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HIF-2α Protein and Progression of Clear Cell Kidney Cancer

By: Jocelyn Solis-Moreira, MS
Posted: Monday, March 9, 2020

Once considered to be an undruggable protein, HIF-2α may now become a therapeutic target to prevent progression of clear cell renal cell carcinoma, according to prospective study findings published in Clinical Cancer Research. James Brugarolas, MD, PhD, of UT Southwestern, Dallas, and colleagues discovered a pocket in HIF-2α’s protein structure allowing the HIF-2 inhibitor PT2385 to dissociate the HIF-2 complex.

“This study exposes the Achilles’ heel of [clear cell renal cell carcinoma] tumors,” stated Dr. Brugarolas in a UT Southwestern Medical Center press release.

Ten patients with advanced or metastatic clear cell renal cell carcinoma enrolled in this companion trial (ClinicalTrials.gov identifier NCT02293980). Researchers used contrast-enhanced MRIs and blood samples as well as optional tumor biopsies to study PT2385’s specific effect on HIF-2α and subsequent cancer expression. After 2 weeks of treatment, a 29% loss of blood circulating in tumors was correlated with a smaller tumor size. Tumor biopsies showed a specific drug effect targeting the HIF-2α/HIF-2β complex—but not the HIF-1α/HIF-1β complex. Through RNA sequencing, PT2385 treatment showed a decrease in 277 genes compared with vehicle-treated tumor grafts. Additionally, a correlation was found between HIF-2–targeted gene downregulation and the HIF-2 complex dissociation.

One patient’s tumor developed drug resistance after 1 year of PT2385 treatment. Researchers found prolonged treatment created an HIF-2α G323E mutation. The same mutation was also discovered in another patient. Through biopsies, they found the HIF-2α G323E mutation acted as a gatekeeper to prevent HIF-2 complex dissociation. Gene analysis of 116 genes in the M4 metastasis with the HIF-2α G323E mutation further supported interference of PT2385 activity, as more than 40% of gene expression was preserved rather than downregulated.

Disclosures: For full disclosures of the study authors, visit clinicalcancerres.aacrjournals.org.



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