Abstract C044: The role of cryptochrome 1 (CRY1) on oncometabolic rewiring and tumor progression in lethal prostate cancer

Prostate cancer (PCa) is the most common type of cancer and the second leading cause of cancer-related death in men in the United States. The disease burden is particularly substantial among African American (AA) men, who have 1.5-fold incidence, and 2.5-fold mortality rates compared to Caucasian American (CA) men. Since the predictors of PCa aggressiveness at initial cancer detection are sorely lacking, the need to generate race specific information for PCa disease course is high. Recent evidence suggests that circadian disruption contributes to cancer risk and may underlie some of the aggressive disease features observed in AA patients. Correspondingly, circadian factors have been implicated in noncanonical physiological functions beyond the circadian clock involved in oncogenic signaling, including metabolic rewiring. Considering health disparities, proteogenomic data from racially diverse PCa samples indicate that several metabolic pathways are enriched in AA compared to CA, specifically including pathways impacting glutathione metabolism. Our preliminary data identify Cryptochrome 1 (CRY1), a core circadian clock factor, as a pro-tumorigenic driver in PCa through modulation of DNA repair and metabolic pathways. To assess the molecular impact of clinically observed CRY1 deregulation on metabolic signaling, we utilized hormone therapy-sensitive (HTS) and castration-resistant prostate cancer (CRPC) models with pharmacological and genetic perturbations of CRY1 to elucidate the role of CRY1 in disease progression, interplay with metabolic rewiring, and identify novel mechanism(s) of action. Our multiomic analysis upon integration of transcriptomic and metabolomic analysis revealed that CRY1 is integral to regulation of oncometabolic pathways, including fatty acid, amino acid, and glutathione metabolism pathways in HTS and CRPC models, indicating that CRY1 mediates metabolic rewiring across the PCa disease continuum. Furthermore, CRY1 perturbation via knockdown as well as chemical inhibition via pharmacological inhibitors decreased cell growth in vitro and in vivo underscoring the importance of CRY1 in tumor growth. Moreover, a metabolic focused CRISPR KnockOut screen is ongoing in the CRY1 depleted PCa models to identify potential targets for functional validation. Lastly, we are currently using the 10X Genomics Xenium platform to perform spatial transcriptomics on our established tissue microarray (TMA) comprised of a racially diverse patients, with a tailored panel that includes circadian and metabolic targets. This has the potential to reveal novel candidates to be therapeutically targeted as monotherapy or in combination with CRY1 inhibitors. Lastly, all multimoic studies will be conducted and validated in racially diverse PCa in vitro and in vivo models. In sum, our findings reveal that CRY1 promotes tumor growth, and its suppression disrupts metabolic hemostasis in PCa.Thus, targeting PCa with CRY1 inhibitors in combination with metabolic inhibitors has the translational potential improve the health of AA men who are at high risk to develop PCa Citation Format: Stefan DiFazio, Lakshmi Ravindranath, Ayesha Shafi, Arwa Fallatah. The role of cryptochrome 1 (CRY1) on oncometabolic rewiring and tumor progression in lethal prostate cancer [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C044.