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Targeting of HIF2-driven cachexia in kidney cancer.

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Clear cell renal cell carcinoma (ccRCC) causes hypercalcemia and cachexia via HIF2-driven PTHLH. HIF2 inhibitors effectively treat these paraneoplastic syndromes in kidney cancer patients.

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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.