Mechanistic basis and therapeutic strategies for ARID1A mutation in ovarian cancer

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途径的抑制选择性敏感;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， 从目前的研究中获得的机械见解将对许多不同类型的 癌症也是。

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.