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

• 批准号: 10454901
• 负责人: Rugang Zhang
• 金额: $ 11.92万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454901
• 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; 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

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 ARID1A编码SWI/SNF染色质重塑复合体的一个亚单位，是最频繁的突变 人类癌症的表观遗传调控。最值得注意的是，ARID1A的失活突变发生在约50%的 卵巢透明细胞癌(OCCC)和卵巢子宫内膜样癌(OEC)约占30%。有一个未满足的人 ARID1A基因突变的卵巢癌需要有效的治疗方式。例如，OCCC通常是 对用于治疗上皮性卵巢癌的标准药物无效，当诊断为晚期时， OCCC是所有卵巢癌亚型中预后最差的。这项提议的总体目标是发展 靶向IRE1a/XBP1通路治疗ARID1A突变卵巢癌的新策略 内质网(ER)应激反应单独或与免疫检查点阻断。我们 表明ARID1A失活产生了对IRE1a/XBP1途径的依赖。我们还表明， ARID1A失活使卵巢癌对抗PD-L1治疗敏感。此应用程序的目标是 探讨ARID1A对IRE1a/XBP1通路依赖的机制 ARID1A突变的失活及基于IRE1a/XBP1抑制的新治疗策略的研究 卵巢癌。我们的中心假设是ARID1A突变的卵巢癌是可以治疗的，并最终 通过单独或与免疫联合靶向ER应激反应的IRE1a/XBP1通路而被根除 检查站封锁。提出了两个具体的目标：目标1是研究其作用机制。 ARID1A突变的卵巢癌细胞对抑制IRE1a/XBP1通路选择性敏感； 目的2将以IRE1a/XBP1通路为靶点，开发ARID1A突变的新治疗策略。这个 拟议的研究具有很高的创新性，因为它们挑战了当前的研究/临床范式，并利用 探索ARID1A突变卵巢癌新的干预策略的创新方法。这项研究 它的提出具有很大的影响，因为它将为开发急需的小说提供科学的理论基础 单独或联合靶向内质网应激反应的IRE1a/XBP1通路的治疗策略 通过对ARID1A突变的卵巢癌进行免疫检查点阻断，这种疾病目前没有 有效的治疗。由于ARID1A是人类癌症中最频繁突变的表观遗传调控因子， 从当前研究中获得的机械论见解将对许多不同类型的 癌症也是如此。