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

科学抽象 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个月内复发，并伴有化疗耐药疾病。有 我们在支持疾病复发的机制方面的知识存在几个关键空白， 最近十年支持肿瘤起始细胞（TIC）的概念，即耐药肿瘤细胞的亚群， 负责促进复发，靶向这些难以捉摸的细胞的联合治疗可能会导致更长时间的复发。 缓解甚至治愈。尽管许多基因和信号通路与维持 尽管如此，在我们对这些细胞在细胞毒性作用下存活的过程的理解中， 化疗并成功重建肿瘤。例如，目前尚不清楚TIC中的活性通路是否 是组成性的，或者它们是否可以由肿瘤微环境（TME）中的因子诱导。我们以前的研究 揭示了替代性NF-κ B信号在维持卵巢TIC和对细胞毒性T细胞的抵抗中的重要作用。 化疗NF-kB是一个转录因子家族，其响应于TME中的信号以促进TME的表达。 癌细胞的增殖、化学抗性和存活。新出现的证据表明TME的改变 细胞毒性化疗后可导致释放可激活癌症中NF-kB的信号传导因子 细胞我们最近的数据表明，TWEAK，一种由巨噬细胞和基质分泌的多功能细胞因子， 在化疗后的TME中升高，并可诱导替代性NF-κ B的活化， 干细胞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 新辅助化疗显示，编码TWEAK和替代性NF-κ B家族成员的基因是 在细胞毒性化疗后切除的肿瘤中相对于治疗前水平显著升高。这些 数据使我们得出了我们的中心假设，即化疗提供了有利于TIC发展的环境 通过激活替代NF-kB。为了研究这个假设，我们将1）确定是否 卵巢TME中化疗诱导的TWEAK信号传导激活卵巢癌细胞中的替代性NF-κ B 2)确定替代性NF-kB激酶NIK在卵巢癌化疗耐药和复发中的作用 和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中的通路和活动， 化疗，以产生新的范例，用于评估复发机制。鉴于最初的强烈反应 对于化疗，确定可以靶向治疗的早期治疗后事件是非常有意义的。 与细胞毒性药物组合以抑制维持TIC的途径。澄清新颖的机制， 这一未被充分研究的途径支持化疗耐药性将指导更好的治疗方法的设计， 缓解或可能达到治愈卵巢癌患者。

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.