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: 10555185
• 负责人: George Victor Thomas
• 金额: $ 13.72万
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555185
• 关键词: Antibiotics; Arachidonic Acids; Area; Bioenergetics; Biogenesis; Biological Markers; Bypass; Cell Death; Cell model; Cells; Clinical; Combined Modality Therapy; Consumption; Diagnosis; Diet; Dietary Supplementation; Drug Kinetics; FDA approved; Fatty Acids; Glucose; Glycolysis Inhibition; 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; Pharmacotherapy; Phospholipids; Polyunsaturated Fatty Acids; Production; Proto-Oncogene Proteins c-akt; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research Proposals; Respiration; Sampling; Signal Pathway; Signal Transduction; Survival Rate; System; Testing; Therapeutic; Therapeutic Effect; Translating; Tumor Promotion; Unsaturated Fatty Acids; cancer cell; cancer therapy; clinically relevant; drug testing; glutathione peroxidase; improved outcome; in vivo; inhibitor; kidney cell; mouse model; new therapeutic target; novel; pharmacodynamic biomarker; programs; response; restraint; synergism; tigecycline; transcriptomic profiling; 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：开发治疗非透明细胞肾癌的新综合疗法 非透明细胞肾细胞癌(NCCRCC)是肾癌的治疗异常值，因为有 这些患者还没有得到批准的治疗方法。因此，目前给予的各种治疗方法 NCCRCC患者导致可变的、不完整的和短暂的反应，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。 癌症治疗中未得到满足的需求。我们最近报道了一种联合JAK和AKT的治疗方法 抑制物(JAK-AKT)有效地熄灭了抑制NCCRCC肿瘤生长的两条信号通路，具有良好的疗效 容忍度1.然而，尽管有效地抑制了关键的生长、生存和旁路信号，我们并没有 实现肿瘤的深度消退。因此，JAK-AKT治疗后的代谢和转录图谱 NCCRCC细胞和患者肿瘤显示，虽然联合治疗抑制了糖酵解，减少了 葡萄糖的消耗和乳酸的产生，也矛盾地诱导磷脂的水解和释放 在24小时内补充游离脂肪酸，以满足它们的生物能量需求，从而使它们得以存活。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 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，线粒体呼吸抑制与JAK-AKT抑制剂协同作用导致肿瘤消退 在活体内。此外，JAK-AKT在细胞和患者肿瘤中诱导的TIMR促进磷脂水解， NCCRCC中花生四烯酸和亚油酸等多不饱和脂肪酸(PUFA)的后续释放 细胞和治疗的患者肿瘤，建立我们的研究结果的临床相关性。我们观察到， 在多不饱和脂肪酸中，增强了脂质过氧化，导致对谷胱甘肽过氧化物酶(Gpx4)抑制的敏感性增加 以及铁下垂，一种非凋亡调节的细胞死亡程序。加在一起，共同瞄准TIMR和JAK- AKT在NCCRCC细胞和小鼠模型中具有合成致死性。 因此，这项新研究方案的长期目标是改善患者的预后 NCCRCC通过利用我们发现的势头进入机械引导的新联合治疗 战略。因此，我们现在的目标是确定管理TIMR的机制，并提供证据-- 靶向TIMR是NCCRCC有价值的治疗策略的概念。我们的中心假设是 TIMR使癌细胞能够通过劫持新陈代谢过程来适应和生存抗癌治疗，并且 这些漏洞可以在治疗上加以利用。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在多大程度上增强JAK-AKT的作用 NCCRCC中的抑制剂。 目的：建立JAK-AKT抑制条件下诱导铁性下垂的治疗效果。