Developing novel polytherapies for Non-Clear Cell Renal Cell Carcinoma

开发非透明细胞肾细胞癌的新型多疗法

• 批准号: 10308505
• 负责人: George Victor Thomas
• 金额: $ 40.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308505
• 关键词: Address; Antibiotics; Arachidonic Acids; Area; Bioenergetics; Biogenesis; Biological Markers; Bypass; Cell Death; Cell model; Cells; Clinical; Consumption; Diagnosis; Diet; Dietary Supplementation; Drug Kinetics; FDA approved; Fatty Acids; Glucose; Glycolysis; Goals; Growth; Half-Life; Hour; Hydrolysis; In Vitro; Knowledge; Laboratories; Linoleic Acids; Lipid Peroxidation; Lipids; Malignant Epithelial Cell; Malignant Neoplasms; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Nonesterified Fatty Acids; Oxidative Phosphorylation; Patient-Focused Outcomes; Patients; Peroxidases; Phospholipids; Polyunsaturated Fatty Acids; Production; Proto-Oncogene Proteins c-akt; Renal carcinoma; Reporting; Research Proposals; Respiration; Sampling; Signal Pathway; Signal Transduction; Survival Rate; System; Testing; Therapeutic; Therapeutic Effect; Translating; Unsaturated Fatty Acids; base; cancer cell; cancer therapy; clinically relevant; drug testing; improved outcome; in vivo; inhibitor; mouse model; new therapeutic target; nondrug therapy; novel; pharmacodynamic biomarker; phospholipid-hydroperoxide glutathione peroxidase; programs; response; tigecycline; transcriptomics; treatment strategy; tumor; tumor growth

PROJECT SUMMARY: Developing novel polytherapies for Non-Clear Cell Renal Carcinoma Non-clear cell renal cell carcinoma (NCCRCC) is the therapeutic outlier in kidney cancer because there are no approved treatments for these patients. Consequently, diverse treatments that are currently given to NCCRCC patients result in variable, incomplete and short-lived responses, contributing to a dismal 5-year survival rate of just 8%. Accordingly, the lack of mechanistically-guided therapies to treat NCCRCC is a critical unmet need in cancer treatment. We recently reported that a therapeutic approach combining JAK and AKT inhibitors (JAK-AKT) potently extinguished both signaling pathways to restrain NCCRCC tumor growth, with good tolerability1. However, despite effective inhibition of critical growth, survival and bypass signals, we did not achieve deep tumor regressions. Consequently, metabolic and transcriptomic profiling of JAK-AKT treated NCCRCC cells and patient tumors revealed that while the co-treatment inhibited glycolysis with decreases in glucose consumption and lactate production, it also paradoxically induced phospholipid hydrolysis with release of free fatty acids within 24 hours to meet their bioenergetic needs, therefore enabling their survival. We have termed this rapidly emergent non-mutational metabolic survival adaptation: treatment-induced metabolic reprogramming (TIMR). Here, we now show that TIMR is associated with increased mitochondrial mass and respiration. Importantly, inhibition of mitochondrial respiration synergizes with JAK-AKT inhibitors to cause tumor regressions in vivo. Further, JAK-AKT induced TIMR in cells and patient tumors promotes phospholipid hydrolysis, with subsequent release of polyunsaturated fatty acids (PUFA) such as arachidonic acid and linoleic acid in NCCRCC cells and treated patient tumors, establishing the clinical relevance of our findings. We observed that the increase in PUFAs enhanced lipid peroxidation, causing increased sensitivity to glutathione peroxidase (GPX4) inhibition and ferroptosis, a non-apoptotic regulated cell death program. Taken together, co-targeting TIMR and JAK- AKT was synthetically lethal in NCCRCC tumors in cells and mouse models. Therefore, the long-term goal of this new research proposal is to improve the outcomes for patients with NCCRCC by leveraging the momentum of our findings into mechanistically guided new combination treatment strategies. Accordingly, our objective now is to identify the mechanisms regulating TIMR, and to provide proof- of-concept that targeting TIMR is a valuable therapeutic strategy in NCCRCC. Our central hypothesis is that TIMR enables cancer cells to adapt and survive anti-cancer therapies by hijacking metabolic processes, and that these vulnerabilities can be therapeutically exploited. We will test this hypothesis in the following specific aims: Aim 1: Determining the extent to which inhibition of mitochondrial respiration enhances the effect of JAK-AKT inhibitors in NCCRCC. Aim 2: Establish the therapeutic effect of inducing ferroptosis in the setting of JAK-AKT inhibition.

项目总结：开发治疗非透明细胞肾癌的新型综合疗法 非透明细胞肾细胞癌（NCCRCC）是肾癌中的治疗异常值，因为 对这些患者没有批准的治疗方法。因此，目前给予的各种治疗 NCCRCC患者导致可变的、不完全的和短暂的反应，导致令人沮丧的5年 存活率只有8%。因此，缺乏治疗NCCRCC的机械引导疗法是一个关键问题。 未满足的癌症治疗需求。我们最近报道了一种联合JAK和AKT的治疗方法 抑制剂（JAK-AKT）有效地消除了这两种信号通路，以抑制NCRCC肿瘤生长， 容忍度1.然而，尽管有效地抑制了临界生长、存活和旁路信号， 实现肿瘤深度消退。因此，JAK-AKT治疗的代谢和转录组学分析 NCCRCC细胞和患者肿瘤显示，虽然共同治疗抑制糖酵解， 葡萄糖消耗和乳酸产生，它也矛盾地诱导磷脂水解与释放 在24小时内释放游离脂肪酸，以满足他们的生物能量需求，从而使他们能够生存。我们有 称为这种快速出现的非突变代谢生存适应：治疗诱导的 代谢重编程（TIMR）。 在这里，我们现在表明，TIMR与线粒体质量和呼吸增加有关。 重要的是，抑制线粒体呼吸与JAK-AKT抑制剂协同作用，导致肿瘤消退 in vivo.此外，JAK-AKT诱导的细胞和患者肿瘤中的TIMR促进磷脂水解， NCRCC中多不饱和脂肪酸（PUFA）如花生四烯酸和亚油酸随后释放 细胞和治疗的患者肿瘤，建立我们的发现的临床相关性。我们观察到， PUFAs增强了脂质过氧化作用，导致对谷胱甘肽过氧化物酶（GPX 4）抑制的敏感性增加 和铁凋亡，一种非凋亡调节的细胞死亡程序。总之，共同靶向TIMR和JAK- 在细胞和小鼠模型中，AKT在NCCRCC肿瘤中是合成致死的。 因此，这项新研究提案的长期目标是改善患者的结局， NCCRCC通过利用我们的研究结果的势头，以机械方式指导新的联合治疗， 战略布局因此，我们现在的目标是确定调节TIMR的机制，并提供证据- 因此，靶向TIMR是NCCRCC有价值的治疗策略。我们的核心假设是， TIMR使癌细胞能够通过劫持代谢过程来适应抗癌疗法并存活下来， 这些弱点可以被利用来治疗。我们将在以下具体目标中检验这一假设： 目的1：确定线粒体呼吸抑制增强JAK-AKT作用的程度 NCCRCC中的抑制剂。 目的2：建立在JAK-AKT抑制的情况下诱导铁凋亡的治疗效果。