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.

项目摘要：开发非清晰细胞肾脏癌的新型多延展性 非清晰细胞肾细胞癌（NCCRCC）是肾癌的治疗异常值，因为那里 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患者会导致可变，不完整和短暂的反应，导致5年惨淡 生存率仅为8％。因此，缺乏治疗NCCRCC的机械学引导疗法是关键 癌症治疗中未满足的需求。我们最近报道说，将JAK和AKT结合的治疗方法 抑制剂（JAK-AKT）有效地熄灭了两种信号通路以限制NCCRCC肿瘤的生长，并具有良好的 耐受性1。但是，尽管有效抑制了临界增长，生存和旁路信号，但我们没有 实现深肿瘤回归。因此，JAK-AKT治疗的代谢和转录组学分析 NCCRCC细胞和患者肿瘤表明，虽然共同治疗抑制了糖酵解，但糖酵解的降低 葡萄糖消耗和乳酸产生，它也偶然地诱导了磷脂水解，并释放 24小时内游离脂肪酸以满足其生物能的需求，因此可以生存。我们有 称这种迅速出现的非突出代谢生存适应：治疗诱导 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抑制剂协同导致肿瘤回归 体内。此外，JAK-AKT在细胞和患者肿瘤中诱导的TIMR促进磷脂水解，并以 随后释放多不饱和脂肪酸（PUFA），例如蛛网膜酸和亚油酸NCCRCC中 细胞和治疗的患者肿瘤，建立了我们发现的临床相关性。我们观察到增加 在PUFAS增强的脂质过氧化中，导致对谷胱甘肽过氧化物酶（GPX4）的敏感性提高 和铁凋亡，这是一种非凋亡调节的细胞死亡程序。综上 在细胞和小鼠模型的NCCRCC肿瘤中，AKT在合成中致命。 因此，这项新研究的长期目标是改善 NCCRCC通过利用我们的发现的动量进入机械化的新组合处理 策略。因此，我们现在的目标是确定调节Timr的机制，并提供证明 - 概念认为针对TIMR是NCCRCC的宝贵治疗策略。我们的中心假设是 TIMR使癌细胞能够通过劫持代谢过程来适应和生存抗癌疗法，并且 这些漏洞可以被治疗。我们将在以下具体目的中检验这一假设： 目的1：确定线粒体呼吸抑制的程度可以增强JAK-AKT的影响 NCCRCC的抑制剂。 AIM 2：在JAK-AKT抑制作用中建立诱导铁凋亡的治疗作用。