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Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer

卵巢癌ARID1A突变的机制基础及治疗策略

基本信息

批准号：
10219750
负责人：
Rugang Zhang
金额：
$ 43.47万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10219750
关键词：
ARID1A gene ATF6 gene Apoptotic Beds Cell Line Cell Survival Cells Cessation of life Chromatin Remodeling Factor Chromatin Structure Clinical Data Dependence Development Diagnosis Disease Epigenetic Process Epithelial ovarian cancer Genes Genetic Genetic Transcription Goals Growth Human Immunocompetent Intervention Knock-out Knowledge Malignant Neoplasms Malignant neoplasm of ovary Mediating Messenger RNA Methods Mission Modality Molecular Mutate Mutation Nucleotides Ovarian Clear Cell Tumor Ovarian Endometrioid Adenocarcinoma Pathway interactions Platinum Pre-Clinical Model Primary Neoplasm Prognosis Proteins Public Health RNA Splicing Refractory Research Resolution Ribonucleases Role Series T-Lymphocyte Testing Therapeutic Tumor Immunity Tumor Suppressor Proteins United States National Institutes of Health Up-Regulation XBP1 gene Xenograft procedure anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy base biological adaptation to stress cancer cell cancer subtypes cancer type cell growth chemotherapy clinically relevant cytotoxic CD8 T cells effective therapy endoplasmic reticulum stress experimental study gene repression genetic makeup genome-wide immune checkpoint blockade inhibitor/antagonist innovation insight mouse model mutant neoplastic cell novel novel therapeutic intervention patient derived xenograft model pre-clinical precision medicine prototype response small molecule small molecule inhibitor transcription factor tumor

项目摘要

Project Summary ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this proposal is to develop a novel therapeutic strategy for ARID1A-mutated ovarian cancers by targeting the IRE1a/XBP1 pathway of the endoplasmic reticulum (ER) stress response alone or in combination with an immune checkpoint blockade. We show that the ARID1A inactivation creates a dependence on the IRE1a/XBP1 pathway. We also show that ARID1A inactivation sensitizes ovarian cancer to anti-PD-L1 treatment. The objectives of this application are to investigate the mechanisms underlying the dependence on the IRE1a/XBP1 pathway created by ARID1A inactivation and to investigate novel IRE1a/XBP1 inhibition-based therapeutic strategies for ARID1A-mutated ovarian cancer. Our central hypothesis is that ARID1A-mutated ovarian cancers can be treated and ultimately eradicated by targeting the IRE1a/XBP1 pathway of the ER stress response alone or in combination with immune checkpoint blockade. Two Specific Aims are proposed: Aim 1 is to investigate the mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of the IRE1a/XBP1 pathway; and Aim 2 will target the IRE1a/XBP1 pathway for developing novel therapeutic strategies for ARID1A mutation. The proposed studies are highly innovative because they challenge current research/clinical paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian cancers. The research proposed is of high impact because it will provide a scientific rationale for developing urgently needed novel therapeutic strategies by targeting the IRE1a/XBP1 pathway of the ER stress response alone or in combination with an immune checkpoint blockade for ARID1A-mutated ovarian cancer, a disease that currently has no effective therapy. Since ARID1A is the most frequently mutated epigenetic regulator across human cancers, the mechanistic insights gained from the current studies will have broad implications for many different types of cancers as well.

项目摘要 ARID 1A，编码SWI/SNF染色质重塑复合物的亚基，是最常见的突变，人类癌症的表观遗传调节因子。最值得注意的是，ARID 1A的失活突变发生在约50%的人中。卵巢透明细胞癌（OCCC）和约30%的卵巢类上皮癌（OEC）。存在未满足的对ARID 1A突变卵巢癌的有效治疗方式的需求。例如，OCCC通常对于用于治疗上皮性卵巢癌的标准药物是难治的，并且当诊断为晚期时， OCCC是所有卵巢癌亚型中预后最差的。该提案的总体目标是发展 ARID 1A突变卵巢癌的一种新的治疗策略，内质网（ER）应激反应单独或与免疫检查点阻断组合。我们表明ARID 1A失活产生了对IRE 1a/XBP 1通路的依赖性。我们也证明了 ARID 1A失活使卵巢癌对抗PD-L1治疗敏感。本申请的目的是研究依赖ARID 1A产生的IRE 1a/XBP 1通路的潜在机制研究基于IRE 1a/XBP 1抑制的ARID 1A突变的治疗策略。卵巢癌我们的中心假设是ARID 1A突变的卵巢癌可以治疗，通过单独靶向ER应激反应的IRE 1a/XBP 1通路或与免疫抑制剂联合使用，检查站封锁。提出了两个具体的目标：目标1是调查的机制， ARID 1A突变的卵巢癌细胞对IRE 1a/XBP 1通路的抑制选择性敏感;和目的2将靶向IRE 1a/XBP 1通路，为ARID 1A突变的治疗提供新的策略。的拟议的研究具有高度创新性，因为它们挑战了当前的研究/临床范式，创新方法，探索ARID 1A突变卵巢癌的新干预策略。研究提出的是高影响，因为它将提供一个科学的理由，开发迫切需要的新的通过单独或联合靶向ER应激反应的IRE 1a/XBP 1途径的治疗策略 ARID 1A突变卵巢癌的免疫检查点阻断，这种疾病目前没有有效的治疗。由于ARID 1A是人类癌症中最常突变的表观遗传调节因子，从当前研究中获得的机械见解将对许多不同类型的癌症也是。