Project 3: MITF in Drug Resistance and Metabolism in Melanoma

总结-项目3：MITF在黑色素瘤耐药性和代谢中的作用 长期目标：本研究的长期目标是了解肿瘤的压力 微环境和药物治疗，改变黑色素瘤细胞表型，并导致耐药性 和侵袭性表型。该研究旨在确定新的杠杆点，可以有针对性地开发新的 毒品 未满足的医疗需求：美国癌症协会（ACS）的估计预测，2013年， 在美国诊断出80，000例新的黑色素瘤病例，预计将有近10，000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组，是最常见的癌症之一。 40岁以下成人的恶性肿瘤对于治疗黑色素瘤的新疗法存在迫切的未满足的医学需求， 特别是因为接受BRAF抑制剂治疗的患者仅经历短期获益， 当肿瘤对药物产生抗药性时，最终会复发。 假设：本研究的主要假设是，适应两种类型的压力，（一）营养 剥夺和（ii）和BRAF抑制，引起黑色素瘤中相关的分子和代谢适应， 导致侵入性、肿瘤引发和耐药性表型。 我们提出了两个问题作为具体的目的：（1）什么是分子机制的产生， 表型侵袭性，肿瘤启动或耐药黑色素瘤细胞的ATF 4-MITF轴？(2)什么 代谢变化伴随着获得耐受营养剥夺和抵抗BRAFi？ 研究团队：项目负责人和co-I具有开展研究的唯一资格。科林博士 Goding是路德维希癌症研究所的教授，也是牛津干细胞研究所的联合主任。 牛津大学。Goding博士是国际公认的思想领袖之一， 黑素瘤Jeffrey W.史密斯领导了一个研究小组，专注于定义中央碳代谢， 癌症在过去十年该团队的主要策略是使用同位素示踪剂来量化代谢 通量，代谢途径活性的直接量度。与Andrei Osterman博士（ 核心B），该小组已经发表了六篇重要论文，为理解 黑色素瘤细胞代谢本项目建议的工作将与项目1概述的研究密切结合 (UPR)项目2（PGC 1）与两个科学核心一样。

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.