Defining the Mitotic Role of Chk2 for the Treatment of Pancreatic Cancer

确定 Chk2 在胰腺癌治疗中的有丝分裂作用

• 批准号: 10679609
• 负责人: Elizabeth Maureen Black
• 金额: $ 3.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679609
• 关键词: ATR gene; Acceleration; Alleles; Apical; Automobile Driving; Award; Cancer Biology; Cancer Etiology; Cell Cycle; Cell Cycle Arrest; Cells; Cessation of life; Chromosome Segregation; Clinic; Clinical; Communication; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Defect; Development; Disease; Disease Progression; Drug resistance; Educational process of instructing; Engineering; Ensure; Exhibits; Failure; Fluorescence Resonance Energy Transfer; Funding; Genome Stability; Genomic Instability; Goals; Institution; Interphase; Label; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Mitosis; Mitotic; Mitotic Chromosome; Molecular; Mutation; Neoplasm Metastasis; PLK1 gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phosphotransferases; Polynucleotide 5' -Hydroxyl-Kinase; Population; Positioning Attribute; Predisposition; Proteins; Regulation; Research; Research Personnel; Role; Running; Science; Signal Transduction; Survival Rate; Testing; Therapeutic; Tissues; Training; Treatment Protocols; Unresectable; Work; Writing; analog; cancer cell; cancer genome; cancer therapy; career; career development; chemotherapy; chromosome missegregation; effective therapy; experimental study; gemcitabine; genome integrity; in vitro activity; inhibitor; insight; live cell imaging; loss of function; loss of function mutation; member; mortality; mouse model; novel; novel marker; novel therapeutics; pancreatic ductal adenocarcinoma cell; patient prognosis; pharmacologic; prevent; repaired; research faculty; response; sensor; skill acquisition; targeted treatment; therapeutic target; therapy resistant; tumor

PROJECT SUMMARY Genome instability (GIN) is a hallmark of cancer and a leading cause of therapeutic resistance. This is especially true for pancreatic ductal adenocarcinoma (PDAC), where an estimated 95% of PDAC cells exhibit GIN. GIN is characterized by both a failure to accurately repair DNA in interphase and high rates of chromosome mis- segregation in mitosis. It is not fully understood how these pathways work in concert throughout the cell cycle to defend against GIN. Our previous work has demonstrated a link between the DNA damage response (DDR) protein ATR and the mitotic machinery in promoting faithful chromosome segregation. This observation has prompted me to hypothesize that other components of the DDR promote faithful chromosome segregation and genome stability. My preliminary work has elucidated a novel mitotic function for Chk2, an important DDR kinase that is activated following DNA double-stranded breaks. I have shown that Chk2 is active in a DNA damage-independent manner in mitosis. Moreover, I have demonstrated that Chk2 promotes proper activity of the major mitotic kinase PLK1. In this application, I propose to investigate the mechanism by which Chk2 promotes faithful chromosome segregation (Aim 1), determine how Chk2 activity is regulated in mitosis (Aim 2), and use PLK1 inhibition to specifically target Chk2-deficient cancer cells (Aim 3). My proposed studies will define the mitotic and DNA damage-independent role for Chk2. This will further our understanding of how the DDR pathway and mitotic machinery work in concert to promote faithful chromosome segregation and genome stability. Lastly, experiments from this proposal may develop a targeted therapeutic strategy to specifically kill Chk2-deficient cancers. This is critically important, as Chk2 loss-of-function mutations make up a significant portion of familial PDAC cases, and Chk2 mutations render cells insensitive to current front-line treatments. My career goal is to obtain a research faculty position at a leading institution where I will dissect the noncanonical and understudied mechanisms by which DDR proteins promote genome stability. My scientific development will be bolstered by successful completion of this project, including gaining expertise in cancer biology and mouse models. I will use these acquired skills to investigate whether PLK1 inhibitors can be used to specifically target Chk2-deficient cancer cells. Importantly, funding for this application will also enhance my training in science communication, writing, teaching, mentoring, and career development, all of which will be essential for successfully running my own laboratory. This project is supported by an outstanding network of sponsors and collaborators that will ensure this project is successfully completed. Receipt of this award will allow me to expand my research plan and establish myself as a primary investigator in the field of cancer biology and genome stability.

项目摘要 基因组不稳定性（GIN）是癌症的标志，也是治疗性抗性的主要原因。尤其是 胰腺导管腺癌（PDAC）是正确的，其中估计有95％的PDAC细胞表现出杜松子酒。杜松子酒是 其特征是无法准确修复相间的DNA和高染色体错误的速率 有丝分裂的分离。尚未完全理解这些途径在整个单元周期中如何共同运行 防御杜松子酒。我们以前的工作表明了DNA损伤响应（DDR）之间的联系 蛋白ATR和有丝分裂机制促进忠实的染色体隔离。这个观察结果 促使我假设DDR的其他组成部分促进忠实的染色体 隔离和基因组稳定性。 我的初步工作已经阐明了CHK2的新型有丝分裂功能，这是一种激活的重要DDR激酶 DNA双链休息后。我已经证明CHK2以DNA损伤无关的方式活跃 在有丝分裂中。此外，我已经证明CHK2促进了主要有丝分裂激酶PLK1的适当活性。 在此应用中，我建议研究CHK2促进忠实染色体的机制 隔离（AIM 1），确定CHK2活性如何在有丝分裂中调节（AIM 2），并使用PLK1抑制作用进行 特异性靶向CHK2缺陷型癌细胞（AIM 3）。我提出的研究将定义有丝分裂和DNA CHK2无损害的作用。这将进一步了解DDR途径和有丝分裂的方式 机械共同努力，以促进忠实的染色体隔离和基因组稳定性。最后， 该提案的实验可能会制定有针对性的治疗策略，以特别杀死CHK2缺陷。 癌症。这至关重要，因为CHK2功能丧失突变构成了家族性的很大一部分 PDAC病例和CHK2突变使细胞对当前一线治疗不敏感。 我的职业目标是在领先的机构中获得研究教师职位，在那里我将剖析非规范 以及DDR蛋白促进基因组稳定性的研究机制。我的科学发展将 通过成功完成该项目，包括获得癌症生物学和鼠标的专业知识，以支持 型号。我将使用这些获得的技能来研究PLK1抑制剂是否可以专门针对 CHK2缺陷癌细胞。重要的是，该应用程序的资金也将增强我在科学方面的培训 沟通，写作，教学，指导和职业发展，所有这些对于 成功运营自己的实验室。该项目得到了杰出的赞助商网络的支持， 确保该项目成功完成的合作者。收到此奖项将使我扩大 我的研究计划并确立自己是癌症生物学和基因组领域的主要研究者 稳定。