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

核因子-kappaB包括一系列信号激活的转录因子，它们通常调节对损伤和感染的反应，但在许多癌症中被异常激活。越来越多的证据表明，在肿瘤的发生、发展和转移过程中，核因子-kappaB参与了细胞存活、炎症、血管生成、扩散和治疗耐药。抑制核因子-kappaB的非特异性天然和合成试剂已证明在预防或治疗中具有活性和安全性。核因子-kappaB激活酶和蛋白酶体正在研究中，用于肿瘤的靶向预防和治疗。 我们完成了蛋白酶体抑制剂Bortezomib再次照射治疗复发HNSCC患者的I期临床试验(01-C-0104)。相关研究表明，治疗可显著促进细胞凋亡并抑制核相关蛋白，但其他核转录因子-kappaB亚单位ERK1/2和STAT3受到或不同程度影响，肿瘤进展通常在3个月内观察到。总体而言，在初始剂量水平治疗的17名患者中，有5名患者出现部分反应。6名患者的累积剂量已在0.9 mg/m2剂量水平上完成，将其定义为最大耐受剂量，并制定了新的时间表，提供两周的停药时间。在HNSCC细胞系中的研究表明，Bortezomib部分抑制了NF-kappaB1/relA的基础激活，但不能抑制NF-kappaB2/RELb或MAPK-AP-1的激活。我们的结论是，尽管Bortezomib抑制了规范途径亚单位的激活，但它并不阻止非规范的NF-kappaB或MAPK-AP-1或STAT3生存信号通路的核激活，这可能是导致HNSCC异质性反应的原因之一。Bortezomib与MAPK JNK抑制剂在体外联合应用显示活性增强，提示Bortezomib与其他信号通路抑制剂联合应用的可能性。 一项与NCI和匹兹堡大学NCI孢子研究人员合作的试验启动了(NIH方案08-C-0071)，该试验联合Bortezomib抑制核因子-kB，与表皮生长因子受体抑制抗体西妥昔单抗联合抑制MAPK和STAT3。累积7例，剂量递增3例，剂量分别为0.7、1.0和1.3 mg/m2，无剂量限制毒性。初步评估表明，3/6的受试者有适度的完全应答率，无病生存期比预期的要短，促使应计项目关闭。数据分析正在进行中。 确定上游激酶CK2、IKKalpha和β以及PKA作为核因子-kB relA反式激活的关键信号激活因子的研究已经完成，已发表或正在准备手稿。

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. We completed our 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. Overall, 5/17 patients treated at the initial dose level demonstrated partial responses. Accrual of 6 patients has been completed at the 0.9mg/m2 dose level, defining it as the maximally tolerated dose with a new schedule that provides a two week break from drug treatment. 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. Combination of bortezomib with MAPK JNK inhibitor in vitro showed increased activity, indicating potential of combining bortezomib with other signal pathway inhibitors. An collaborative trial 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 initiated (NIH protocol 08-C-0071). 7 patients were accrued, with dose escalation of 3 patients each at 0.7,1.0, and one at 1.3mg/m2 without dose limiting toxicity. Preliminary assessment indicated a modest complete responses rate in 3/6 subjects, with shorter than expected disease free survival, prompting closure of accrual. Data analysis is pending. Studies defining the role of upstream kinases CK2, IKKalpha and beta and PKA as key signal activators of NF-kB RELA transactivation were completed and manuscripts were published or in preparation.