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

• 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
• 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

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.

项目摘要 雄激素受体(AR)在人类前列腺癌的发生发展中起着基础性的作用。多数 目前针对AR表达(AR+)转移癌的治疗以抑制AR为目标，例如 接受雄激素剥夺疗法(ADT)或AR抑制剂苯扎鲁胺(ENZA)的新治疗。 尽管最近取得了进展，但抗AR治疗(ADT/ENAA)的有效性和可持续性仍然有限 由于治疗耐药，导致肿瘤进展和患者死亡。对新世纪的新认识 因此，迫切需要一种抵抗机制。肿瘤缺氧常见于实体癌 包括转移性前列腺癌，长期以来一直被认为是治疗抵抗的原因。然而， 确切的机制尚不清楚。最近，我们发现缺氧通过以下途径增强对ADT/Enza的抗性 代谢重编程(耿氏等人，NAT.通讯。2018年)。本课题旨在进一步阐明其作用机制。 作用以胞浆谷丙转氨酶(GPT1)为中心。在文献中，GPT1被称为 代谢酶处于葡萄糖和谷氨酰胺代谢途径的交汇点，许多GPT1- 下游代谢产物是致癌的，对癌细胞具有细胞保护作用。然而，GPT1在基因转录中的作用 产生抗AR治疗耐药性的机制尚不清楚。我们通过代谢和转录鉴定了GPT1 我们的抗AR抗性细胞的筛选。我们新的先导数据进一步表明：1)GPT1的表达和 在低氧条件下，ADT/Enza的活性上调，II)ADT/Enza的上调是一致的。 耐药细胞、异种移植、PDX和患者样本，以及iii)临床GPT1 mRNA与低氧相关， 疾病转归差，患者对ADT/Enza耐药。在这项建议中，我们将决定是否和 前列腺癌细胞如何利用GPT1逃避ADT/Enza在细胞和肿瘤模型中的研究 病人样本。我们将确定GPT1在AIM中诱导ADT/Enza抗性的分子功能 1、了解Aim的作用机制，并确定其在Aim中的临床意义3.前列腺癌 癌症是美国男性癌症死亡的第二大原因。新的机械论理解和 治疗策略是未得到满足的需求。这里基于GPT1的研究可能会带来新的机械论见解， 为新的预后和治疗策略铺平道路，以预测药物疗效，监测疾病的发病 抵抗，并防止或逆转抵抗。