Project 3: MITF in Drug Resistance and Metabolism in Melanoma

项目 3：MITF 在黑色素瘤耐药性和代谢中的作用

• 批准号: 9071970
• 负责人: Jeffrey W Smith
• 金额: $ 42.88万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071970
• 关键词: Adult; American Cancer Society; Amino Acids; BRAF gene; Biogenesis; Carbon; Cell Cycle Progression; Cells; Cellular Metabolic Process; Cellular Stress; Chronic; Collaborations; Diagnosis; Disease; Drug resistance; Enzymes; Event; Exposure to; Feedback; Foundations; Generations; Genetic; Genetic Transcription; Glutamine; Glycolysis; Human; Institutes; Isoenzymes; Lactate Dehydrogenase; Lead; Malignant Neoplasms; Measures; Mediating; Medical; Melanoma Cell; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Lung; Mitochondria; Modeling; Molecular; Mus; Mutate; Paper; Patients; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Process; Publishing; Pyruvate; Qualifying; Reaction; Regulation; Relapse; Research; Resistance; Skin Cancer; Solid Neoplasm; Stem cells; Stress; Testing; Therapeutic; Tracer; Translations; Universities; Work; acquired drug resistance; activating transcription factor 4; age group; anticancer research; deprivation; drug metabolism; drug sensitivity; experience; genetic manipulation; inhibitor/antagonist; knock-down; melanoma; microphthalmia-associated transcription factor; neoplastic cell; novel therapeutic intervention; novel therapeutics; nutrient deprivation; professor; response; tumor; tumor microenvironment

SUMMARY – PROJECT 3: MITF IN DRUG RESISTANCE AND METABOLISM IN MELANOMA Long Term Objective: The long-term objective of this study is too understand how stress from the tumor microenvironment, and from treatment with drug, alter melanoma cell phenotype and lead to a drug resistant and invasive phenotype. The study seeks to identify new leverage points that can be targeted to develop new drugs. The Unmet Medical Need: Estimates by the American Cancer Society (ACS) predict that in 2013 close to 80,000 new melanoma cases were diagnosed in the US, and almost 10,000 people were expected to die from the disease. Unlike many other cancers, melanoma occurs in all age groups, and is one of the most common malignancies in adults under 40. There is a pressing unmet medical need for new therapies to treat melanoma, especially because patients treated with BRAF inhibitors experience only short term benefit, the vast majority ultimately relapse as the tumor becomes resistant to drug. The Hypothesis: The primary hypothesis of the study is that adaptation two types of stress, (i) nutrient deprivation and (ii) and BRAF inhibition, evoke related molecular and metabolic adaptations in melanoma that lead to an invasive, tumor-initiating and drug-resistant phenotype. We pose two questions as Specific Aims: (1) What are the molecular mechanisms underlying the generation of phenotypically invasive, tumor-initiating or drug-resistant melanoma cells by the ATF4-MITF axis? (2) What metabolic changes accompany acquisition of tolerance to nutrient deprivation and resistance to BRAFi? The Research Team: The Project Leader and co-I are uniquely qualified to conduct the studies. Dr. Colin Goding is Professor at the Ludwig Institute for Cancer Research and Co-Director, Oxford Stem Cell Institute at the University of Oxford. Dr. Goding is one of the internationally recognized thought leaders in the field of melanoma. Dr. Jeffrey W. Smith has led a research team focused on defining central carbon metabolism in cancer for the past decade. The team's primary strategy has been to use isotopic tracers to quantify metabolic flux, a direct measure of activity of metabolic pathways. In collaboration with Dr. Andrei Osterman (leader of Core B), the group has published six key papers that lay the foundation for understanding regulation of melanoma cell metabolism. Work proposed in this project will closely integrate with studies outlined in Project 1 (UPR), Project 2 (PGC1) as with the two scientific Cores.

项目3：MITF在黑色素瘤耐药和代谢中的作用 长期目标：这项研究的长期目标是太了解来自肿瘤的压力 微环境，并从药物治疗，改变黑色素瘤细胞表型并导致耐药 和侵袭性表型。这项研究试图确定新的杠杆点，可以有针对性地开发新的 毒品。 未得到满足的医疗需求：据美国癌症协会(ACS)估计，2013年将接近 美国新诊断出8万例黑色素瘤病例，预计将有近1万人死于 这种疾病。与许多其他癌症不同，黑色素瘤发生在所有年龄段，是最常见的癌症之一 40岁以下成年人的恶性肿瘤。对治疗黑色素瘤的新疗法的迫切需要尚未得到满足， 尤其是因为接受BRAF抑制剂治疗的患者只获得了短期的益处，绝大多数 随着肿瘤对药物产生抗药性，最终会复发。 假设：这项研究的主要假设是适应两种类型的压力，(I)营养 剥夺和(Ii)和BRAF抑制，在黑色素瘤中引起相关的分子和代谢适应 导致侵袭性、肿瘤起始和耐药表型。 我们提出了两个问题作为具体目标：(1)产生这种疾病的分子机制是什么 ATF4-MITF轴的表型侵袭性、肿瘤起始或耐药黑色素瘤细胞？(2)什么 代谢变化伴随着获得对营养剥夺的耐受性和对BRAFi的抵抗力？ 研究团队：项目负责人和第一合作伙伴是唯一有资格进行研究的人。科林博士 戈丁是路德维希癌症研究所教授，牛津干细胞研究所联席主任 牛津大学。戈丁博士是国际公认的思想领袖之一，在 黑色素瘤。杰弗里·W·史密斯博士领导了一个研究小组，专注于定义 过去十年的癌症。该团队的主要策略是使用同位素示踪剂来量化新陈代谢 通量，直接衡量新陈代谢途径的活性。与Andrei Osterman博士合作( 核心B)，该小组发表了六篇关键论文，为理解监管奠定了基础 黑色素瘤细胞代谢。本项目中提出的工作将与项目1中概述的研究紧密结合 (普遍定期审议)，项目2(PGC1)与两个科学核心一样。