Pilot: Plk1 in Serine Metabolism of Prostate Cancer

Program Director/Principal Investigator (Last, First, Middle): Liu, Xiaoqi PROJECT SUMMARY (See instructions): Serine metabolism is at the center of energy metabolism as it links glycolysis, one-carbon cycle, nucleotide biosynthesis, and lipid metabolism. Notably, serine metabolism is frequently dysregulated in cancer cells, and D-3-phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the de novo serine biosynthetic pathway, is highly expressed in some tumors as results of gene amplification, enhanced transcription or protein stability. As such, PHGDH has been proposed as a target for cancer treatment and inhibitors such as NCT-503 have been developed. The objective of the proposed research is to determine how serine biosynthesis/uptake, its-associated one-carbon cycle and sphingolipid metabolism are regulated by upstream signaling events, eventually identifying new approaches to enhance the efficacy of inhibitors of serine metabolism. It has been documented that androgen receptor (AR) signaling remains to play a critical role in castration-resistant prostate cancer (CRPC). Indeed, Androgen Signaling Inhibitors (ASI), such as abiraterone, an inhibitor of de novo androgen synthesis pathway, and enzalutamide, a direct AR inhibitor, are major drugs used in clinic to manage CRPC now. Unfortunately, ASI-based treatment only improves the overall patient survival by several months. Therefore, new targets/approaches are urgently needed to treat patients with CRPC. Our central hypothesis is that a combination of polo-like kinase 1 (Plk1) inhibitor BI2767 with PHGDH inhibitor NCT-503 is an effective approach to treat CRPC. Our working model is that Plk1-associated phosphorylation of PHGDH targets it for degradation, resulting in inhibition of de novo serine biosynthesis. Consequently, extracellular serine uptake is significantly increased, followed by elevation of one-carbon metabolism, nucleotide and sphingolipid biosynthesis. Our hypothesis will be tested by pursuing three Specific Aims – (1) dissect how Plk1-associated kinase activity regulates serine metabolism; (2) understand how Plk1-dependent serine metabolism promotes cancer growth; and (3) determine whether BI2767 plus NCT-503 is a novel approach to treat CRPC. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing gain-of-function and loss-of-function strategies with culture systems and human PCa xenograft methodologies. The rationale for the research is that it will be the first to comprehensively probe the importance of Plk1 in serine metabolism in CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1-associated phosphorylation regulates PHGDH; (ii) evaluate the role of Plk1 in serine-associated metabolic pathways such as one-carbon cycle, nucleotide biosynthesis and lipid metabolism; and (iii) demonstrate that Plk1 inhibition enhances the efficacy of PHGDH inhibitor NCT-503. The team, with expertise in Plk1 (Liu), cancer metabolism (Higashi), GU pathology (Allison), and biostatistics (Moseley, Wang) will be able to finish the research in a timely manner. The preliminary data generated from this pilot grant will form the basis for a competitive R01 application in 2023. Indeed, an initial attempt for an R01 application in 2021 was not successful due to lacking of enough preliminary data to justify the proposed experiments. Generous support from COBRE will likely address this major concern, eventually resulting in a major grant from NIH. Of note, both two CCM cores (Metabolism and Imaging) will be heavily used for the proposed work. RELEVANCE (See instructions): PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) Project/Performance Site Primary Location Organizational Name: University of Kentucky Research Foundation DUNS: 93-901-7877 Street 1: 500 South Limestone Street 2: 109 Kinkead Hall City: Lexington County: State: KY Province: Country: Zip/Postal Code: 40526-0001 Project/Performance Site Congressional Districts: KY-006 Additional Project/Performance Site Location Organizational Name: DUNS: Street 1: Street 2: City: County: State: Province: Country: Zip/Postal Code: Project/Performance Site Congressional Districts: Page 2 OMB No. 0925-0001 PHS 398 (Rev. 03/2020 Approved Through 02/28/2023) Form Page 2