Targeting Fanconi Anemia pathway to overcome platinum drug resistance in ovarian cancer

项目摘要 卵巢癌（OC）是女性癌症相关死亡的第五大原因，也是最致命的 妇科癌症在美国目前卵巢癌的标准治疗包括 手术后进行铂类药物化疗。铂类药物可诱导DNA链间 交联（ICL），这导致复制叉停滞，从而降低细胞活力。虽然大部分 患者最初对基于铂类药物的化疗有反应并达到缓解，高达80%的患者 随着时间的推移变得对铂类药物难治，并最终由于对铂类药物的耐药性而死于疾病。 铂类药物治疗因此，迫切需要开发新的方法来克服铂类药物的耐药性 卵巢癌（PROC）Fanconi贫血（FA）通路是ICL修复和FA活性升高的关键 信号转导是导致卵巢癌铂类耐药的主要机制之一。FA途径的作用 ICL的修复在过去十年中得到了很好的研究，然而，如何从一个停滞的调节开关， 铂类药物引起的复制叉对FA信号传导的启动以及FA在PROC细胞中是如何被激活的 我们对此知之甚少。 为了阐明调节FA信号起始的机制，我们进行了有意义的 大量的初步研究表明，和-1是关键的激活FA信号和FA- 介导的铂类药物耐药性。本提案的主要目的是确定 And-1-FANCM轴如何调节FA信号传导和铂耐药的机制。在这里，我们 提出三个具体目标。目标1：确定And-1如何将停止的复制分叉转换为 在ICL处启动FA信号传导。目的2：确定And-1在铂类药物调节中的作用 PROC细胞中的抗性。目的3：评价And-1抑制剂对铂类耐药的影响。 原位PROC PDX和同基因模型。完成拟议的研究不仅可以阐明 新的机制调节铂耐药的PROC，而且还提供了一个创新的治疗策略 也是治疗PROC患者的一种新的潜在药物。

Project Summary Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women and the deadliest gynecological cancer in the United States. The current standard treatment for ovarian cancer consists of surgery followed by platinum drug-based chemotherapy. Platinum drugs could induce DNA interstrand crosslink (ICL), which results in replication fork stalling and thus decrease cell viability. Although most of patients initially respond to platinun drug-based chemotherapy and achieve remission, up to 80% of patients become refractory to platinum drugs over time and ultimately succumb to the disease due to the resistance to platinum-based therapy. Thus, it is urgent to develop novel approaches to overcome platinum drug resistance of ovarian cancer (PROC). Fanconi anemia (FA) pathway is critical to repair ICLs and elevated activity of FA signaling is one of major mechanisms leading to platinum-resistance in ovarian cancer. The role of FA pathway in repair of ICL has been well studied last decade, however, how the regulatory switch from a stalled replication fork caused by platinum drugs to initiation of FA signaling and how FA is activated in PROC cells are poorly understood. To elucidate the mechanism regulating initiation of FA signaling, we have conducted the significant amount of preliminary studies to demonstrate that And-1 is critical for activation of FA signaling and FA- mediated platinum drug resistance in ovarian cancer. The major objective of this proposal is to determine the mechanism of how And-1-FANCM axis regulates FA signaling and platinum resistance in PROC. Here, we propose three specific aims. Aim 1: Determine how And-1 promotes the switch from stalled replication forks to initiation of FA signaling at ICLs. Aim 2: Determine the role of And-1 in the regulation of platinum drug resistance in PROC cells. Aim 3: Evaluate the effects of And-1 inhibition on platinum drug resistance using orthotopic PROC PDX and syngeneic models. The completion of proposed studies will not only elucidate a novel mechanism regulating platinum resistance in PROC, but also provide an innovative therapeutic strategy as well as a new potential drug for treatment of PROC patients.