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.

科学文摘