# Enhancing the efficacy of androgen signaling inhibitors in prostate cancer

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2022 · $485,160

## Abstract

Title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
Abstract
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, understanding the underlying mechanisms of ASI
resistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgently
needed. With the goal to identify new pathways/targets whose inhibition might overcome ASI resistance,
we performed extensive bioinformatics analyses of RNA-seq data including those from paired prostate
cancer (PCa) cells with different sensitivities to enzalutamide, 498 PCa tumors with different responses
to hormone therapy and 52 pairs of PCa specimen (tumors vs adjacent normal). Both the -catenin-
dependent canonical Wnt cascade and the -catenin-independent non-canonical Wnt signaling were
identified as pathways whose elevation might contribute to acquisition of ASI resistance. The objective
of the proposed research is to define the roles of Wnt signaling in acquisition of ASI resistance in CRPC
and to exploit these pathways as novel therapeutic targets for CRPC patients who no longer respond to
ASIs. The central hypothesis is that Wnt signaling causes constitutive activation of AR signaling, thus
CRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing three
Specific Aims - (1) to dissect the role of-catenin signaling in enzalutamide resistance of PCa; (2) to
examine how activation of the non-canonical Wnt signaling contributes to enzalutamide resistance in
PCa; and (3) to test whether simultaneous inhibition of canonical and non-canonical Wnt cascades is an
effective approach to treat enzalutamide-resistant PCa and to probe the significance of tumor
microenvironment Wnt in the acquisition of enzalutamide resistance. 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, human PCa xenograft,
and patient-derived organoid methodologies. The rationale for the research is that it will be the first to
comprenhensively probe the importance of Wnt signaling in acquisition of ASI resistance of CRPC. This
contribution is significant because it will (i) define the molecular mechanism by which Wnt signaling
activates AR; (ii) genetically evaluate how these pathways contribute to PCa progression and metastasis;
and (iii) demonstrate Wnt cascades as critical therapeutic targets to enhance the efficacy of ASI.

## Key facts

- **NIH application ID:** 10427416
- **Project number:** 5R01CA256893-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** XIAOQI LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $485,160
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427416

## Citation

> US National Institutes of Health, RePORTER application 10427416, Enhancing the efficacy of androgen signaling inhibitors in prostate cancer (5R01CA256893-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10427416. Licensed CC0.

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