Dissecting the role of CPT1C in advanced prostate cancer

About This Grant

ABSTRACT Prostate cancer remains the second leading cause of cancer-related mortality among men in the United States, with neuroendocrine prostate cancer (NEPC) representing an aggressive and lethal subtype that emerges from castration-resistant prostate cancer (CRPC). NEPC often develops following long-term androgen deprivation therapy or androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, and is characterized by poor prognosis and a low 5-year survival rate. Understanding the molecular mechanisms driving NEPC progression is essential to developing novel therapeutic approaches. Carnitine Palmitoyltransferase 1C (CPT1C), known for its role in regulating brain energy homeostasis, is upregulated under stress in various cancers, promoting tumor adaptation and aggressiveness. Emerging evidence from our lab indicates that CPT1C expression is significantly elevated in NEPC and correlates with neural lineage markers. Functional studies reveal that CPT1C inhibition reduces NEPC growth and arrests the cell cycle. These findings suggest that CPT1C plays a pivotal role in NEPC and is a promising therapeutic target. This project hypothesizes that CPT1C regulates neural lineage plasticity, tumor aggressiveness, and therapy resistance in advanced prostate cancer. Aim 1 focuses on elucidating CPT1C’s role in prostate cancer progression, with a particular emphasis on neural lineage plasticity, resistance to enzalutamide, and its interactions with lipid metabolic proteins. Aim 2 investigates the mechanisms underlying CPT1C protein regulation, including its interaction with the chaperone complex, and evaluates CPT1C turnover pharmacologically in both in vitro and in vivo models. Aim 3 leverages RNA bioengineering technologies to validate CPT1C as a target in advanced prostate cancer models, using liposome-polyethylenimine nanocomplexes for targeted delivery. The primary goal of this project is to dissect novel mechanisms of neural lineage plasticity and develop new therapeutic strategies for NEPC by targeting CPT1C. We anticipate that the results of this study will define the role of CPT1C in the development, progression, and therapy resistance of NEPC. These findings will provide a foundation for developing BioRNA/CPT1C-siRNA as a potential therapeutic approach for NEPC, offering the promise of significantly improving the quality of life for prostate cancer patients.