Therapeutic potential of targeting DNA repair deficiency in TSC

针对 TSC 中 DNA 修复缺陷的治疗潜力

• 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
• 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

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，研究人员已经确定体细胞突变是肿瘤病因学的关键 和进化论。我们现在知道，许多癌症也有大量的生殖系成分。生殖系 突变会增加终生癌症的风险，通常会导致更早的发病和更晚期的疾病。一个 很大一部分生殖系癌症突变发生在DNA损伤反应(DDR)基因中，这导致 DNA损伤修复失败，体细胞突变和促进 致癌作用。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)修复缺陷在生殖系中很常见。TSC是一种肿瘤综合征 以肿瘤抑制基因TSC1和TSC2突变为特征，导致TSC1和TSC2激活失调 MTOR途径。乳腺癌、卵巢癌和转移性前列腺癌也存在致病胚系突变。 DDR修复基因和体细胞突变导致mTOR信号过度活跃。因此，我们的目标是评估 DDR靶向药物单独及联合mTOR抑制剂治疗肿瘤的活性 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，缺陷的DNA损伤反应与mTOR途径的激活协同作用 推动肿瘤生长。我们将使用基因组编辑工具将特定的DSB修复变体引入等基因细胞 然后测量DNA损伤和mTOR信号。我们将分析细胞活性和锚定能力- 独立生长以确定DSB突变是否促进克隆形成潜力和在同基因细胞中的存活。 此外，在具体目标2中，我们计划单独使用靶向药物治疗DDR和 体内联合应用mTOR抑制剂。具体地说，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的有效性。 通过拟议的研究，我们将确定胚系DSB修复缺陷是否会产生独特的 MTOR驱动的肿瘤的治疗机会。我们的结果可能会产生广泛的影响，因为 种系DDR突变和体细胞mTOR通路突变在肿瘤形成和转移中的重要作用 恶性病变。