.