Abstract B019: Discern the Impact of Cryptochrome 1 (CRY1) on Metabolic Rewiring in PCa

Abstract Background: Disruptions in circadian rhythm have been implicated in prostate cancer (PCa) biology. Previous studies have shown that the core circadian regulatory cryptochrome 1, CRY1, is pro-tumorigenic and associated with poor outcome in PCa. Furthermore, metabolic reprogramming is a hallmark of oncogenic progression, promoting tumor growth through nutrient and energy imbalance. While evidence links circadian rhythm disruptions to metabolic disorders, the underlying mechanism(s) connecting circadian dysregulation and metabolic rewiring in PCa remain poorly understood. Our preliminary data suggest that CRY1 modulates metabolic homeostasis in both preclinical and clinical models of PCa. This study investigates CRY1 as a crucial regulator of PCa growth and survival through metabolic rewiring, aiming to identify novel therapeutic vulnerabilities in CRY1-driven disease. Methods: To elucidate the role of CRY1 in metabolic regulation and disease progression, we utilized hormone therapy-sensitive (HTS) and castration-resistant prostate cancer (CRPC) models with both pharmacological and genetic perturbations of CRY1. Multiomic analyses, including bulk RNA-seq, steady-state metabolomics, and a metabolic focused CRISPR loss-of-function screen, were performed to define CRY1-dependent transcriptional and metabolic programs driving PCa progression. Functional validation studies are being conducted in vitro and ex vivo to assess the impact of CRY1 inhibition on tumor growth and metabolic adaptation. Results: Integrated multiomic analyses revealed that CRY1 drives significant metabolic alterations in bile acid metabolism, epithelial–mesenchymal transition (EMT), apoptosis, and inflammatory in HTS models, while lipid metabolism and cell proliferation Pathways were significantly altered in CRPC models. Furthermore, both CRY1 knockdown and pharmacological inhibition suppressed cell growth in vitro and in vivo, underscoring the importance of CRY1 in maintaining metabolic fitness and tumor viability. Overlapping targets identified across transcriptomic, metabolomic, and CRISPR screening datasets are undergoing biochemical validation. Ongoing drug response studies using CRY1 inhibitor, alone or in combination with metabolic inhibitors, are being conducted in preclinical models and patients derived explants (PDEs) to better recapitulate tumor microenvironmental context and therapeutic response. These studies aim to uncover synergistic vulnerabilities that can be leveraged for precision medicine approaches. Conclusions: Collectively, our findings demonstrate that CRY1 promotes tumor growth by sustaining metabolic homeostasis in PCa. Inhibition of CRY1 disrupts this metabolic balance, impairing tumor viability. Thus, these results support the development of combinatorial therapeutic strategies targeting circadian and metabolic dependencies to improve PCa patient outcome. Citation Format: Arwa Fallatah, Stefan DiFazio, Lakshmi Ravindranath, Ayesha Shafi. Discern the Impact of Cryptochrome 1 (CRY1) on Metabolic Rewiring in PCa [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B019.