Nucleotide Metabolism in Senescence and Platinum Resistance of Ovarian Cancer

卵巢癌衰老过程中的核苷酸代谢和铂类耐药

• 批准号: 8869303
• 负责人: Katherine Marie Aird
• 金额: $ 11.5万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-03 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869303
• 关键词: 3-Dimensional; Address; Automobile Driving; Biogenesis; Cancer Cell Growth; Cancer Patient; Cancer Relapse; Cancer cell line; Caring; Cell Cycle; Cell Proliferation; Cells; Characteristics; Cisplatin; Clinical Trials; DNA; Data; Data Set; Development; Disease; Engineering; Enzymes; Epithelial Cells; Epithelial ovarian cancer; Event; Experimental Models; Female; Goals; Growth; Health; Human; Human Resources; Immunocompromised Host; KRAS2 gene; Knowledge; MYC Family Protein; MYCN gene; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mediating; Mentors; Metabolic Pathway; Modeling; Molecular; Mus; Normal tissue morphology; Nucleotides; Oncogenes; Oncogenic; Outcome; Ovarian; Pathway interactions; Patients; Pennsylvania; Phase; Platinum; Play; Population; Process; Prognostic Marker; Proteins; Publishing; Records; Recurrent disease; Relapse; Reporting; Research; Research Institute; Research Personnel; Resistance; Resources; Ribonucleotide Reductase; Role; Serous; Signal Pathway; Specimen; Stem cells; Surface; Testing; The Cancer Genome Atlas; The Wistar Institute; Therapeutic; Training; Training Support; Transgenic Mice; Tumor Suppression; Universities; Woman; Xenograft procedure; aldehyde dehydrogenase 1; base; cancer cell; cancer stem cell; career; career development; cell growth; cell transformation; improved; in vivo; mouse model; novel; novel therapeutics; nucleotide metabolism; outcome forecast; overexpression; promoter; response; senescence; skills; standard care; standard of care; tumor; tumor progression; tumorigenesis

 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.

 描述（由适用提供）：独立职业发展途径的目标是要求支持培训以开发卵巢癌的专家模型，同时解决知识的基本差距，这可能会对卵巢癌患者的治疗产生重大影响。在我职业生涯的过渡阶段，K99/R00的支持将是我成功发展的一流研究所或大学的独立研究者的一部分。本文概述的培训计划将 利用Wistar Institute和邻国宾夕法尼亚大学提供的广泛资源，以及具有科学卓越记录的主要高级人员，可以担任导师，联合会和合作者。该提案的科学部分着重于实验和机械地确定核乙中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基于铂的基于铂的疗法抑制化学疗法癌干细胞并获得持续的治疗治疗反应。拟议的研究是基于我以前的发现，即核苷酸合成中的限制蛋白，核糖核苷酸还原M2（RRM2）在癌基因诱导的感应期间被下调，核拓扑基的增加可以克服这种肿瘤抑制生长。此外，在人EOC样品中，RRM2表达高度增加，并且与总体存活率较差相关。我已经发表了敲低或抑制RRM2可以通过诱导感应来降低EOC细胞的生长。我的初步数据表明，RRM2的敲低可以降低醛脱氢酶1（ALDH1）活性，这是推定的卵巢癌干细胞（CSC）的标志。因此，根据这些数据，我将探讨两个总体科学目的：1）确定使用与疾病相关的KRAS/MYC模型在EOC肿瘤发生的早期事件中核苷酸代谢是否增加； 2）阐明核苷酸代谢的抑制是否通过抑制CSC与铂治疗协同作用。该提案的科学目标的完成将在EOC的实验模型中发展我的研究技能，同时还为临床试验的基本原理提供了对铂金的持续治疗反应。