Scripps Research has received a USD 1.39 million NCI R01 renewal to investigate how circadian clock proteins regulate HIF2α activity in clear cell renal cell carcinoma (ccRCC), a cancer subtype where therapeutic options remain limited despite the approval of HIF2α inhibitors such as belzutifan (Welireg).
The grant, awarded to principal investigator Katja Lamia, extends a project initiated in 2017 through May 2029. The research focuses on BMAL1, CRY1, and CRY2 — core components of the molecular circadian clock — and their demonstrated ability to modulate HIF2α transcriptional activity. In ccRCC, HIF2α is constitutively active following loss of the VHL tumor suppressor, driving angiogenesis and metabolic reprogramming. The Lamia lab's prior work established that circadian proteins can suppress this activity, raising the possibility that clock dysregulation contributes to tumor progression and that clock components represent underexplored therapeutic targets.
The renewed project will map the molecular mechanisms by which BMAL1, BMAL2, CRY1, and CRY2 influence HIF2α-dependent gene expression, and assess how depletion of these factors affects ccRCC cell proliferation and xenograft tumor growth. RNA sequencing and Cancer Genome Atlas data are among the analytical tools cited.
The translational relevance is notable. Belzutifan, developed by Merck, demonstrated efficacy in VHL-mutant ccRCC and received US FDA approval in 2021, validating HIF2α as a clinical target. Understanding how circadian clock components modulate the same pathway could inform combination strategies or identify patient subpopulations with altered clock function.