Because prostate cancer (PCa) requires androgen for development, castration is the primary treatment for patients with late stage PCa. Because androgen receptor (AR) signaling continues to be active in castration-resistant prostate cancer (CRPC), androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However, two FDA-approved ASIs, abiraterone and enzalutamide, only improve overall patient survival for several months. Thus, it is urgent to identify new targets and develop new approaches to treat ASI-resistant CRPC. Metformin, an antidiabetic drug widely used for over 40 years, is now believed to have anti-neoplastic activity in different types of cancers. Recent clinical data suggests that metformin use may reduce development of CRPC and PCa mortality. However, the detailed molecular mechanisms underlying this very important observation is not completely understood. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the mTOR (mammalian target of rapamycin) pathway and AR signaling, and to exploit this unique pathway as a novel therapeutic target for ASI- resistant CRPC patients. The central hypothesis is that a combination of Plk1 inhibition with metformin is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing two Specific Aims - (1) to dissect how Plk1 phosphorylation of TSC1 (tuberous sclerosis complex 1), a negative regulator of the mTOR pathway, leads to activation of the mTOR pathway in vivo; (2) to determine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. These two complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models, culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance f Plk1 to the mTOR/AR pathways and to examine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 regulates the mTOR/AR signaling; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1 as a critical therapeutic target to enhance the efficacy of metformin. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the mTOR/AR signaling that is critical for generating and maintaining the CRPC phenotype.

Public Health Relevance

The proposed research is relevant to public health because it focuses on discovery of novel signaling pathways that drive castration-resistant prostate cancer. These studies will establish new avenues of investigation to develop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus, the proposed research is relevant to NCI's mission of fostering creative discoveries and innovative research strategies for protecting and improving health and reducing the burdens associated with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA192894-05
Application #
9850516
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Forry, Suzanne L
Project Start
2016-02-08
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
Li, Zhiguo; Kong, Yifan; Song, Longzhen et al. (2018) Plk1-Mediated Phosphorylation of TSC1 Enhances the Efficacy of Rapamycin. Cancer Res 78:2864-2875
Zhang, Zhuangzhuang; Cheng, Lijun; Li, Jie et al. (2018) Inhibition of the Wnt/?-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer. Cancer Res 78:3147-3162
Shao, C; Chien, S-J; Farah, E et al. (2018) Plk1 phosphorylation of Numb leads to impaired DNA damage response. Oncogene 37:810-820
Mao, Fengyi; Li, Jie; Luo, Qian et al. (2018) Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer. Mol Cancer Ther 17:1554-1565
Kong, Yifan; Cheng, Lijun; Mao, Fengyi et al. (2018) Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC). J Biol Chem 293:14328-14341
Wilking-Busch, Melissa J; Ndiaye, Mary A; Liu, Xiaoqi et al. (2018) RNA interference-mediated knockdown of SIRT1 and/or SIRT2 in melanoma: Identification of downstream targets by large-scale proteomics analysis. J Proteomics 170:99-109
Li, Jie; Wang, Ruixin; Kong, Yifan et al. (2017) Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer. Mol Cancer Ther 16:469-479
Li, Zhiguo; Shao, Chen; Kong, Yifan et al. (2017) DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability. Mol Cell Biol 37:
Li, Zhiguo; Liu, Jinghui; Li, Jie et al. (2017) Polo-like kinase 1 (Plk1) overexpression enhances ionizing radiation-induced cancer formation in mice. J Biol Chem 292:17461-17472
Li, Zhiguo; Li, Jie; Kong, Yifan et al. (2017) Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response. Cancer Res 77:3169-3180

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