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

项目摘要 卵巢癌是女性癌症相关死亡的第五大原因，也是最致命的 美国的妇科癌症。目前卵巢癌的标准治疗方法包括 手术后以铂类药物为基础的化疗。铂类药物可诱导DNA间链 交链(ICL)，这会导致复制分叉停滞，从而降低细胞存活率。尽管大多数人 患者最初对铂类药物为主的化疗有反应并实现缓解，高达80%的患者 随着时间的推移，对铂类药物变得难以抗拒，并最终因对 以铂为基础的疗法。因此，迫切需要开发新的方法来克服铂耐药 卵巢癌(PROC)。Fanconi贫血(FA)途径是修复ICL和提高FA活性的关键 信号转导是导致卵巢癌铂耐药的主要机制之一。FA途径的作用 在修复ICL上已经有了很好的研究，然而，如何从停滞不前的监管切换 铂类药物对FA信号启动的复制分叉及Proc细胞中FA是如何被激活的 人们对此了解甚少。 为了阐明FA信号启动的调控机制，我们进行了显著的 大量的初步研究表明，And-1是激活FA信号和FA-1的关键。 在卵巢癌中介导的铂耐药。这项建议的主要目标是确定 -1-FANCM轴在Proc中调节FA信号和铂抗性的机制。在这里，我们 提出三个具体目标。目标1：确定和-1如何推动从停滞的复制分支切换到 在ICL启动FA信号。目的2：确定And-1在铂类药物调控中的作用 Proc细胞中的耐药性。目的3：评价AND-1抑制对铂类药物耐药的影响 原位pDX和同种异体模型。拟议研究的完成不仅将阐明 Proc中调节铂耐药的新机制，但也提供了一种创新的治疗策略 以及一种治疗PROC患者的新的潜在药物。

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.