Metabolic Vulnerabilities in Melanoma Tumors

黑色素瘤的代谢脆弱性

• 批准号: 8760634
• 负责人: Pere Puigserver
• 金额: $ 34.84万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760634
• 关键词: Address; Anabolism; Apoptosis; Applications Grants; BRAF gene; Biochemical; Bioenergetics; Bioinformatics; Biological Assay; Biology; Cell Respiration; Cell Survival; Cells; Clinical Treatment; Critical Pathways; Data; Development; Drug Metabolic Detoxication; Financial compensation; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic Engineering; Genomics; Glycolysis; Goals; Grant; Heterogeneity; Human; In Vitro; Laboratories; Malignant Neoplasms; Medical; Melanoma Cell; Metabolic; Metabolism; Metastatic Melanoma; Mitochondria; Molecular; Molecular Genetics; Mutation; Neoplasm Metastasis; Nude Mice; Nutrient; Outcome; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation Inhibition; Process; Procollagen-Proline Dioxygenase; Publishing; Regulation; Resistance; Role; Therapeutic; Transcription Coactivator; Translating; Up-Regulation; Validation; Warburg Effect; aerobic glycolysis; cancer cell; cell growth; combinatorial; fitness; flexibility; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; meetings; melanoma; metabolomics; metastatic process; mouse model; mutant; neoplastic cell; new therapeutic target; novel; overexpression; oxidation; programs; public health relevance; research study; resistance mechanism; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Melanoma tumors are characterized by their aggressiveness as well as by their resistance to therapeutic treatments. In the last years, major breakthroughs have been achieved in melanoma treatment as exemplified by the successful development and use of BRAF mutant inhibitors, a mutation that occurs in approximately 50% of human melanomas. However, the high degree of heterogeneity of melanoma tumors allows them to rapidly develop resistant mechanisms after clinical treatment. Thus, there are fundamental questions in melanoma biology that need to be addressed. Among them are the metabolic vulnerabilities and mechanisms of metastasis that will be investigated in this grant. Cancer cells use metabolic/energetic pathways that are critical to maintain survival and promote tumor growth and metastasis, however the specific role of these pathways and the effect on tumor progression are not completely understood. We have recently identified a subset of human melanomas (8-10%) that aberrantly overexpress the transcriptional coactivator PGC1¿ (OXPHOS high) that induces mitochondrial and ROS detoxification genes. PGC1¿ maintains survival and protect these tumors against oxidative stress and ROS-inducing drugs, but are vulnerable to mitochondrial OXPHOS inhibition. However, PGC1¿ suppression in melanoma tumors allows metabolic/energetic compensation through HIF1¿-dependent glycolysis and metastatic progression. These results underscore the metabolic plasticity of melanomas and show that a rational combinatorial therapy will be required to treat tumors using metabolic targets. Here, we propose to continue our studies on the identification of mechanisms and targets by which human melanoma tumors reprogram metabolism conferring different vulnerabilities on cell growth and survival as well as the impact on metastasis. The goals are centered in three central aims: 1) defining the mechanisms and targets by which PGC1¿ controls melanoma tumor progression (Specific Aim 1), 2) identifying the metabolic compensatory mechanisms that allow survival in melanoma tumors via the HIF1¿ pathway (Specific Aim 2) and, 3) defining the impact and mechanisms of PGC1¿ on melanoma metastatic processes (Specific Aim 3). The outcomes of this proposal will advance our understanding of tumor melanoma and metabolic/energetic vulnerabilities and inform us on the identification of novel therapeutic targets in melanoma progression and metastasis.

描述（由申请人提供）：黑色素瘤的特点是其侵袭性以及对治疗性治疗的抵抗力。在过去的几年中，黑色素瘤治疗取得了重大突破，例如BRAF突变抑制剂的成功开发和使用，这种突变发生在大约50%的人类黑色素瘤中。然而，黑色素瘤的高度异质性使其在临床治疗后迅速形成耐药机制。因此，在黑色素瘤生物学中有一些基本问题需要解决。其中包括代谢脆弱性和转移机制，将在本基金中进行研究。癌细胞利用代谢/能量途径维持生存，促进肿瘤生长和转移，但这些途径的具体作用和对肿瘤进展的影响尚不完全清楚。我们最近发现了人类黑色素瘤的一个子集（8-10%）异常地过度表达诱导线粒体和ROS解毒基因的转录辅助激活因子PGC1¿（OXPHOS高）。PGC1维持肿瘤存活并保护这些肿瘤免受氧化应激和ros诱导药物的侵害，但易受线粒体OXPHOS抑制的影响。然而，黑色素瘤中的PGC1抑制允许代谢/能量补偿通过HIF1依赖的糖酵解和转移进展。这些结果强调了黑色素瘤的代谢可塑性，并表明需要合理的组合治疗来利用代谢靶点治疗肿瘤。在这里，我们建议继续研究人类黑色素瘤肿瘤重编程代谢的机制和靶点，从而赋予细胞生长和存活的不同脆弱性以及对转移的影响。目标集中在三个中心目标：1)确定PGC1控制黑色素瘤肿瘤进展的机制和靶点（Specific Aim 1）， 2)确定通过HIF1途径允许黑色素瘤肿瘤存活的代谢代偿机制（Specific Aim 2）， 3)确定PGC1对黑色素瘤转移过程的影响和机制（Specific Aim 3）。这项提议的结果将促进我们对肿瘤黑色素瘤和代谢/能量脆弱性的理解，并为我们确定黑色素瘤进展和转移的新治疗靶点提供信息。