Investigating p16 Loss in Pro-tumorigenic Metabolism

研究促肿瘤代谢中的 p16 丢失

基本信息

批准号：
9980661
负责人：
Katherine Marie Aird
金额：
$ 37.04万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980661
关键词：
Address BRAF gene Benign Bypass Cell Aging Cell Cycle Cell Cycle Arrest Cell Cycle Inhibition Cell Line Cells Couples Data Development Disease Down-Regulation Event Future Goals Human Isomerase Knowledge Malignant Neoplasms Mediating Mediator of activation protein Melanoma Cell Metabolic Metabolism Modeling Molecular Mutation Nevus Nucleosides Nucleotide Biosynthesis Nucleotides Oncogene Activation Oncogenes Pathway interactions Patients Pentosephosphate Pathway Phenotype Publishing Research Resistance Ribose Role Signal Pathway Signal Transduction Skin Supplementation TSC1 gene Testing Therapeutic Translations Tumor Suppressor Proteins Up-Regulation Xenograft procedure base cancer cell cancer type enzyme pathway experimental study improved inhibitor/antagonist insight knock-down melanocyte melanoma mutant new therapeutic target novel novel therapeutics nucleotide metabolism patient population patient subsets replication stress senescence standard of care stress tolerance targeted treatment therapy outcome treatment response treatment strategy tumorigenesis tumorigenic

项目摘要

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.

项目摘要/摘要该提案的最终目标是解决有关细胞周期角色知识的基本差距抑制剂p16在调节促肿瘤代谢方面。这些研究的结果可能具有重要的对黑色素瘤患者的治疗的影响，其中约30-40％的下调或缺失为p16。这研究计划的重点是实验和机械地确定p16损失在促肿瘤中的作用核苷酸代谢以及该途径是否可以单独靶向p16-low黑色素瘤或组合使用突变的BRAF抑制剂获得持续的治疗反应。拟议的研究基于 p16表达丧失的初步发现将新识别的ATR-MTORC1信号轴上调至通过五磷酸戊糖途径增加核苷酸代谢，该途径的调节是A P16-低癌细胞的代谢脆弱性。与这些数据一致，我们将探索两个总体科学目的：1）在黑色素作和p16损失下游的机械学剖析ATR-MTORC1途径并确定促肿瘤核苷酸代谢对观察到的表型的贡献；和2）到阐明将ATR-MTORC1途径靶向组合是否在P16-低黑色素瘤中是协同作用单独或与突变BRAF抑制剂结合使用。该提议的科学目的的完成将不仅为新陈代谢与细胞周期之间的相互作用提供新的机械见解肿瘤发生，但也将建立针对新型ATR-MTORC1轴的靶向作为改善治疗的策略 p16表达低的黑色素瘤患者的结果。拟议的研究具有很高的影响，因为这些途径的机械基础有可能改变黑色素瘤的管理低P16。由于所有人类癌症中约有50％的P16发生了变化，因此这些研究将对确定代谢脆弱性并开发未来的癌症治疗策略患者。