Investigating Mechanisms of Deregulated Nucleotide Metabolism in Cancer

项目总结 目前，许多癌症都是通过细胞毒性化疗来治疗的，这些化疗利用了这些癌症对 增强了核苷酸的生物合成。然而，使这些化合物如此具有细胞毒性的特性 有效地杀死癌细胞也会对正常的增殖细胞和组织造成严重破坏。为了 了解如何更有效和更安全地利用此漏洞，我们必须将努力集中在 肿瘤细胞特别需要的靶点，但正常细胞不需要，增殖和存活。我的 发现了一个这样的靶点--磷酸核糖焦磷酸合成酶2 (PRPS2)。PRPS2和它的同源物PRPS1产生一种关键的前体，是生产所有 核苷酸和分子油门的作用，能够增加或降低这些 基因积木就形成了。这项提议试图解开这种选择性的分子基础。 通过使用代谢流量分析，优雅的结构/功能研究，以及生物正交化学和 分子生物学的方法。我们的研究将为理解新陈代谢开辟新的途径 这可能会导致癌症细胞的脆弱性，并可能导致未来智能设计的合理治疗策略。 我们将使用MYC驱动的淋巴瘤和骨髓瘤模型进行研究，使用这两种基因- 转基因小鼠模型和人类癌细胞系。重要的是，MYC一直被描述为 癌症的转录引擎及其刺激核苷酸和核酸产生的能力是标志性的 其促生长合成代谢计划的特征是驱动B细胞谱系中的恶性肿瘤所必需的。使用我们的 在MYC过表达细胞中阻断PRPS2功能的遗传方法，我们可以利用这种依赖性 破译MYC过表达癌核苷酸代谢失控的机制基础 并发现核苷酸代谢网络中关键节点之间的新连接。为 例如，我们提议的研究将通过确定如何确定核苷酸代谢的经济学 中断核苷酸供应会影响它所驱动的机器，反之亦然。总的来说，拟议的研究 将改变我们对这些关键分子在正常和癌症中的作用的理解 并提供了一种新的概念范式，可以作为下一步开发的基础 产生更安全、更有效的以精确为基础的疗法和方法。

PROJECT SUMMARY Many cancers are currently treated by cytotoxic chemotherapies that exploit those cancers' dependence on enhanced nucleotide biosynthesis. However, the cytotoxic properties which make these compounds so efficacious in killing cancer cells also wreak havoc on normal proliferating cells and tissues. In order to understand how to exploit this vulnerability more effectively and more safely, we must focus our efforts on targets that are specifically required by cancer cell, but not normal cell, proliferation and survival. My discoveries have identified one such target – the enzyme phosphoribosyl pyrophosphate synthetase 2 (PRPS2). PRPS2, and its homolog PRPS1, generate a critical precursor necessary for producing all nucleotides and function as a `molecular throttle' capable of increasing or decreasing the rate at which these genetic building blocks are made. This proposal seeks to unravel the molecular basis for this selectivity through use of metabolic flux analysis, elegant structure/function studies, and bioorthogonal chemistry and molecular biology approaches. Our studies will open up new avenues for understanding the metabolic vulnerabilities of cancer cells and may lead to intelligently-designed rational therapeutic strategies of the future. We will conduct our studies using models of MYC-driven lymphoma and myeloma, using both genetically- engineered mouse models and human cancer cell lines. Importantly, MYC has been characterized as the transcriptional engine of cancer and its ability to stimulate nucleotide and nucleic acid production are signature features of its pro-growth anabolic program necessary to drive malignancies in the B cell lineage. Using our genetic approaches that block PRPS2 function in MYC overexpressing cells, we can leverage this dependency to decipher the mechanistic basis for the deregulation of nucleotide metabolism in MYC-overexpressing cancer cells and uncover novel connections between critical nodes in the nucleotide metabolism network. For example, our proposed studies will elucidate the economics of nucleotide metabolism by determining how disrupting nucleotide supply affects the machineries it fuels, and vice-versa. Collectively, the proposed studies will be transformative in our understanding of the roles of these key molecules in the normal and cancer setting, and provide a new conceptual paradigm which can be the foundation for the development of the next generation of safer, more effective precision-based therapies and approaches.