Therapeutic potential of targeting DNA repair deficiency in TSC

针对 TSC 中 DNA 修复缺陷的治疗潜力

基本信息

批准号：
10435553
负责人：
Jeffrey Paul MacKeigan
金额：
$ 17.93万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435553
关键词：
Ablation Aftercare Anchorage-Independent Growth Animal Model Automobile Driving BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Benign Breast CCI-779 Cancer Patient Cell Line Cell Survival Cell model Cells Cellular Assay Clinical Combined Modality Therapy Cytostatics DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA lesion Data Defect Disease Disease Management Dose Double Strand Break Repair Drug Targeting Essential Genes Etiology Evolution FRAP1 gene Gene Mutation Gene Targeting Genes Genetic Genomic Instability Genomics Germ-Line Mutation Growth Hamartoma Health Hereditary Breast Carcinoma Hereditary Nonpolyposis Colorectal Neoplasms Human Hyperactivity Immune checkpoint inhibitor Individual Inherited Knock-out Lead Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Measures Metastatic Prostate Cancer Metastatic to Mismatch Repair Mutation Oncogenic Ovarian Pathogenesis Pathogenicity Pathway interactions Patients Phase RAD51C gene RAD54L gene Research Research Personnel Role SDZ RAD Signal Transduction Sirolimus Somatic Mutation Symptoms Syndrome TSC1 gene TSC2 gene Testing Therapeutic Therapeutic Effect Tuberous Sclerosis Tumor Burden Tumor Suppressor Genes Tumor Suppressor Proteins Variant Withholding Treatment Work advanced disease advanced prostate cancer analog cancer risk checkpoint inhibition early onset efficacy evaluation gene repair genetic variant genome editing genome integrity improved in vivo inhibitor insight lifetime risk mTOR Inhibitor malignant breast neoplasm mouse model mutant neoplastic cell next generation sequencing novel therapeutic intervention precision medicine rare genetic disorder rational design repaired response targeted agent tool tuberous sclerosis patients tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY/ ABSTRACT Using next-generation sequencing, researchers have identified somatic mutations as essential for tumor etiology and evolution. We now know that many cancers also have a substantial germline component. Germline mutations increase the lifetime risk of cancer and often result in earlier onset and more advanced disease. A significant portion of germline cancer mutations occur in DNA damage response (DDR) genes, which lead to the failed repair of DNA lesions, the accumulation of somatic mutations and structural variants that promote oncogenesis. In our recent genomic analysis of tuberous sclerosis (TSC) patients, we unexpectedly found that double-strand break (DSB) repair deficiencies are frequent in the germline. TSC is a tumor syndrome characterized by mutations in the tumor suppressors, TSC1 and TSC2, causing dysregulated activation of the mTOR pathway. Breast, ovarian, and metastatic prostate cancers also harbor pathogenic germline mutations in DDR repair genes and somatic mutations leading to hyperactive mTOR signaling. As such, we aim to evaluate the therapeutic activity of DDR-targeted agents alone and in combination with mTOR inhibitors for reduced tumor burden in TSC, which may also provide valuable insights for cancers characterized by hyperactive mTOR signaling. Our central hypothesis is that a defective DNA damage response cooperates with mTOR pathway activation to drive tumor growth. We will use genome editing tools to introduce specific DSB repair variants into isogenic cell lines and then measure DNA damage and mTOR signaling. We will assay cell viability and anchorage- independent growth to determine if DSB mutations promote clonogenic potential and survival in isogenic cells. Further, in Specific Aim 2, we plan to explore therapeutic potential using targeted agents to DDR alone and in combination with mTOR inhibitors in vivo. Specifically, we will use syngeneic mouse models to evaluate the efficacy of CHK inhibitors or PARP inhibitors as single agents and in combined dosing strategies with everolimus. Through the proposed research, we will determine whether germline DSB repair defects create a unique therapeutic opportunity in mTOR-driven tumors. Our results could have broad-reaching implications given the essential roles of germline DDR mutations and somatic mTOR pathway mutations in tumor formation and malignant lesions.

项目概要/摘要使用下一代测序，研究人员已经确定体细胞突变对于肿瘤病因学至关重要和进化。我们现在知道许多癌症也有大量的种系成分。种系突变会增加终生患癌症的风险，并常常导致更早发病和更严重的疾病。一个很大一部分种系癌症突变发生在 DNA 损伤反应 (DDR) 基因中，这导致 DNA损伤修复失败、体细胞突变和结构变异的积累肿瘤发生。在我们最近对结节性硬化症 (TSC) 患者的基因组分析中，我们意外地发现双链断裂（DSB）修复缺陷在种系中很常见。 TSC 是一种肿瘤综合征其特点是肿瘤抑制因子 TSC1 和 TSC2 发生突变，导致肿瘤抑制因子激活失调 mTOR 通路。乳腺癌、卵巢癌和转移性前列腺癌也含有致病性种系突变 DDR 修复基因和体细胞突变导致 mTOR 信号传导过度活跃。因此，我们的目标是评估单独使用 DDR 靶向药物以及与 mTOR 抑制剂联合使用以减少肿瘤的治疗活性 TSC 的负担，这也可能为以 mTOR 过度活跃为特征的癌症提供有价值的见解发信号。我们的中心假设是，有缺陷的 DNA 损伤反应与 mTOR 通路激活相配合，驱动肿瘤生长。我们将使用基因组编辑工具将特定的 DSB 修复变体引入同基因细胞中线，然后测量 DNA 损伤和 mTOR 信号传导。我们将测定细胞活力和贴壁- 独立生长以确定 DSB 突变是否促进同基因细胞的克隆形成潜力和存活。此外，在具体目标 2 中，我们计划探索使用靶向药物单独治疗 DDR 以及在与体内 mTOR 抑制剂联合使用。具体来说，我们将使用同基因小鼠模型来评估 CHK 抑制剂或 PARP 抑制剂作为单一药物以及与依维莫司联合给药策略的疗效。通过拟议的研究，我们将确定种系 DSB 修复缺陷是否会产生独特的 mTOR 驱动的肿瘤的治疗机会。鉴于种系 DDR 突变和体细胞 mTOR 通路突变在肿瘤形成和治疗中的重要作用恶性病变。