Targeting molecular vulnerabilities of ovarian cancer

针对卵巢癌的分子脆弱性

• 批准号: 9976800
• 负责人: Sarah James Hill
• 金额: $ 25.34万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2020-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976800
• 关键词: Aftercare; Anatomy; Animal Model; Award; Biological Assay; Biological Models; CHEK1 gene; Cancer Patient; Carboplatin; Cells; Clinical; Clinical Trials; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Gene; DNA Sequence Alteration; DNA replication fork; DNA sequencing; Dana-Farber Cancer Institute; Data; Defect; Discipline; Disease; Doctor of Philosophy; Drug Targeting; Early Diagnosis; Enrollment; Epithelial; Epithelium; Evaluation; Genomics; Goals; Growth; Human; Immune; In Vitro; K-Series Research Career Programs; Lead; Malignant neoplasm of ovary; Mentors; Mentorship; Mesenchymal; Methods; Molecular Biology; Molecular Target; Molecular and Cellular Biology; Mus; Mutation; Organoids; Parents; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Physicians; Prediction of Response to Therapy; Prevalence; Prevention; Property; RUNX3 gene; Research; Research Personnel; Role; Scientist; Serous; Signal Transduction; Testing; Therapeutic; Training; Training Programs; Translating; Tumor Tissue; Validation; Western Blotting; Work; Xenograft Model; Xenograft procedure; base; career; career development; cytotoxicity; epithelial to mesenchymal transition; functional mimics; gemcitabine; gene repair; genome sequencing; homologous recombination; in vivo; inhibitor/antagonist; mouse model; novel; patient population; patient response; predictive test; repaired; research study; response; standard of care; targeted agent; targeted treatment; therapy resistant; three dimensional structure; transcription factor; treatment response; tumor; whole genome

PROJECT SUMMARY Genomic analysis suggests that up to 50% of High Grade Serous Ovarian Cancers (HGSCs) harbor a genomic alteration that might confer a DNA damage repair defect, making therapies that target such defects potential treatment options. There is no method to predict which patients will respond to such therapies, which is a major problem in the field. Preliminary data indicate that patient derived HGSC organoids may be a faithful model system in which to perform functional assays to predict patient therapeutic response. Data from a limited analysis of HGSC organoids suggest that stalled replication fork protection defects are more common than homologous recombination defects in HGSC and that more patients may benefit from the wider array of therapies available to target such defects, including carboplatin, gemcitabine, ATR, WEE1, and CHK1 inhibitors. The goal of this mentored research career development proposal is to utilize patient derived HGSC organoid cultures to understand the prevalence, mechanisms, and therapeutic relevance of stalled replication fork protection defects in HGSC. The proposed research studies encompass multiple disciplines including molecular biology, DNA sequencing, and animal modeling which will help investigate the role of stalled replication fork protection defects in HGSC and also provide a well-rounded career development strategy for becoming scientifically independent through execution of the following specific aims: Specific Aim 1: Assess the prevalence of fork protection defects in HGSC and whether fork protection defects predicted by HGSC organoid functional assays lead to therapeutic sensitivity to carboplatin and ATR, WEE1, and CHK1 inhibitors. This will be accomplished by generating organoids from patients being treated with carboplatin and ATR, WEE1, and CHK1 inhibitors, performing functional assays to assess stalled fork protection capacity and therapeutic sensitivity of the organoids in parallel to sequencing analysis, and comparing organoid and patient outcomes. Specific Aim 2: Uncover mechanisms leading to fork instability in the organoids and whether different mechanisms of fork protection defects lead to differing sensitivities to the above agents. This will be accomplished using molecular and cellular biology analysis of specific pathways in the organoids. Specific Aim 3: In vivo validation of in vitro mechanisms of stalled replication fork protection defects leading to therapeutic responses in organoid xenograft models of HGSC. This will be accomplished by generating mouse models using select organoids from aim 2 and testing them for therapeutic responses to agents used in aim 2. The career development award candidate is an MD/PhD clinically trained in anatomic pathology. The proposed research will occur at Dana-Farber Cancer Institute under the mentorship of Dr. Alan D'Andrea. The candidate will utilize the additional training provided by this award to facilitate her ultimate career goal of becoming an independent physician scientist and leader in the field of ovarian cancer.

项目摘要 基因组分析表明，高达50%的高级别浆液性卵巢癌（HGSC）具有一种 基因组改变可能导致DNA损伤修复缺陷，从而产生针对此类缺陷的治疗方法 潜在的治疗选择。目前还没有方法来预测哪些患者会对这些治疗产生反应， 是这个领域的一个主要问题。初步数据表明，患者来源的HGSC类器官可能是忠实的 模型系统，其中执行功能测定以预测患者治疗反应。数据来自有限的 对HGSC类器官的分析表明，停滞的复制叉保护缺陷比 HGSC中的同源重组缺陷，更多的患者可能受益于更广泛的 可用于靶向此类缺陷的治疗，包括卡铂、吉西他滨、ATR、WEE 1和CHK 1 抑制剂的这项指导研究职业发展建议的目标是利用患者衍生的HGSC 类器官培养，以了解停滞复制的患病率，机制和治疗相关性 HGSC中的叉保护缺陷。拟议的研究涵盖多个学科，包括 分子生物学，DNA测序和动物模型，这将有助于研究停滞的作用， HGSC中的复制叉保护缺陷，并提供全面的职业发展战略， 通过实现以下具体目标，实现科学独立： 具体目标1：评估HGSC中分叉保护缺陷的普遍性，以及分叉保护缺陷是否 通过HGSC类器官功能测定预测导致对卡铂和ATR的治疗敏感性，WEE 1， 和CHK 1抑制剂。这将通过从接受以下治疗的患者产生类器官来实现： 卡铂和ATR、WEE 1和CHK 1抑制剂，进行功能测定以评估停滞的叉 与测序分析平行的类器官的保护能力和治疗敏感性，以及 比较类器官和病人的结果 具体目标2：揭示导致类器官中叉不稳定性的机制，以及是否存在不同的 叉保护缺陷的机制导致对上述试剂的不同敏感性。这将是 使用类器官中特定途径的分子和细胞生物学分析来完成。 具体目标3：在体内验证停滞的复制叉保护缺陷的体外机制， 在HGSC的类器官异种移植模型中的治疗反应。这将通过生成鼠标 使用来自目标2的选择类器官的模型，并测试它们对目标2中使用的药剂的治疗反应。 职业发展奖候选人是一个医学博士/博士临床解剖病理学培训。的 拟议的研究将在Dana-Farber癌症研究所进行，由Alan D 'Andrea博士指导。的 候选人将利用该奖项提供的额外培训，以促进她的最终职业目标， 成为卵巢癌领域的独立医生科学家和领导者。