# Hormone signaling and translation control in advanced prostate cancer

> **NIH NIH R37** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $166,667

## Abstract

PROJECT SUMMARY/ABSTRACT
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
20-014. The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has
had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular,
castration resistant prostate cancer (CRPC) that is resistant to therapies such as enzalutamide and abiraterone
are increasing in occurrence amongst patients and is uniformly fatal. The main barriers against therapeutic
advances are a paucity of relevant disease models and a very poor understanding of the mechanisms that give
rise to this phenotype. The process of protein synthesis has long been considered subordinate to alterations at
the levels of DNA and RNA in cancer etiology. However, work from our laboratory and others have revealed that
protein synthesis control is a dynamic process that coordinates not only bulk mRNA translation, but also the
specialized translation of distinct mRNAs important for cancer phenotypes.
Recently, our laboratory has uncovered a new functional link between androgen receptor signaling and the
process of mRNA translation initiation. We found that decreases in androgen receptor activity lead to a
compensatory increase in the activity of the eIF4F translation initiation complex which drives hormone signaling
independence in CRPC. Importantly, this is mediated through the translation of distinct subsets of mRNAs.
Based on these findings, we hypothesize that aberrant mRNA translation of distinct gene networks enables
resistance to nuclear hormone receptor inhibition and CRPC progression. Our long-term objective is to utilize
state-of-the-art patient derived models, ribosome profiling, and next-generation translation inhibitors to
definitively investigate the fundamental link between the androgen receptor and protein synthesis control in a
highly relevant and newly emerging disease course for prostate cancer patients. To do so, we will address the
following aims: 1) determine how alterations in mRNA translation initiation promote resistance to AR pathway
directed therapies, and 2) delineate the translational gene networks that promote resistance to AR signaling
inhibitors.
Ultimately, these studies are poised to uncover a new paradigm for gene regulation in nuclear hormone receptor
inhibitor resistance and provide the preclinical basis for targeting the protein synthesis apparatus in an
increasingly common and highly aggressive disease.

## Key facts

- **NIH application ID:** 10175894
- **Project number:** 3R37CA230617-02S1
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Andrew Caleb Hsieh
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $166,667
- **Award type:** 3
- **Project period:** 2018-12-06 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10175894

## Citation

> US National Institutes of Health, RePORTER application 10175894, Hormone signaling and translation control in advanced prostate cancer (3R37CA230617-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10175894. Licensed CC0.

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