Novel Treatment Strategies for Cancer

癌症新治疗策略

基本信息

批准号：
10193053
负责人：
George Victor Thomas
金额：
$ 28.8万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10193053
关键词：
Address Antibiotics Arachidonic Acids Area Bioenergetics Biogenesis Biological Biological Markers Bypass Cell Death Cell Survival Cell model Cells Chromophobe Renal Cell Carcinoma Clinical Clinical Trials Combined Modality Therapy Communities Consumption Conventional (Clear Cell) Renal Cell Carcinoma Diagnosis Drug Kinetics FDA approved Fatty Acids Future Genetic Transcription Glucose Glycolysis Goals Growth Half-Life Hour Hydrolysis Knowledge Laboratories Lead Linoleic Acids Lipid Peroxidation Lipids Lysophospholipids Malignant Epithelial Cell Malignant Neoplasms Marshal Metabolic Metabolic Pathway Metabolic stress Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Target Mus Nonesterified Fatty Acids Nutrient Depletion Oncology Oxidative Phosphorylation Papillary Papillary Carcinoma Patient-Focused Outcomes Patients Peroxidases Phospholipids Polyunsaturated Fatty Acids Production Proto-Oncogene Proteins c-akt Regimen Renal carcinoma Reporting Research Respiration Sampling Signal Pathway Signal Transduction Subgroup Survival Rate System Testing Therapeutic Therapeutic Effect Translating Unsaturated Fatty Acids Work base cancer cell cancer therapy clinically relevant cytotoxicity driver mutation drug testing effective therapy fatty acid oxidation improved improved outcome in vivo inhibitor/antagonist mouse model non-genomic novel novel drug combination pharmacodynamic biomarker phospholipid-hydroperoxide glutathione peroxidase response synergism tigecycline transcriptional reprogramming transcriptomics treatment strategy tumor tumor growth tumor metabolism

项目摘要

PROJECT SUMMARY: Novel treatment strategies for cancer The urgent need to develop effective treatments for non-clear cell renal cell carcinomas (NCCRCC) is underscored by consistently poor overall survival, despite decades of clinical trials. This is because there are no biologically rational treatments for NCCRCC, compared to conventional clear cell renal cell carcinomas. Accordingly, the lack of therapies for NCCRCC is a critical clinical unmet need. We addressed this need by developing a novel JAK and AKT inhibitor combination treatment that blocked the growth of NCCRCC cancer cells invitro and in mouse models. Importantly, we discovered a non-genomic early adaptive survival signal following JAK-AKT inhibition therapy characterized by a “lipid reprogrammed” transcriptional state. This non-genomic metabolic adaptation resulted in phospholipid hydrolysis to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Our objective is to definitely establish the mechanistic and functional basis for this observed effect. This leads us to hypothesize that the induction of metabolic catastrophe is essential to inducing cytotoxicity. We will test this hypothesis as follows: In Aim 1, we will explore how mitochondrial biogenesis and dynamics converge to increase respiration in the setting of metabolic stress. Next, in Aim 2, we will elucidate how lysophospholipids and fatty acids are marshalled to maintain cancer cell survival despite nutrient depletion. Importantly, in both aims we will seek to discover molecular targets that can potentially lead to even more potent therapeutic combinations. The extension of this research to the broader scientific and clinical community will be significant because this work will establish the framework for co-targeting of signaling and metabolic pathways to improve and extend the lives of patients with NCCRCC.

项目摘要：癌症的新型治疗策略迫切需要开发有效的细胞肾细胞癌（NCCRCC）的有效治疗方法，其总体生存率持续较差，临床试验的Dospice死亡。这是因为与常规的透明细胞肾细胞癌相比，NCCRCC没有生物学上的合理治疗方法。根据缺乏NCCRCC疗法，这是一个关键的临床未满足需求。我们通过开发一种新型的JAK和AKT抑制剂组合治疗来解决这种需求，该治疗阻止了NCCRCC癌细胞Invitro和小鼠模型中的生长。重要的是，我们在JAK-AKT抑制治疗后发现了一个非基因组早期自适应生存信号，其特征在于“脂质重编程”的转录状态。这种非基因组代谢适应导致磷脂水解动员溶血磷脂和游离脂肪酸，以维持脂肪酸氧化和氧化磷酸化。我们的目标是确保为这种观察到的效果建立机械和功能基础。这使我们假设诱导代谢灾难对于诱导的细胞毒性至关重要。我们将测试该假设如下：在AIM 1中，我们将探讨线粒体生物发生和动力学如何在代谢应激的环境中融合以增加呼吸。接下来，在AIM 2中，我们将阐明如何对溶血磷脂和脂肪酸进行编组以维持癌细胞存活目的地养分耗竭。重要的是，在这两个目标中，我们都将寻求发现可能导致更多潜在的治疗组合的分子靶标。这项研究向更广泛的科学和临床界的扩展将是重要的，因为这项工作将建立与信号传导和代谢途径共同定位的框架，以改善和延长NCCRCC患者的生活。