Targeting of HIF2-driven cachexia in kidney cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Kidney cancer, particularly clear cell renal cell carcinoma (ccRCC), often presents with paraneoplastic syndromes like hypercalcemia and cachexia.
• The molecular mechanisms driving these syndromes in ccRCC are not fully elucidated.
• Loss of the pVHL tumor suppressor protein and subsequent HIF2 upregulation are key events in ccRCC pathogenesis.

Purpose of the Study:

• To investigate the role of HIF2 in mediating paraneoplastic syndromes in ccRCC.
• To identify downstream targets of HIF2 involved in hypercalcemia and cachexia.
• To evaluate the therapeutic potential of HIF2 inhibitors for managing these syndromes.

Main Methods:

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

Main Results:

• PTHLH was identified as a direct HIF2 transcriptional target in ccRCC.
• Increased PTHLH expression was found to be both necessary and sufficient for inducing hypercalcemia and cachexia in preclinical models.
• HIF2 inhibitors rapidly improved hypercalcemia and cachexia in ccRCC patients, irrespective of tumor shrinkage.

Conclusions:

• HIF2-driven PTHLH expression is a critical mechanism underlying hypercalcemia and cachexia in ccRCC.
• HIF2 inhibitors demonstrate therapeutic efficacy against these paraneoplastic syndromes.
• Further clinical studies are warranted to explore HIF2 inhibitors for treating cancer-associated cachexia in renal cell carcinoma.