Investigating p16 Loss in Pro-tumorigenic Metabolism

项目摘要/摘要 这项建议的最终目标是解决人们对细胞周期作用的认识上的根本差距。 抑制物p16在调节促肿瘤代谢中的作用。这些研究的结果可能会对 对黑色素瘤患者治疗的影响，其中~30%-40%的人p16基因下调或缺失。这 研究计划集中在实验和机制上确定p16缺失在促肿瘤发生中的作用。 核苷酸代谢以及该通路是否可以单独或联合作用于p16-低黑色素瘤 使用突变的BRAF抑制剂以获得持续的治疗反应。建议的研究是基于 初步发现，p16表达的缺失上调了新发现的ATR-mTORC1信号轴 通过磷酸戊糖途径增加核苷酸代谢，这一途径的调节是一种 P16-Low癌细胞的代谢脆弱性。根据这些数据，我们将探索两个最重要的科学 目的：1)从机制上剖析黑色素瘤发生中p16缺失下游的ATR-mTORC1通路 并确定促肿瘤核苷酸代谢对观察到的表型的贡献；以及2) 阐明联合靶向ATR-mTORC1通路在p16-低黑色素瘤中是否具有协同作用 单独或与突变的BRAF抑制剂联合使用。这项提议的科学目标的完成将 不仅为新陈代谢和细胞周期之间的相互作用提供了新的机械见解 肿瘤发生，但也将建立以新的ATR-mTORC1轴为靶点作为改进治疗的策略 P16低表达的黑色素瘤患者的预后。这项拟议的研究具有很高的影响力，因为 这些途径的机械性基础有可能改变黑色素瘤的管理 低位p16。由于p16基因在约50%的人类癌症中发生了改变，这些研究将对 确定新陈代谢的脆弱性，并为广泛的 病人。

Project Summary/Abstract The ultimate goal of this proposal is to address a fundamental gap in knowledge on the role of the cell cycle inhibitor p16 in regulating pro-tumorigenic metabolism. The results from these studies could have a significant impact on the treatment of melanoma patients, of which ~30-40% have downregulation or deletion of p16. This research plan focuses on experimentally and mechanistically determining the role of p16 loss in pro-tumorigenic nucleotide metabolism and whether this pathway can be targeted in p16-low melanomas alone or in combination with mutant BRAF inhibitors to obtain a sustained therapeutic response. The proposed studies are based on preliminary findings that loss of p16 expression upregulates the newly-identified ATR-mTORC1 signaling axis to increase nucleotide metabolism through the pentose phosphate pathway, and modulation of this pathway is a metabolic vulnerability for p16-low cancer cells. In line with these data, we will explore two overarching scientific aims: 1) to mechanistically dissect the ATR-mTORC1 pathway downstream of p16 loss in melanomagenesis and determine the contribution of pro-tumorigenic nucleotide metabolism to the observed phenotypes; and 2) to elucidate whether targeting the ATR-mTORC1 pathway in combination is synergistic in p16-low melanomas alone or in combination with mutant BRAF inhibitors. The completion of the scientific aims of this proposal will not only provide new mechanistic insights into the interplay between metabolism and the cell cycle during tumorigenesis, but will also establish targeting the novel ATR-mTORC1 axis as a strategy to improve therapeutic outcome for melanoma patients with low p16 expression. The proposed research is of high impact because the mechanistic underpinning of these pathways has the potential to transform the management of melanomas with low p16. As p16 is altered in ~50% of all human cancers, these studies will have far-reaching implications for identifying metabolic vulnerabilities and developing future cancer therapeutic strategies for a wide range of patients.