NF-kappaB in pathogenesis and therapy of head and neck cancer

NF-κB 在头颈癌发病机制和治疗中的作用

• 批准号: 8745647
• 负责人: CARTER VAN WAES
• 金额: $ 87.09万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745647
• 关键词: Adverse effects; Affect; Alcohols; Antibodies; Apoptosis; Biological Markers; Bortezomib; Carcinoma; Cell Line; Cell Survival; Cessation of life; Cetuximab; Clinical; Correlative Study; Cyclic AMP-Dependent Protein Kinases; Cytotoxic Chemotherapy; Cytotoxic agent; Defect; Deglutition; Development; Diagnosis; Disease-Free Survival; Early Diagnosis; Early treatment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Exposure to; Family; Gene Expression; Gene Targeting; Genetic; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heat-Shock Proteins 90; Hereditary Disease; Human Papillomavirus; In complete remission; Infection; Inflammation; Investigation; Laboratories; Larynx; MAP Kinase Gene; MAP3K7 gene; MAPK3 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mediator of activation protein; Molecular Target; Mutation; NF-kappa B; Neoplasm Metastasis; Normal tissue morphology; Nuclear; Oncogenes; Oral cavity; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharyngeal structure; Phase I Clinical Trials; Phosphotransferases; Play; Prevention; Prevention approach; Prevention therapy; Progressive Disease; Proteasome Inhibition; Proteasome Inhibitor; Protein Kinase; Protocols documentation; Quality of life; RELA gene; Radiation; Radiosurgery; Recurrence; Recurrent disease; Research Personnel; Resistance; Role; STAT3 gene; Safety; Schedule; Serum; Signal Pathway; Signal Transduction; Speech; TNF gene; The Cancer Genome Atlas; Therapeutic; Tobacco; Toxic effect; Transactivation; Transcription Factor AP-1; United States National Institutes of Health; Universities; Voice; activating transcription factor; angiogenesis; chemotherapy; collaborative trial; cytokine; cytotoxic; cytotoxicity; human study; improved; inhibitor/antagonist; lyt-10 protein; malignant phenotype; multicatalytic endopeptidase complex; novel strategies; p65; preclinical study; response; response to injury; therapy resistant; tumor; tumor progression

NF-kappaB includes a family of signal-activated transcription factors that normally regulate responses to injury and infection but which are aberrantly activated in many carcinomas. Cumulative evidence implicates NF-kappaB in cell survival, inflammation, angiogenesis, spread and therapeutic resistance during tumor development, progression and metastasis of carcinomas. Non-specific natural and synthetic agents that inhibit NF-kappaB have demonstrated activity and safety in prevention or therapy. NF-kappaB-activating kinases and the proteasome are under investigation for targeted prevention and therapy of carcinoma. In a phase I clinical trial of proteasome inhibitor bortezomib with reirradiation for patients with recurrent HNSCC (01-C-0104), correlative studies revealed that treatment significantly enhanced apoptosis with inhibition of nuclear RELA, but other NF-kappaB subunits, ERK1/2, and STAT3 were variably or not affected, and tumor progression was often observed within 3 months (Allen, Clinical Cancer Res, 2008). Studies in HNSCC cell lines, indicated that bortezomib partially inhibits basal activation of NF-kappaB1/RELA, but not NF-kappaB2/RELB, or MAPK-AP-1 activation. We conclude that although bortezomib inhibits activation of subunits of the canonical pathway, it does not block nuclear activation of the noncanonical NF-kappaB or MAPK-AP-1 or STAT3 prosurvival signal pathways, which may contribute to the heterogeneous responses observed in HNSCC. A collaborative trial (NIH protocol 08-C-0071) with NCI and University of Pittsburgh NCI SPORE investigators combining bortezomib to inhibit NF-kB, with Epidermal Growth Factor Receptor inhibitor antibody cetuximab to inhibit MAPK and STAT3, was completed (Argiris et al., Clin Cancer Res, 2011). A modest complete response rate in 3/7 subjects, with shorter than expected disease free survival, prompted closure of accrual. Correlative stuides revealed that Bortezomib antagonized degradation of Epidermal Growth Factor Receptor and ERK signaling. In the past year we completed studies that help define a role for both IKKalpha and beta in canonical and alternative NF-kB subunit activation, and EGFR-AP-1 signaling, that explain why inhibition of canonical signaling and RELA by bortezomib was insufficient, and point to potential of heat shock protein 90 inhibitors that block both pathways for therapy (Nottingham, Oncogene, 2013). As part of The Cancer Genome Atlas group characterizing head and neck cancer, we have identified components of PI3K and TNF pathway as candidate genetic drivers for aberrant NF-kB activation and defects in death signaling.

NF-κ B包括一个信号激活的转录因子家族，通常调节对损伤和感染的反应，但在许多癌中被异常激活。累积的证据表明NF-κ B在肿瘤发展、进展和癌转移过程中参与细胞存活、炎症、血管生成、扩散和治疗抗性。抑制NF-κ B的非特异性天然和合成试剂已证明在预防或治疗中的活性和安全性。NF-κ B活化激酶和蛋白酶体正在研究用于肿瘤的靶向预防和治疗。 在蛋白酶体抑制剂硼替佐米与复发性HNSCC患者再照射的I期临床试验中（01-C-0104），相关研究显示，治疗显著增强细胞凋亡，抑制核RELA，但其他NF-κ B亚基、ERK 1/2和STAT 3不受影响或不受影响，并且通常在3个月内观察到肿瘤进展（艾伦，Clinical Cancer Res，2008）。在HNSCC细胞系中的研究表明，硼替佐米部分抑制NF-κ B1/RELA的基础活化，但不抑制NF-κ B2/RELB或MAPK-AP-1活化。我们的结论是，虽然硼替佐米抑制经典途径的亚基的激活，但它并不阻断非经典NF-κ B或MAPK-AP-1或STAT 3促生存信号通路的核激活，这可能有助于在HNSCC中观察到的异质性反应。 完成了NCI和匹兹堡大学NCI SPORE研究者联合硼替佐米抑制NF-κ B与表皮生长因子受体抑制剂抗体西妥昔单抗抑制MAPK和STAT 3的合作试验（NIH方案08-C-0071）（Argiris等人，Clin Cancer Res，2011）。3/7例受试者的中度完全缓解率，无病生存期短于预期，提示结束招募。相关研究表明硼替佐米可拮抗表皮生长因子受体的降解和ERK信号通路。 在过去的一年中，我们完成了有助于确定IKK α和β在经典和替代NF-kB亚基激活以及EGFR-AP-1信号传导中的作用的研究，这些研究解释了硼替佐米对经典信号传导和RELA的抑制不足的原因，并指出了热休克蛋白90抑制剂阻断两种治疗途径的潜力（诺丁汉，Oncogene，2013）。 作为表征头颈癌的癌症基因组图谱组的一部分，我们已经鉴定了PI 3 K和TNF途径的组分作为异常NF-kB活化和死亡信号传导缺陷的候选遗传驱动因子。