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

化疗后的替代性 NF-kB 激活可阐明卵巢癌复发的新机制

• 批准号: 10367670
• 负责人: Carrie Danielle House
• 金额: $ 36.8万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367670
• 关键词: Address; Aftercare; Cancer Biology; Cancer Patient; Cancer Relapse; Carboplatin; Cell Survival; Cell physiology; Cells; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Development; Diagnosis; Disease; Disease remission; Drug resistance; Ensure; Environment; Event; Experimental Designs; Family; Family member; Genes; Goals; Human; Imaging technology; Immunocompetent; Investigation; Knock-out; Knowledge; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Morbidity - disease rate; NF-kappa B; Natural regeneration; Neoadjuvant Therapy; Paclitaxel; Pathway interactions; Patients; Phosphotransferases; Play; Population; Property; Publishing; Recurrence; Recurrent disease; Relapse; Reporter; Reproducibility; Research; Resected; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; Stimulus; Stromal Cells; Tissues; United States; Work; Xenograft procedure; aldehyde dehydrogenases; base; cancer cell; cancer drug resistance; cancer recurrence; cancer survival; cell type; chemotherapy; cytokine; design; inhibitor; interest; macrophage; mortality; mouse model; neoplastic cell; notch protein; novel; ovarian neoplasm; relB protein; response; self-renewal; standard of care; stemness; targeted treatment; therapeutically effective; transcription factor; transcriptome sequencing; tumor; tumor initiation; tumor microenvironment; tumor progression

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.

科学摘要 卵巢癌是美国最致命的妇科恶性肿瘤，尽管患者最初是 对细胞毒性化学疗法的反应，大多数在24个月内通过化学抗性疾病复发。有 我们对支持疾病复发的机制的知识的一些关键差距，但研究 最近十年支持肿瘤发射细胞（TICS），一种耐药性肿瘤细胞的亚群，是 负责促进靶向这些难以捉摸细胞的复发和组合疗法可能会导致更长的 缓解甚至治愈。尽管许多基因和信号通路已与维持 抽搐，我们对这些细胞用于生存的细胞毒性的过程的理解有几个关键差距 化学疗法并成功重新建立肿瘤。例如，目前尚不清楚途径是否活跃在抽动中 是本构或可以由肿瘤微环境（TME）中的因素诱导的。我们以前的研究 揭示了替代NF-KB信号传导的重要作用 化学疗法。 NF-KB是一个转录因子家族，对TME中的信号响应以促进 癌细胞的增殖，化学抗性和存活。新兴的证据表明TME改变了 遵循细胞毒性化疗会导致释放信号传导因子，这些因素可以激活NF-KB癌症 细胞。我们最近的数据表明，Tweak是一种从巨噬细胞和基质中分泌的多功能细胞因子 化疗后，细胞在TME中升高，可以诱导替代NF-KB的激活 在多种卵巢癌细胞中干性基因的表达。来自接受患者的临床数据 新辅助化疗表明，编码调整和替代NF-KB家庭成员的基因是 相对于治疗水平，细胞毒性化疗后切除的肿瘤的肿瘤显着升高。这些 数据导致我们提出了核心假设，即化学疗法提供了有利于抽动开发的环境 通过激活替代NF-KB。为了研究这一假设，我们将1）确定是否 化学疗法诱导的卵巢TME调整信号传导激活卵巢癌细胞中的替代NF-KB 2）建立替代NF-KB激酶NIK在卵巢癌化学抗性和复发中的功能 3）研究NF-KB介导的Notch激活在支持卵巢抽搐中的作用 化学疗法。与大多数发表的研究不同，我们关注这些细胞的途径和活动 化学疗法，以产生用于评估复发机制的新范例。考虑到强烈的初始响应 对于化学疗法，确定可以针对的早期治疗事件引起了极大的兴趣 结合细胞毒性药物抑制维持抽动的途径。澄清新型机制 这种不足的途径支持化学耐药性将指导更好的疗法的设计以延长 缓解或可能为卵巢癌患者固化。