Investigating p16 Loss in Pro-tumorigenic Metabolism

项目总结/摘要 这项建议的最终目标是解决一个根本的知识差距的作用，细胞周期 抑制剂p16在调节促肿瘤代谢中的作用。这些研究的结果可能会有重大意义。 影响黑色素瘤患者的治疗，其中约30 - 40%的患者具有p16的下调或缺失。这 研究计划集中在实验和机械确定p16丢失在促肿瘤发生中的作用， 核苷酸代谢以及该途径是否可以单独或联合靶向p16-低水平黑色素瘤 与突变BRAF抑制剂一起使用以获得持续的治疗反应。拟议的研究是基于 初步发现，p16表达的缺失上调了新鉴定的ATR-mTORC 1信号轴， 通过戊糖磷酸途径增加核苷酸代谢，并且调节该途径是一种有效的方法。 p16低水平癌细胞的代谢脆弱性。根据这些数据，我们将探讨两个总体科学 目的：1）从机制上剖析黑色素瘤发生中p16缺失下游的ATR-mTORC 1通路 并确定促肿瘤发生核苷酸代谢对观察到的表型的贡献;和2） 阐明联合靶向ATR-mTORC 1通路在p16低水平黑色素瘤中是否具有协同作用 单独或与突变BRAF抑制剂组合。该提案的科学目标的完成将 不仅为代谢和细胞周期之间的相互作用提供了新的机制见解， 肿瘤发生，但也将建立靶向新的ATR-mTORC 1轴作为一种策略，以改善治疗 低p16表达的黑色素瘤患者的预后。这项研究具有很大的影响力，因为 这些途径的机制基础有可能改变黑色素瘤的管理， 低p16由于p16在约50%的人类癌症中发生了改变，这些研究将对癌症的治疗产生深远的影响。 确定代谢脆弱性，并为广泛的癌症治疗策略制定未来的治疗策略， 患者

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.