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（由适用提供）：黑色素瘤肿瘤的特征是它们的侵袭性以及对治疗性治疗的耐药性。在过去的几年中，在黑色素瘤治疗中取得了重大突破，这是通过成功发展和使用BRAF突变抑制剂的例证，这种突变发生在大约50％的人类黑色素瘤中。但是，黑色素瘤肿瘤的高度异质性使它们能够在临床治疗后快速发展抗性机制。那是黑色素瘤生物学中的基本问题，需要解决。其中包括将在这笔赠款中调查的转移的代谢脆弱性和机制。癌细胞使用代谢/能量途径，对于维持生存和促进肿瘤生长和转移至关重要，但是这些途径的特定作用以及对肿瘤进展的影响尚不完全了解。我们最近确定了人类黑色素瘤（8-10％）的子集，使转录共激活因子PGC1¿（Oxphos High）诱导了线粒体和ROS毒素解毒基因。 PGC1¿保持生存，并保护这些肿瘤免受氧化应激和诱导ROS诱导药物的影响，但容易受到线粒体oxphos抑制的影响。然而，黑色素瘤肿瘤中的PGC1抑制允许通过HIF1®依赖性糖酵解和转移性进展来代谢/能量补偿。这些结果强调了黑色素瘤的代谢可塑性，并表明使用代谢靶标需要有理组合疗法来治疗肿瘤。在这里，我们建议继续研究人类黑色素瘤肿瘤重编代代谢的机制和靶标的识别，会议对细胞生长和生存的不同脆弱性以及对转移的影响。目标集中在三个中心目的中：1）定义PGC1¿控制黑色素瘤肿瘤进展的机制和靶标（特定目的1），2）确定允许通过HIF1途径在黑色素瘤肿瘤中存活的代谢补偿机制（特定目标2），以及特定于PGC1的影响（特定目标2）和机构3次梅兰群体（3）。该提案的结果将提高我们对肿瘤黑色素瘤和代谢/能量脆弱性的理解，并告知我们在黑色素瘤进展和转移中鉴定新的治疗靶标。