Overcoming drug resistance of castration-resistant prostate cancer. Over the last decade, tremendous progress has been made in the understanding of castration-resistant prostate cancer (CRPC), a disease state that retains androgen receptor (AR)-dependent in most cases. That understanding led to the notion that targeted inhibition of AR signaling would be an effective approach for treatment of CRPC. In support, the landscape for CRPC treatment is now changing from docetaxel-based therapy to treatment with Androgen Signaling Inhibitors (ASI), such as abiraterone, an inhibitor of de novo androgen synthesis pathway, and enzalutamide, a direct AR inhibitor. However, ASI- based treatment only improves the overall patient survival by several months. Therefore, understanding the underlying mechanisms of ASI resistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgently needed. Besides AR signaling, activation of the PI3K pathway due to lose-of-function PTEN tumor suppressor has a well-established role in CRPC. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with CRPC. The objective is to define the role of Polo-like kinase 1 (Plk1) in activating AR signaling and the PI3 pathway and to exploit this unique pathway as a novel therapeutic target for CRPC patients. The central hypothesis is that Plk1-associated activity towards AR and PTEN causes constitutive activation of AR signaling and the PI3K pathway, respectively, thus CRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing three Specific Aims - (1) to identify the molecular mechanism(s) by which Plk1 activity activates AR signaling; (2) to examine whether Plk1-associated activity affects PCa progression in vivo; and (3) to test whether Plk1 phosphorylation of AR regulates ASI sensitivity. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing gain-of-function and loss-of-function strategies with inducible PCa mouse models, culture systems and human PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the AR and the PI3K signaling pathways and to examine how Plk1 induces ASI resistance in CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 activates AR; (ii) examine how Plk1 activates the PI3K pathway; (iii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iv) validate Plk1 as a critical therapeutic target to enhance the efficacy of ASI. 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 AR/PI3K pathways that are 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 #
5R01CA157429-06
Application #
9414442
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2011-09-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Purdue University
Department
Biochemistry
Type
Earth Sciences/Resources
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
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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; Li, Jie; Kong, Yifan et al. (2017) Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response. Cancer Res 77:3169-3180
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
Chen, Long; Li, Jie; Farah, Elia et al. (2016) Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer. Mol Cancer Ther 15:2107-18
Shao, Chen; Ahmad, Nihal; Hodges, Kurt et al. (2015) Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate cancer. J Biol Chem 290:2024-33
Zhang, Zhe; Chen, Long; Wang, Hexiang et al. (2015) Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer. Cell Cycle 14:2142-8
Li, Jie; Karki, Anju; Hodges, Kurt B et al. (2015) Cotargeting Polo-Like Kinase 1 and the Wnt/?-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer. Mol Cell Biol 35:4185-98
Chen, Long; Li, Zhiguo; Ahmad, Nihal et al. (2015) Plk1 phosphorylation of IRS2 prevents premature mitotic exit via AKT inactivation. Biochemistry 54:2473-80
Liu, Xiaoqi (2015) Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment. Transl Oncol 8:185-95

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