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Project 4: The BRCA Network in Medulloblastoma Responses to Replication Stress

项目 4：髓母细胞瘤中 BRCA 网络对复制压力的反应

基本信息

批准号：
10396611
负责人：
Zhiyuan Shen
金额：
$ 42.25万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
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：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396611
关键词：
Aftercare BRCA mutations BRCA1 gene BRCA2 gene Binding Brain Neoplasms C-terminal CDKN1A gene Cells Cessation of life Characteristics Chromosomal Breaks Chromosomes Code Complex DNA Binding Domain DNA Damage DNA Repair DNA Repair Gene DNA biosynthesis DNA replication fork DNA strand break Data Defect Development Down-Regulation Embryo Epigenetic Process Exhibits Functional disorder Genes Genome Genomics Germ-Line Mutation Glial Fibrillary Acidic Protein Goals Health Human Hypersensitivity In Vitro Individual Malignant Childhood Neoplasm Malignant Neoplasms Mammary gland Mediating Modeling Molecular Mus Mutation Organ Ovary PALB2 gene Pancreas Patients Pediatric Neoplasm Penetration Pharmaceutical Preparations Play Progression-Free Survivals Prostate Proteins Radiation Recurrence Risk Role Signal Transduction Site Structure Testing Time Topoisomerase Treatment Protocols Ursidae Family Ustilago base brca gene cancer predisposition chemotherapy conditional knockout efficacy validation gene network genome-wide genomic biomarker genomic signature high risk homologous recombination inhibitor irinotecan knock-down medulloblastoma medulloblastoma cell line neoplastic cell novel therapeutic intervention novel therapeutics preclinical study promoter recruit replication stress response stem cells success targeted treatment therapeutic development treatment response tumor tumorigenesis

项目摘要

The BRCA Network in Medulloblastoma Responses to Replication Stress (Project-4) Abstract: BRCA1 and BRCA2 are critical genes for the repair of DNA strand breaks (DSB) via homologous recombination (HR). PALB2 functions to bridge BRCA1 with BRCA2. Due to the intimate relationship between BRCA1, PALB2, and BRCA2, these genes and their coded proteins are considered the core of a “BRCA network.” Cancers with BRCA mutations display unique molecular features of “BRCAness,” including hypersensitivity to replication stress drugs. In addition to the core BRCA proteins, defects of other BRCA1/2- associated genes often share the “BRCAness” characteristics. Brain tumors are the leading cause of childhood cancer-related deaths, and medulloblastomas (MBs) account for more than 60% of pediatric tumors. Current treatments of MBs mainly rely on local control by radiation in combination with generic chemotherapy. Targeted therapy has not been vigorously considered for MBs. Recently, it has been recognized that germline mutations in BRCA2 and PALB2, two of the core genes in the “BRCA Network,” are among the top causes of MBs. Furthermore, widespread basal activation of DNA damage signaling and excessive replication stress were common among different groups of MBs. Based on genomic signatures, 20-30% of sporadic MBs, including those from MB groups 2, 3, and 4, likely bear HR defects (HRD). These recent developments raise an important question of whether DNA damage repair defects and replication stress represent common vulnerabilities of MBs to new therapeutic developments targeting HRD. If so, how to efficiently identify the individual cases with HRD remains an issue. In the preliminary studies, we established conditional knockouts of Brca1, Palb2, and Brca2 in embryonic multi-potential stem and progenitor cells using the glial fibrillary acidic protein (GFAP) promoter-driven Cre expression. For the first time, we demonstrated that conditional loss of Palb2 and Brca1 are effective inducers of MBs, with a similar potency as that of Brca2 loss. An initial genomic characterization of these MBs exhibiting “BRCAness” had identified several unique structural features that can be used to define the HRD status. By treating the de novo MBs with a developing topoisomerase 1 inhibitor, we found it to be very effective to extend the survival of mice with MBs. Thus, we hypothesize that MBs originated from BRCA defects have unique genomic signatures to define the MBs with HRD, and targeted therapy of MBs with HRD will be more effective than the current treatment regimens. In Project-4, we take advantage of our recent success in establishing BRCA-related mouse MB models and strive to identify the genomic signatures associated with HRD and to validate the MB “BRCAness” response to replication stress drugs. Aim 1 will identify the structural and chromosome-context signatures that accurately reflect the HDR status in MBs exhibiting “BRCAness”. Aim 2 will experimentally target the vulnerability of HRD in MBs and investigate the potential mechanism of tumor recurrence after the treatment. The success of this study would effectively establish a new remedy for MB treatment.

BRCA网络在成神经管细胞瘤复制应激反应中的作用（Project-4）