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尽管有数十年的临床试验，但迫切有效地发展了有效的细胞癌（NCCRCC）。因为NCCRCCCC是一个关键的临床未满足需求。我们添加了这种新颖的JAK和AKT抑制剂组合，它阻止了使用模型中NCCRCCC癌细胞的生长。 - 基因组的适应性导致磷脂水解对动员ID和游离脂肪酸，以维持脂肪酸和氧化磷酸化。线粒体生物发生和动力学在AIM 2中增加了呼吸，我们将阐明溶血磷脂如何编码以维持癌症的癌症，尽管我们将试图发现可能导致更多的分子靶标。更有效的组合更有效。更广泛的科学界的扩展之所以扩展，是因为Thelk Worl建立了信号传导和代谢途径的共同定位，以改善和延长NCCRCC患者的生活。