# Targeting eIF4A1-dependent HK2 translation axis for prevention of castration-resistant prostate cancer

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $394,636

## Abstract

Project Summary/Abstract
Our overarching goal is to identify a novel mechanism-driven chemoprevention strategy that can effectively
prevent or delay the development and progression of currently incurable castration-resistant prostate cancer
(CRPC) to revolutionize long-term survival. In the United States, prostate cancer strikes one in six men and is
the second leading cause of cancer-related deaths in men. Clinically, androgen deprivation therapy (ADT) with
surgical or medical castration remains standard-of-care for advanced/metastatic prostate cancer for decades.
Despite its efficacy in the short term, ADT is inevitably followed by the development of CRPC in the majority of
patients. The discovery that persistent AR signaling axis plays a crucial role in CRPC led to FDA-approval of
“second-generation” ADT drugs, such as the novel AR antagonist enzalutamide/Xtandi, providing 4-5 months
survival benefits. However, nearly all the patients will develop resistance to these new drugs within 6 to 12
months. Thus, development of CRPC following ADT is a major clinical problem but presents a unique window
for innovative secondary/tertiary chemoprevention. We demonstrate that Warburg effect caused by the
elevated hexokinase 2 (HK2), which catalyzes the irreversible first step of glycolysis by phosphorylating
glucose to glucose-6-phosphate (G-6-P), is required for tumor growth of CRPC. Accordingly, targeting HK2
enzymatic activity could prevent or delay CRPC. Unfortunately, current HK2 inhibitors, such as 2-deoxyglucose
(2-DG), are not specific with side effects due to inhibition of ubiquitously expressed HK1, which is required for
glucose metabolism of normal cells. Based on our published data and preliminary studies, we hypothesize
that inhibition of HK2-mediated Warburg effect by targeting eIF4A1-dependent HK2 protein synthesis prevents
or delays CRPC progression. We will test this central hypothesis by accomplishing 3 specific aims. Aim 1 is to
structurally elucidate the molecular mechanism underlying eIF4A1-dependent HK2 mRNA translation in CRPC.
Aim 2 is to genetically demonstrate that targeting eIF4A1 blocks HK2 mRNA translation to prevent tumor
growth of CRPC in vivo; and Aim 3 is to pharmacologically demonstrate that eIF4A1specific inhibitor silvestrol
blocks HK2 mRNA translation to prevent tumor growth in preclinical CRPC models. Successful
accomplishment of the proposed studies will provide Proof-of-Principle that targeting eIF4A1-HK2 translation
axis serves as a mechanisms-driven novel and actionable strategy to prevent CRPC progression at structural,
genetic and pharmacological levels.

## Key facts

- **NIH application ID:** 10051412
- **Project number:** 5R01CA225973-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Yibin Deng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,636
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051412

## Citation

> US National Institutes of Health, RePORTER application 10051412, Targeting eIF4A1-dependent HK2 translation axis for prevention of castration-resistant prostate cancer (5R01CA225973-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10051412. Licensed CC0.

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