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Examine the function of APOBEC3B in epithelial ovarian cancer stem cells

检查 APOBEC3B 在上皮性卵巢癌干细胞中的功能

基本信息

批准号：
10438420
负责人：
Qingfei Jiang
金额：
$ 7.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438420
关键词：
Address Adoption Apoptosis Area Cancer Patient Cancer Relapse Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Maintenance Cells Chromosome abnormality Combined Modality Therapy Cytidine DNA DNA Damage DNA Double Strand Break DNA Modification Process DNA Repair DNA Sequence Alteration DNA Single Strand Break Data Deaminase Deamination Development Diagnosis Disease Drug resistance Enzymes Epithelial ovarian cancer Family Frequencies Goals Induced Mutation Inherited Innate Immune Response L1 Elements Lead Maintenance Therapy Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Medical Mission Modeling Molecular Monitor Mutation Neoplasm Metastasis Organism Organoids Pathway interactions Patients Phase Play Point Mutation Population Prevalence Primary Neoplasm Progression-Free Survivals Proteins Recurrence Recurrent disease Research Resistance Resistance development Role Single-Stranded DNA Source Survival Rate Testing Treatment Efficacy United States National Institutes of Health Uridine Viral Virus Replication Work apolipoprotein B mRNA editing enzyme brca gene cancer stem cell cancer type chemotherapy effective therapy gene repair improved inhibitor innovation insight mutant new therapeutic target novel novel therapeutics overexpression particle patient subsets polypeptide prevent rare cancer response self-renewal stem cell biology stem cell function stem cells stemness therapy resistant tumor tumor growth

项目摘要

SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecologic malignancy and is frequently diagnosed at an advanced-stage. One of the most aggressive types of ovarian cancer is epithelial ovarian cancer (EOC) and 5-year survival is less than 20%. In recent years, PARP inhibitors (PARPi) has shown impressive therapeutic efficacy as both maintenance therapy and in recurrent setting. However, since the wide application of PARPi, patients ultimately develop drug resistance to PARPi which leaves them with few treatment options. Thus, the development of novel therapies to overcome PAPRi resistance represents an urgent unmet medical need. The PARPi-resistant patients often have enriched cancer stem cells (CSCs) with enhanced pro-survival and self-renewal capacity. Evidence demonstrations that EOC CSCs are responsible for primary tumor growth, metastasis, disease relapse and resistance to chemotherapy, suggesting CSC is an attractive target for eradicating EOC. Our long-term goal is to identify new targets for development of less toxic and more effective therapies by eliminating this cell population. Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins are a family of DNA deaminase that catalyze cytidine to uridine (C-to-U) on single-strand DNA. This important DNA modification is abundant in a wide array of cancer types and represent the only enzymatic source of mutations. We discovered that APOBEC3B (A3B) is the main DNA mutators in EOC CSC. The C-to-U DNA mutation activity and A3B expression is reduced in EOC CSCs compared to non-CSCs. Importantly, inhibition of A3B leads to PARPi resistance, elevated frequency of CSCs, and enhanced expression of stemness factor SOX2. These novel insights raise the possibility that A3B activation may sensitize EOC CSCs to PARPi. Our central hypothesis is that EOC CSCs maintain low level of A3B in order to avoid excess DNA damage thereby counters the effect of PARPi. The overall goal of this study is to dissect the mechanism through which A3B and DNA deamination regulates CSC maintenance and promote response to PARPi in EOC CSC. We will address our hypothesis in two specific aims: 1) Determine if modified A3B activity will sensitize CSCs to combination therapy with PARPi, 2) Identify the novel mechanisms by which A3B regulates response to PARP inhibitor in EOC CSCs. We will perform A3B overexpression studies in patient-derived organoid models and comprehensively evaluate changes in EOC CSC functions and the response to PARPi. Mechanistically, we will assess DNA damage pathways, chromosomal abnormalities, and ssDNA break levels in CSCs that overexpress A3B alone and in combination treatment with PARPi. In addition, the molecular mechanism of how A3B regulates CSC’s response to PARPi will also be examined. This innovative study will improve our understanding of how A3B sensitize EOC CSCs to PARPi by promoting DNA damage and uncover valuable novel therapeutic targets to preventing ovarian cancer relapse. These mechanisms may be broadly applicable to other CSC-driven malignancies.

摘要/文摘