The role of mTORC2 in reprogramming cancer cell metabolism

MTORC2在癌细胞代谢中的作用 项目总结 新陈代谢重新编程是癌症的一个标志。生长因子受体信号通路的突变 通过改变营养物质的吸收和利用来促进肿瘤的生长。脂类的从头合成是一个关键 这一过程的一个方面，提供必要的脂类 用于膜生物发生和信号转导。 目前， 我们对致癌信号如何调节特定基因合成的认识存在很大差距。 脂质导致肿瘤生长，以及通过什么机制。 这笔RO1赠款(NS 73831)，我们已经证明了 通过前五年资助的研究 雷帕霉素(MTORC2)的作用靶点 生长因子受体信号的关键介质，重新编程肿瘤细胞代谢，有力地刺激 高致命性脑肿瘤胶质母细胞瘤(GBM)的生长及对几乎所有化疗药物的耐药性 治疗。具体地说，我们的初步研究表明，mTORC2推动营养物质流入造脂。 通过调节水平和/或促进特定脂类的合成来驱动肿瘤生长 关键限速酶的活性。这些数据揭示了一个新的、潜在的可下药靶点的图景。 然而，在这些机制可以应用于新疗法的开发之前，一些 紧急问题必须得到回答。MTORC2如何调节GBM养分的吸收和利用 把它转向癌症中特定脂质的合成？信号是什么，生化和 转录机制以及它们如何驱动肿瘤生长和耐药性？它们可以下药吗？ 这项提议旨在检验mTORC2通过以下方式促进GBM生长和耐药性的假设 推动脂肪生成，重塑特定信号脂的组成。我们的目标是了解 对于打破开发更有效治疗方法的主要障碍最关键的机制。在目标1中， 我们提出了一系列实验，将我们的代谢分析扩展到患者体内的GBM，以 确定mTORC2如何控制特定磷脂和鞘脂的合成以驱动GBM 生长和耐药性，并确定信号，生化和转录机制，通过 MTORC2控制着调节这一过程的关键酶。在目标2中，我们将确定mTORC2如何 控制营养物质的吸收和利用，以合成这些特定的脂类。在《目标3》中，我们将 识别和开发靶向mTORC2依赖代谢的中枢神经系统穿透性小分子 重新编程并评估它们的治疗潜力。拟议的研究将产生更深层次的 了解mTORC2在癌细胞新陈代谢中的作用，并将产生以前 未被认识到的代谢脆弱性，可被大脑穿透性化合物靶向，潜在地导致 更好地进行GBM治疗

The role of mTORC2 in cancer cell metabolism PROJECT SUMMARY Metabolic reprogramming is a hallmark of cancer. Mutations in growth factor receptor signaling pathways promote tumor growth by altering the uptake and utilization of nutrients. De novo synthesis of lipids is a critical aspect of this process, providing necessary lipids for membrane biogenesis and signal transduction. Currently, there is a major gap in our knowledge about how oncogenic signaling regulates the synthesis of specific lipids to cause tumor growth, and by what mechanisms. this RO1 grant (NS 73831), we have demonstrated that Through studies supported by the first five years of the mechanistic target of rapamycin (mTORC2), a critical mediator of growth factor receptor signaling, reprograms tumor cellular metabolism, potently stimulating the growth of the highly lethal brain cancer glioblastoma (GBM) and causing resistance to almost all current treatments. Specifically, our preliminary studies indicate that mTORC2 drives nutrient flux into lipogenic pathways and boosts the synthesis of specific lipids to drive tumor growth by regulating the levels and/or activities of key rate limiting enzymes. These data reveal a landscape of new, potentially druggable targets. However, before these mechanisms can be applied to inform the development of new therapies, a number of urgent questions must be answered. How does mTORC2 regulate GBM nutrient uptake and utilization and shift it towards the synthesis of specific lipids in cancer? What are the signaling, biochemical and transcriptional mechanisms and how do they drive tumor growth and drug resistance? Are they druggable? This proposal is designed to test the hypothesis that mTORC2 promotes GBM growth and drug resistance by driving lipogenesis and remodeling the composition of specific signaling lipids. Our goal is to understand the mechanisms most critical for breaking down a major barrier to developing more effective treatments. In aim 1, we propose a set of experiments that will extend our metabolic analyses into patient-derived GBMs in vivo, to determine how mTORC2 controls the synthesis of specific phospholipids and sphingolipids to drive GBM growth and drug resistance, and to identify the signaling, biochemical and transcriptional mechanisms by which mTORC2 controls the key enzymes that regulate this process. In aim 2, we will determine how mTORC2 controls the uptake and utilization of nutrients towards the synthesis of these specific lipids. In aim 3, we will identify and develop CNS-penetrant small molecules that target mTORC2-dependent metabolic reprogramming and evaluate their therapeutic potential. The proposed studies will generate a deeper understanding of the role of mTORC2 in cancer cell metabolism and will generate a landscape of previously unappreciated metabolic vulnerabilities that can be targeted by brain penetrant compounds, potentially leading to better GBM treatments