权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要/摘要