Targeting Metabolic Vulnerabilities with Synergistic Therapeutic Agents for Treatment of Metastatic Castration-Resistant Prostate Cancer.

用协同治疗剂针对代谢脆弱性治疗转移性去势抵抗性前列腺癌。

• 批准号: 10677412
• 负责人: Gabrelle Lavender Hackman
• 金额: $ 3.83万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2026-08-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677412
• 关键词: Allografting; American; Androgens; Automobile Driving; Biomass; Brain; Bypass; Cancer Etiology; Caring; Castration; Cell Line; Cell Proliferation; Cells; Cessation of life; Chemicals; Chemoresistance; Citric Acid Cycle; Combined Modality Therapy; Cystine; DU145; Data; Development; Diagnosis; Disease; Distant; Drug Synergism; Drug resistance; Enzymes; Epigallocatechin Gallate; Essential Amino Acids; Event; Exhibits; Formulation; Generations; Glutamate Dehydrogenase; Glutamate Metabolism Pathway; Glutamates; Glutaminase; Glutamine; Goals; Growth; Homeostasis; In Vitro; Kidney; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Neoplasm Metastasis; Nutrient; Oxidation-Reduction; PC3 cell line; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Probability; Process; Production; Prognosis; Proliferating; Protein Isoforms; Reporting; Research; Resistance; Role; Signal Transduction Pathway; Site; Survival Rate; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissues; Tracer; Treatment Efficacy; Treatment outcome; Validation; Work; acquired drug resistance; advanced prostate cancer; alpha ketoglutarate; androgen deprivation therapy; androgen sensitive; antiporter; bone; cancer cell; cancer diagnosis; cancer drug resistance; cancer subtypes; cancer type; carbon skeleton; castration resistant prostate cancer; chemotherapy; combinatorial; common treatment; comparative efficacy; curative treatments; docetaxel; druggable target; effective therapy; efficacy outcomes; experimental study; improved; improved outcome; in vivo; in vivo Model; inhibitor; insight; lymph nodes; men; metabolomics; meter; mortality; novel; novel therapeutic intervention; prevent; prostate cancer cell line; prostate cancer progression; resistance mechanism; stable isotope; standard of care; synergism; therapeutically effective; treatment strategy; tumor growth

PROJECT SUMMARY Broad Impact: Prostate cancer (PCa) is the most commonly diagnosed cancer in American men and in 2022 alone will result in the death of over 34,000 men. PCa mortality is typically caused by disease that has advanced to the metastatic castration-resistant stage (mCRPC) and has spread to distant sites such as the bone, brain, liver, and lymph nodes. Currently, there are no effective or curative therapeutic strategies for mCRPC, which is in part due to high rates of acquired drug resistance to androgen deprivation therapy (ADT) and the standard-of-care chemotherapy drug for mCRPC, docetaxel (DTX). Consequently, there is a critical need for novel and effective therapeutic options for mCRPC. Recent findings have indicated glutamine and related glutamate metabolism as significant drivers of the metabolic reprogramming of mCRPC that contributes to drug resistance mechanisms. Indeed, a metabolic switch has been identified in PCa following ADT that allows the cells to rely on the androgen-independent isoform of glutaminase (GLS1, the enzyme that converts glutamine to glutamate) rather than the isoform that is inhibited by ADT, affording drug resistance. Efforts to chemically inhibit GLS1 to overcome this issue have failed since there is a steady influx of glutamate via the xCT transporter when there are physiologically-relevant levels of cystine. However, our preliminary data shows that concurrently inhibiting GLS1 as well as glutamate dehydrogenase (GDH, the enzyme that converts glutamate to the TCA cycle intermediate alpha-ketoglutarate) may be sufficient to overcome this resistance mechanism across PCa subtypes including mCRPC. The overall goal of this project is to identify novel combinatorial treatments for mCRPC that synergize with DTX to target metabolic vulnerabilities and overcome drug resistance for improved treatment outcomes. Central hypothesis: Concurrent inhibition of GLS1 and GDH in combination with DTX can circumvent drug resistance mechanisms and increase therapeutic efficacy compared to SOC in mCRPC. Aim 1: Determine the metabolic role of GLS1 inhibition with CB-839 plus DTX for the synergistic inhibition of PCa tumor growth in vivo. Aim 2: Elucidate the impact of concurrent GLS1 and GDH inhibition plus DTX on PCa growth, proliferation, metabolism, aggressiveness, and invasiveness compared to SOC in vitro. Aim 3: Evaluate whether combination treatment with a GLS1 inhibitor and a GDH inhibitor plus DTX can synergistically inhibit PCa growth more effectively than SOC in vivo. Experimental techniques including metabolomics, metabolic flux analysis using stable isotope tracers, in vitro and in vivo modeling of mCRPC, and validation of drug treatment efficacy will be undertaken to achieve the research goals. These findings will be used to inform novel treatment strategies to accompany docetaxel to prevent cancer growth, proliferation, and aggressiveness in mCRPC for more effective treatments and improved outcomes for patients with mCRPC.

项目摘要 广泛影响：前列腺癌（PCA）是美国男性最常见的癌症，在2022年 仅凭仅将导致超过34,000人死亡。 PCA死亡率通常是由疾病引起的 前进到转移性cast割阶段（MCRPC），并已扩散到远处的地点，例如 骨，大脑，肝脏和淋巴结。目前，没有有效或治愈的治疗策略 MCRPC，部分是由于获得雄激素剥夺治疗（ADT）的高耐药性速率 以及用于MCRPC，多西他赛（DTX）的护理标准化疗药物。因此，有一个关键 需要新颖有效的MCRPC治疗选择。最近的发现表明谷氨酰胺和 相关的谷氨酸代谢是MCRPC代谢重编程的重要驱动力的重要驱动力 耐药机制。确实，在ADT之后，PCA中已经确定了代谢开关 允许细胞依赖于雄激素非依赖性的谷氨酰胺酶的同工型（GLS1，转化的酶 谷氨酰胺至谷氨酸），而不是ADT抑制的同工型，具有耐药性。努力 化学抑制GLS1以克服该问题已经失败了，因为谷氨酸通过 XCT转运蛋白在生理上与胱氨酸的水平相关时。但是，我们的初步数据显示 同时抑制GLS1以及谷氨酸脱氢酶（GDH，转化的酶 谷氨酸到TCA循环中间α-酮戊二酸）可能足以克服这种电阻 PCA亚型在内的机制，包括MCRPC。该项目的总体目标是确定小说 MCRPC的组合治疗与DTX协同靶向代谢脆弱性并克服 耐药性可改善治疗结果。中央假设：同时抑制GLS1和GDH 结合DTX可以规避耐药性机制并提高治疗功效 与MCRPC中的SOC相比。 AIM 1：确定用CB-839加DTX抑制GLS1的代谢作用 为了协同抑制体内PCA肿瘤生长。目标2：阐明并发GLS1和 GDH抑制加DTX对PCA生长，增殖，代谢，侵略性和侵入性 与SOC在体外相比。 AIM 3：评估与GLS1抑制剂和GDH的组合治疗是否 抑制剂加DTX可以比体内更有效地协同抑制PCA的生长。实验 包括代谢组学，包括稳定同位素示踪剂的代谢通量分析的技术，体外和体内 将对MCRPC进行建模以及对药物治疗疗效的验证以实现研究 目标。这些发现将用于为新颖的治疗策略提供信息，以陪伴多西他赛以防止 MCRPC中的癌症生长，增殖和侵略性，以进行更有效的治疗 MCRPC患者的结果。