# Adaptive resistance to AR inhibitors in hypoxia by GPT1

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $334,662

## Abstract

Project Summary
Androgen receptor (AR) plays a fundamental role in driving the development of human prostate cancer. Most
current treatments against the AR-expressing (AR+) metastatic cancer aim to inhibit AR, e.g. the standard of
care with androgen deprivation therapy (ADT), or new treatment with AR inhibitors enzalutamide (Enza).
Despite the recent advance, the efficacy and sustainability of anti-AR-treatments (ADT/Enza) are still limited
due to treatment resistance, which leads to tumor progression and patient mortality. New understanding in the
mechanism of resistance is therefore urgently needed. Tumor hypoxia occurs frequently in solid cancers
including metastatic prostate cancer, and has long been considered a cause of treatment resistance. However,
the exact mechanism is unclear. Recently, we have found that hypoxia confers ADT/Enza resistance via
metabolic reprogramming (Geng et al, Nat. Comm. 2018). This project is to further clarify the mechanism of
action centering on the cytosolic glutamate-pyruvate transaminase (GPT1). In literatures, GPT1 is known as a
metabolic enzyme at the converging point of glucose and glutamine metabolic pathways, and many GPT1-
downstream metabolites are oncogenic and cytoprotective to cancer cells. However, the role of GPT1 in
conferring anti-AR-treatment resistance is unknown. We identified GPT1 through metabolic and transcriptomic
screenings of our anti-AR-resistant cells. Our new pilot data further showed that i) GPT1 expression and
activity were upregulated by ADT/Enza in hypoxia, ii) the upregulation was consistent across ADT/Enza-
resistant cells, xenografts, PDX and patient samples, and iii) clinical GPT1 mRNA correlated with hypoxia,
poor disease outcomes, and ADT/Enza resistance in patients. In this proposal, we will determine whether and
how prostate cancer cells use GPT1 to evade ADT/Enza in hypoxia and in vivo with cell and tumor models and
patient samples. We will determine the molecular function of GPT1 in conferring ADT/Enza resistance in Aim
1, understand the mechanisms in Aim 2, and confirm its clinical significance in Aim 3. Metastatic prostate
cancer has the 2nd-leading cause of cancer death in American men. New mechanistic understanding and
therapy strategy are unmet needs. The GPT1-based studies here may lead to new mechanistic insights,
paving ways to new prognosis and treatment strategies to predict drug efficacy, monitor the onset of
resistance, and prevent or reverse resistance.

## Key facts

- **NIH application ID:** 10829854
- **Project number:** 5R01CA279964-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Zheng David Qian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $334,662
- **Award type:** 5
- **Project period:** 2023-04-18 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10829854

## Citation

> US National Institutes of Health, RePORTER application 10829854, Adaptive resistance to AR inhibitors in hypoxia by GPT1 (5R01CA279964-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10829854. Licensed CC0.

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