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）是美国男性最常诊断的癌症，2022年 光是这一项就将导致超过三万四千人死亡PCa死亡率通常由以下疾病引起： 进展到转移性去势抵抗期（mCRPC），并已扩散到远处，如 骨骼、大脑、肝脏和淋巴结。目前，没有有效的或治愈性的治疗策略， mCRPC，部分原因是对雄激素剥夺治疗（ADT）的获得性耐药率较高 以及mCRPC的标准治疗化疗药物多西他赛（DTX）。因此，有一个关键的 需要新型有效的mCRPC治疗选择。最近的研究结果表明谷氨酰胺和 相关谷氨酸代谢是mCRPC代谢重编程的重要驱动因素， to drug药物resistance抗性mechanisms机制.事实上，在ADT后的PCa中已经确定了代谢开关， 使细胞依赖于雄激素非依赖性的β-氨基丁酸酶（GLS 1，这种酶将 谷氨酰胺转化为谷氨酸），而不是被ADT抑制的同种型，从而产生耐药性。努力 化学抑制GLS 1来克服这个问题已经失败，因为谷氨酸盐通过 当存在生理学相关水平的胱氨酸时，xCT转运蛋白。然而，我们的初步数据显示， 同时抑制GLS 1和谷氨酸脱氢酶（GDH，转化为谷氨酸的酶）， 谷氨酸到TCA循环中间体α-酮戊二酸）可能足以克服这种抗性 包括mCRPC在内的PCa亚型的机制。该项目的总体目标是确定新的 与DTX协同作用的mCRPC组合治疗，以靶向代谢脆弱性并克服 耐药性，以改善治疗效果。中心假设：同时抑制GLS 1和GDH 与DTX联合使用可以规避耐药机制并增加治疗功效 与mCRPC中的SOC相比。目的1：确定CB-839加DTX抑制GLS 1的代谢作用 用于体内PCa肿瘤生长的协同抑制。目标2：阐明并行GLS 1和 GDH抑制加DTX对PCa生长、增殖、代谢、侵袭性和侵袭性的影响 与体外SOC相比。目的3：评价GLS 1抑制剂和GDH联合治疗是否 抑制剂加DTX在体内可协同抑制PCa生长，比SOC更有效。实验 技术包括代谢组学、使用稳定同位素示踪剂的代谢通量分析、体外和体内 将进行mCRPC的建模和药物治疗疗效的验证，以实现研究 目标.这些发现将用于告知伴随多西他赛的新治疗策略，以预防 mCRPC中的癌症生长、增殖和侵袭性，以获得更有效的治疗和改善 mCRPC患者的结局。