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：
10287856
负责人：
Jeffrey Paul MacKeigan
金额：
$ 21.95万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287856
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 Structure Symptoms Syndrome TSC1 gene TSC2 gene Testing Therapeutic Therapeutic Effect Tuberous Sclerosis Tuberous sclerosis protein complex Tumor Burden Tumor Suppressor Genes Tumor Suppressor Proteins Variant Withholding Treatment Work advanced disease advanced prostate cancer analog cancer risk checkpoint inhibition design early onset efficacy evaluation gene repair genetic variant genome editing genome integrity improved in vivo inhibitor/antagonist insight lifetime risk mTOR Inhibitor malignant breast neoplasm mouse model mutant neoplastic cell next generation sequencing novel therapeutic intervention precision medicine rare genetic disorder 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.

项目摘要/摘要使用下一代测序，研究人员确定体细胞突变对于肿瘤病因至关重要和进化。我们现在知道，许多癌症也具有实质性的种系成分。种系突变会增加癌症的终生风险，并且通常会导致早期发作和更晚期疾病。一个在DNA损伤反应（DDR）基因中，生殖线癌突变的显着部分发生，这导致 DNA病变的修复失败，体细胞突变的积累和促进的结构变体肿瘤发生。在我们最近对结节硬化症（TSC）患者的基因组分析中，我们出乎意料地发现双链断裂（DSB）修复缺陷在种系中经常存在。 TSC是肿瘤综合征以肿瘤抑制剂TSC1和TSC2的突变为特征，导致失调的激活 mtor途径。乳房，卵巢和转移性前列腺癌还具有致病性种系突变 DDR修复基因和体细胞突变导致过度活跃MTOR信号传导。因此，我们旨在评估单独使用DDR靶向剂的治疗活性，并与MTOR抑制剂结合使用，以减少肿瘤 TSC中的负担，这也可能为以多动MTOR为特征的癌症提供宝贵的见解信号。我们的中心假设是，有缺陷的DNA损伤反应与MTOR途径的激活合作驱动肿瘤生长。我们将使用基因组编辑工具将特定的DSB修复变体引入等源细胞线，然后测量DNA损伤和MTOR信号传导。我们将测定细胞的生存能力和锚定 - 独立的生长以确定DSB突变是否促进了等生细胞中的克隆发育潜力和存活。此外，在特定的目标2中，我们计划使用针对DDR的靶向剂和在与MTOR抑制剂在体内结合。具体而言，我们将使用合成鼠标模型来评估 CHK抑制剂或PARP抑制剂作为单个药物的功效以及与依维莫司（Everolimus）合并的剂量策略。通过拟议的研究，我们将确定种系DSB维修缺陷是否创造了独特的 MTOR驱动肿瘤的治疗机会。鉴于种系DDR突变和体细胞MTOR途径突变的基本作用在肿瘤形成和恶性病变。