Metabolic Vulnerabilities in Melanoma Tumors

描述(由申请人提供)：黑色素瘤的特点是侵袭性和对治疗方法的抵抗力。在过去的几年里，黑色素瘤的治疗已经取得了重大突破，BRAF突变抑制剂的成功开发和使用就是例证，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它们在临床治疗后迅速形成耐药机制。因此，黑色素瘤生物学中有一些基本问题需要解决。其中包括代谢的脆弱性和转移的机制，将在这项拨款中进行研究。肿瘤细胞使用代谢/能量途径，这些途径对维持生存和促进肿瘤生长和转移至关重要，但这些途径的具体作用和对肿瘤进展的影响尚未完全清楚。我们最近发现了人类黑色素瘤的一个亚型(8%-10%)，它异常过度表达转录辅助激活因子PGC1(OXPHOS HIGH)，诱导线粒体和ROS解毒基因。PGC1？维持生存并保护这些肿瘤免受氧化应激和ROS诱导的药物的影响，但容易受到线粒体OXPHOS的抑制。然而，抑制黑色素瘤中的PGC1？可以通过HIF1？依赖的糖酵解和转移进展来进行代谢/能量补偿。这些结果强调了黑色素瘤的代谢可塑性，并表明使用代谢靶点治疗肿瘤需要合理的联合治疗。在这里，我们建议继续我们的研究，以确定人类黑色素瘤肿瘤重新编程代谢的机制和靶点，这些机制和靶点对细胞生长和生存以及对转移的影响具有不同的脆弱性。这些目标集中于三个中心目标：1)定义PGC1控制黑色素瘤肿瘤进展的机制和靶点(特定目标1)，2)确定通过HIF1途径允许黑色素瘤存活的代谢代偿机制(特定目标2)，以及3)定义PGC1对黑色素瘤转移过程的影响和机制(特定目标3)。这一建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，并为我们在黑色素瘤进展和转移中识别新的治疗靶点提供信息。

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.