Alternative NF-kB activation in post-chemotherapy setting to elucidate novel mechanisms of ovarian cancer relapse

科学文摘 卵巢癌是美国最致命的妇科恶性肿瘤，尽管患者最初 对细胞毒性化疗有反应，大多数在 24 个月内出现化疗耐药性疾病。有 我们对支持疾病复发的机制的认识存在一些关键差距，但对疾病复发的研究 过去十年支持肿瘤起始细胞（TIC）这一耐药肿瘤细胞亚群的观点 负责促进复发，针对这些难以捉摸的细胞的联合疗法可能会导致更长时间 缓解甚至治愈。尽管许多基因和信号通路与维持 TIC，我们对这些细胞在细胞毒性作用下生存的过程的理解存在几个关键差距 化疗并成功地重建肿瘤。例如，尚不清楚 TIC 中是否有活跃的通路 是组成型的还是可以由肿瘤微环境（TME）中的因素诱导的。我们之前的研究 揭示了替代 NF-kB 信号在维持卵巢 TIC 和细胞毒性抵抗中的重要作用 化疗。 NF-kB 是一个转录因子家族，可响应 TME 中的信号以促进 癌细胞的增殖、化疗耐药性和存活。新出现的证据表明 TME 发生了变化 细胞毒性化疗后可能会导致释放信号因子，从而激活癌症中的 NF-kB 细胞。我们最近的数据显示，TWEAK，一种由巨噬细胞和基质分泌的多功能细胞因子 细胞，在化疗后 TME 中升高，并且可以诱导替代 NF-kB 和 干性基因在多种卵巢癌细胞中的表达。接受治疗的患者的临床数据 新辅助化疗表明编码 TWEAK 和替代 NF-kB 家族成员的基因 相对于治疗前的水平，在细胞毒性化疗后切除的肿瘤中显着升高。这些 数据引导我们得出中心假设：化疗提供了有利于 TIC 发展的环境 通过激活替代性 NF-kB。为了研究这个假设，我们将 1）确定是否 化疗诱导的卵巢 TME 中的 TWEAK 信号激活卵巢癌细胞中的替代 NF-kB 2) 建立替代性 NF-kB 激酶 NIK 在卵巢癌化疗耐药和复发中的功能 3) 研究 NF-kB 介导的 Notch 激活在支持卵巢 TIC 中的作用 化疗。与大多数已发表的研究不同，我们关注的是这些细胞在 化疗，以产生评估复发机制的新范例。鉴于最初的强烈反响 对于化疗来说，确定可以针对的早期治疗后事件非常有意义 与细胞毒性药物联合抑制维持 TIC 的途径。阐明新机制 这种未经充分研究的途径支持化疗耐药性，将指导更好的疗法的设计，以延长治疗时间 缓解或可能治愈卵巢癌患者。

Scientific Abstract Ovarian cancer is the most lethal gynecological malignancy in the United States and although patients initially respond to cytotoxic chemotherapy, most relapse with chemoresistant disease within 24 months. There are several critical gaps in our knowledge of the mechanisms that support disease recurrence but research over the last decade support the notion tumor-initiating cells (TICs), a subpopulation of drug resistant tumor cells, are responsible for facilitating relapse and combination therapies targeting these elusive cells may lead to longer remission or even cures. Although numerous genes and signaling pathways have been implicated in maintaining TICs, there are several critical gaps in our understanding of the processes these cells use to survive cytotoxic chemotherapy and successfully re-establish tumors. For example, it is unclear whether pathways active in TICs are constitutive or if they can be induced by factors in the tumor microenvironment (TME). Our previous studies revealed an important role for alternative NF-kB signaling in maintaining ovarian TICs and resistance to cytotoxic chemotherapy. NF-kB is a family of transcription factors that respond to signals in the TME to promote proliferation, chemoresistance, and survival of cancer cells. Emerging evidence suggest alterations of the TME following cytotoxic chemotherapy can result in the release of signaling factors that can activate NF-kB in cancer cells. Our recent data show that TWEAK, a multifunctional cytokine secreted from macrophages and stromal cells, is elevated in the TME following chemotherapy and can induce activation of alternative NF-kB and expression of stemness genes in a variety of ovarian cancer cells. Clinical data from patients undergoing neoadjuvant chemotherapy show that genes encoding TWEAK and alternative NF-kB family members are significantly elevated in tumors resected following cytotoxic chemotherapy relative to pre-treatment levels. These data lead us to our central hypothesis that chemotherapy provides an environment that favors TIC development through activation of alternative NF-kB. To investigate this hypothesis, we will 1) determine whether chemotherapy-induced TWEAK signaling in the ovarian TME activates alternative NF-kB in ovarian cancer cells 2) establish the function of the alternative NF-kB kinase, NIK, in ovarian cancer chemoresistance and relapse and 3) investigate the role of NF-kB-mediated activation of Notch in supporting ovarian TICs following chemotherapy. Unlike most published studies, we are focusing on the pathways and activities in these cells after chemotherapy, to generate new paradigms for evaluating relapse mechanisms. Given the strong initial response to chemotherapy, it is of great interest to identify an early post-treatment event that could be targeted in combination with cytotoxic drugs to inhibit pathways that maintain TICs. Clarifying novel mechanism(s) by which this under-examined pathway supports chemoresistance will guide the design of better therapies to prolong remission or potentially achieve cures for ovarian cancer patients.