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Adaptive resistance to AR inhibitors in hypoxia by GPT1

GPT1对缺氧环境下AR抑制剂的适应性抵抗

基本信息

批准号：
10638774
负责人：
Zheng David Qian
金额：
$ 35.23万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-18 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638774
关键词：
Alanine Algorithms American Anabolism Androgen Antagonists Androgen Receptor Androgens Automobile Driving Biological Biopsy Specimen Bypass CRISPR/Cas technology Cancer Etiology Cancer Patient Cell model Cells Cessation of life Chemicals Clinical Cytoprotection Data Development Disease Outcome Disseminated Malignant Neoplasm Energy Metabolism Enzymes Fatty Acids Genetic Transcription Glucose Glutamates Glutamine Growth Human Hypoxia Immunohistochemistry In Vitro Link Lipids Literature Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Metabolic Metabolic Pathway Metabolism Metastatic Prostate Cancer Modeling Molecular Monitor Mus Oncogenic Pathway interactions Patients Play Prognosis Protein Overexpression Pyruvate Resistance Role Sampling Solid Testing Tissue Sample Transaminases Transcriptional Regulation Treatment Efficacy Up-Regulation Xenograft Model Xenograft procedure alpha ketoglutarate androgen deprivation therapy cancer cell candidate marker castration resistant prostate cancer clinical development clinically significant deprivation design drug efficacy enzalutamide fatty acid biosynthesis glucose metabolism hypoxia inducible factor 1 improved in vivo inhibitor insight lipid biosynthesis men mortality neoplastic cell novel patient derived xenograft model prevent prostate cancer cell prostate cancer cell line prostate cancer progression resistance mechanism response screening single cell analysis standard of care therapeutic target therapy resistant transcriptome transcriptomics treatment response treatment strategy tumor tumor hypoxia tumor progression

项目摘要

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.

项目总结