Nucleotide Metabolism in Senescence and Platinum Resistance of Ovarian Cancer

 描述（由申请人提供）：这条独立职业发展之路的目标是要求支持培训，以发展卵巢癌实验模型的专业知识，同时解决知识的根本差距，可能对卵巢癌患者的治疗产生重大影响。在我职业生涯的这个过渡阶段，K99/R 00的支持将是我成功发展为顶级研究机构或大学的独立研究员不可或缺的一部分。本培训计划将 利用威斯塔研究所和邻近的宾夕法尼亚大学的广泛资源，以及具有卓越科学记录的关键高级人员作为导师、共同导师和合作者。该提案的科学部分侧重于通过实验和机制确定核苷酸代谢在卵巢癌肿瘤发生早期事件中的作用，以及该途径是否可以单独靶向或与铂类药物联合治疗，以抑制耐药癌症干细胞并获得持续的治疗反应。提出的研究是基于我以前的发现，即核苷酸合成中的限速蛋白，核糖核苷酸还原酶M2（RRM 2），在癌基因诱导的衰老过程中下调，核苷酸的增加可以克服这种肿瘤抑制性生长停滞。此外，RRM 2表达在人EOC标本中高度增加，并与较差的总生存期相关。我已经发表了RRM 2的敲低或抑制可以通过诱导衰老来降低EOC细胞生长。我的初步数据显示，RRM 2的敲低可以降低醛脱氢酶1（ALDH 1）的活性，这是一个假定的卵巢癌干细胞（CSC）的标志物。因此，根据这些数据，我将探索两个总体科学目标：1）使用疾病相关KRAS/MYC模型确定核苷酸代谢是否在EOC肿瘤发生的早期事件中增加; 2）阐明核苷酸代谢的抑制是否通过抑制CSC与铂治疗协同。本提案的科学目标的完成将发展我在EOC实验模型方面的研究技能，同时也发展临床试验的基本原理，以获得对铂的持续治疗反应。

 DESCRIPTION (provided by applicant): The goals of this Pathway to Independence Career Development Proposal are to request support for training to develop expertise in experimental models of ovarian cancer while addressing a fundamental gap in knowledge that could have a significant impact on the treatment of ovarian cancer patients. K99/R00 support during this transitional phase of my career will be integral to my successful development as an independent investigator at a top-tier research institute or university. The training plan outlined herein will take advantage of the extensive resources available at The Wistar Institute and neighboring University of Pennsylvania, as well as key senior personnel with track records of scientific excellence to serve as mentors, co-mentors, and collaborators. The scientific portion of this proposal focuses on experimentally and mechanistically determining the role of nucleotide metabolism in the early events in ovarian cancer tumorigenesis and whether this pathway can be targeted alone or in combination with platinum-based therapeutics to suppress chemoresistant cancer stem cells and obtain a sustained therapeutic response. The proposed studies are based on my previous findings that the rate-limiting protein in nucleotide synthesis, ribonucleotide reductase M2 (RRM2), is downregulated during oncogene-induced senescence, and an increase in nucleotides can overcome this tumor suppressive growth arrest. Additionally, RRM2 expression is highly increased in human EOC specimens and correlates with worse overall survival. I have published that knockdown or inhibition of RRM2 can decrease EOC cell growth via induction of senescence. My preliminary data show that knockdown of RRM2 can decrease aldehyde dehydrogenase 1 (ALDH1) activity, which is a marker of putative ovarian cancer stem cells (CSCs). Therefore, in line with these data I will explore two overarching scientific aims: 1) to determine whether nucleotide metabolism is increased in the early events in EOC tumorigenesis using a disease-relevant KRAS/MYC model; and 2) elucidate whether inhibition of nucleotide metabolism is synergistic with platinum treatment through a suppression of CSCs. The completion of the scientific aims of this proposal will develop my research skills in experimental models of EOC while also developing the rationale for clinical trials to obtain a sustained therapeutic response to platinum.