# Improving chemotherapy of castration-resistant prostate cancer

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $348,345

## Abstract

Title: Improving chemotherapy of castration-resistant prostate cancer
Abstract
Because prostate cancer (PCa) requires androgen for development, androgen ablation (castration) is the
primary treatment for patients with late stage PCa. However, recurrent tumors arise within 2 years, whereas
androgen receptor (AR) signaling has been inappropriately restored, and the disease enters a stage called
castration-resistant prostate cancer (CRPC). Docetaxel is the standard treatment for CRPC patients with
limited success. Therefore, it is urgent to understand mechanisms of docetaxel so novel avenues can be
developed to increase its efficacy. It was recently found that the nuclear localization of AR is microtubule
dynamics dependent and that the anti-tumor effect of docetaxel in CRPC is largely due to its inhibition of AR
nuclear import. However, the detailed molecular mechanisms behind these intriguing observations are still
elusive. The long-term goals of this study are to provide novel approaches to overcome docetaxel resistance
of CRPC. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is elevated in PCa and linked
to tumor grades. The objective here is to define the role of Plk1 in activating AR signaling and to examine
whether its inhibition can enhance the efficacy of docetaxel in CRPC. Clip-170 and p150Glued, two regulators of
microtubule dynamics, were recently identified as novel Plk1 substrates. The central hypothesis of the proposal
is that Plk1-associated activity towards Clip-170 and p150Glued increases microtubule dynamics, resulting in
constitutive activation of AR signaling and development of docetaxel resistance. This hypothesis will be tested
by pursuing three specific aims – (1) to test how Plk1 phosphorylation of Clip-170 and p150Glued contributes to
docetaxel resistance in CRPC cells; (2) to analyze whether Plk1-associated kinase activity contributes to
docetaxel resistance in CRPC in mice; and (3) to ask whether a combination of Plk1 inhibition and docetaxel
is a novel avenue for treatment of CRPC. These 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 of Plk1 to the AR signaling and to examine how Plk1 induces docetaxel resistance in
CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1
activates AR; (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 docetaxel. 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 therap...

## Key facts

- **NIH application ID:** 9973149
- **Project number:** 5R01CA196634-06
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** XIAOQI LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,345
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973149

## Citation

> US National Institutes of Health, RePORTER application 9973149, Improving chemotherapy of castration-resistant prostate cancer (5R01CA196634-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9973149. Licensed CC0.

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