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Dissecting the interaction between DNA damage repair defects and the tumor microenvironment

剖析DNA损伤修复缺陷与肿瘤微环境之间的相互作用

基本信息

批准号：
10260641
负责人：
Sarah James Hill
金额：
$ 44.25万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-16 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260641
关键词：
Address Advisory Committees Aftercare B-Lymphocytes Biological Models Blood Vessels Cancer Biology Cancer Patient Carboplatin Cell Communication Cells Clinical Coculture Techniques Combined Modality Therapy Complement DNA DNA Repair DNA Sequence Alteration DNA replication fork Dana-Farber Cancer Institute Defect Dendritic Cells Development Disease Early Diagnosis Environment Epithelial Equipment and Supplies Evolution Financial Support Flow Cytometry Generations Genetic Fingerprintings Genetic Transcription Genomics Goals Growth Growth Factor Immune In Vitro Knowledge Lead Leadership Malignant neoplasm of ovary Medical Oncology Mesenchymal Molecular Natural Killer Cells Neoadjuvant Therapy Normal Cell Organoids Pathway interactions Patients Pharmaceutical Preparations Platinum Publications Publishing Research Research Personnel Research Training Residencies Resistance Selection for Treatments Serous Stress Stromal Cells Stromal Neoplasm Structure System Systemic Therapy T-Lymphocyte Therapeutic Time Tissue Sample Training Tumor-Derived Tumor-infiltrating immune cells Vision Work base career chemotherapy combat crosslink cytokine cytotoxicity experience gene repair human tissue innovation insight macrophage multidisciplinary neoplastic cell neutrophil novel prevent professor programs repaired response single-cell RNA sequencing skills targeted treatment therapy resistant treatment response tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Genomic analysis of high grade serous ovarian cancer (HGSC) has revealed that up to 50% of HGSCs harbor a genomic alteration in a DNA damage repair (DDR) gene, mostly in the BRCA repair pathway. Functional profiling of DDR capacity of patient derived HGSC organoids has revealed that over 60% of HGSCs harbor defects in the stalled replication fork protection DDR pathway. Further analysis of these HGSC organoids reveals that in patients who receive neoadjuvant chemotherapy, a tumor which initially had a replication fork protection defect and was carboplatin sensitive can be induced by the neoadjuvant chemotherapy to undergo replication fork stabilization and become carboplatin resistant. Transcriptional analysis of the post-neoadjuvant fork stable organoids reveals that these cultures have undergone an epithelial-mesenchymal transition. Based on these results, the hypothesis is that defects in the stalled replication fork protection DDR pathway are a fundamental molecular defect in HGSC that when perturbed by treatment with neoadjuvant carboplatin can lead to loss of the defect at the molecular level, alterations in the overall state of the tumor cells, and changes in the way the tumor cells interact with the surrounding stroma and immune cells, all of which combine to create a broadly therapy resistant tumor microenvironment. The research challenge I will pursue is to dissect the evolving mechanisms by which tumor cells which originally harbor fork protection defects and are induced to lose the defect interact with the surrounding stroma and immune cells and how these changing interactions might be manipulated to prevent a deeply resistant tumor microenvironment. The work will utilize a novel HGSC organoid co-culture system which will be highly innovative for the field because it will allow real time assessment of the interactions between DDR defective or altered tumor cells and the surrounding normal cells over time and treatment. Approach: The goal of Aim 1 is to generate growth conditions for co-cultures of fork unstable platinum sensitive organoids with patient matched intra-tumoral stromal cells and all immune cells (T cells, B cells, NK cells, dendritic cells, macrophages, and neutrophils). The goal of Aim 2 will be to generate isogenic pairs of the organoids from Aim 1 that are fork stable and unstable and then study how the interaction of the tumor cells with the surrounding stromal cells changes in the organoid co-culture system as the tumor cells undergo selective fork stabilization. The goal of Aim 3 is to utilize the isogenic pairs of fork unstable and stable organoids from Aim 2 in the co-culture system and determine how the interaction of the tumor cells with the surrounding immune cells changes as the tumor cells undergo fork stabilization and how this may alter response to immuno-oncologic agents. This work will have major impact in HGSC because it will help understand the evolution of the tumor-normal cell interaction as the tumor cell fork protection defects are altered and stressed. This may allow for the development of rational combination therapies that simultaneously target the tumor cell defects and also prevent problematic tumor-normal cell interactions.

项目总结