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

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

项目概要基因组不稳定（GIN）是癌症的一个标志，也是治疗耐药的主要原因。这尤其是对于胰腺导管腺癌 (PDAC) 来说也是如此，估计 95% 的 PDAC 细胞表现出 GIN。杜松子酒是其特点是在间期无法准确修复 DNA，而且染色体错误率很高。有丝分裂中的分离。目前尚不完全了解这些途径如何在整个细胞周期中协同工作防御 GIN。我们之前的工作已经证明了 DNA 损伤反应 (DDR) 之间的联系蛋白质 ATR 和有丝分裂机制促进染色体忠实分离。这一观察有促使我假设 DDR 的其他成分促进了忠实的染色体分离和基因组稳定性。我的前期工作阐明了 Chk2 的一种新的有丝分裂功能，Chk2 是一种重要的 DDR 激酶，被激活 DNA 双链断裂后。我已经证明 Chk2 以与 DNA 损伤无关的方式活跃在有丝分裂中。此外，我还证明 Chk2 可以促进主要有丝分裂激酶 PLK1 的适当活性。在此应用中，我打算研究 Chk2 促进忠实染色体的机制分离（目标 1），确定 Chk2 活性如何在有丝分裂中受到调节（目标 2），并使用 PLK1 抑制来专门针对 Chk2 缺陷的癌细胞（目标 3）。我提议的研究将定义有丝分裂和 DNA Chk2 的损伤独立作用。这将进一步我们对 DDR 途径和有丝分裂的理解机器协同工作以促进忠实的染色体分离和基因组稳定性。最后，该提案的实验可能会开发出一种针对性的治疗策略来特异性杀死 Chk2 缺陷的癌症。这一点至关重要，因为 Chk2 功能丧失突变占家族性突变的很大一部分。 PDAC 病例和 Chk2 突变使细胞对当前的一线治疗不敏感。我的职业目标是在一家领先的机构获得一个研究教职职位，在那里我将剖析非规范的理论以及 DDR 蛋白促进基因组稳定性的机制正在研究中。我的科学发展将因成功完成该项目而受到支持，包括获得癌症生物学和小鼠方面的专业知识模型。我将利用这些获得的技能来研究PLK1抑制剂是否可以用于特异性靶向 Chk2 缺陷的癌细胞。重要的是，该申请的资助也将加强我的科学培训沟通、写作、教学、指导和职业发展，所有这些对于成功运行我自己的实验室。该项目得到了杰出的赞助商网络的支持将确保该项目成功完成的合作者。获得这个奖项将使我的事业得到扩展我的研究计划并将自己定位为癌症生物学和基因组领域的主要研究者稳定。