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

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。 我们完成了蛋白酶体抑制剂硼替佐米与再照射治疗复发性HNSCC患者的I期临床试验（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，并且肿瘤进展通常在3个月内观察到。总体而言，5/17例接受初始剂量水平治疗的患者表现出部分缓解。在0.9 mg/m2剂量水平下完成了6例患者的累积，将其定义为最大耐受剂量，新的时间表提供了两周的药物治疗中断。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。硼替佐米与MAPK JNK抑制剂的体外组合显示出增加的活性，表明硼替佐米与其他信号通路抑制剂组合的潜力。 开始了NCI和匹兹堡大学NCI SPORE研究人员的合作试验，该试验将硼替佐米与表皮生长因子受体抑制剂抗体西妥昔单抗联合抑制NF-κ B，抑制MAPK和STAT 3（NIH方案08-C-0071）。入组7例患者，3例患者剂量递增至0.7、1.0，1例患者剂量递增至1.3mg/m2，无剂量限制性毒性。初步评估表明，3/7例受试者的完全缓解率适中，无病生存期短于预期，提示结束累积。ECOG 1304是一项硼替佐米单药治疗或与伊立替康联合治疗的II期研究，正在进行数据分析。 确定上游激酶TAK 1、CK 2、IKK α和β以及PKA作为NF-kB RELA反式激活的关键信号激活剂的作用的研究已经完成，手稿已经发表或正在编写中。

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 3/7 subjects, with shorter than expected disease free survival, prompting closure of accrual. ECOG 1304, a phase II study of bortezomib alone or in combination with irinotecan is under data analysis. Studies defining the role of upstream kinases TAK1, CK2, IKKalpha and beta and PKA as key signal activators of NF-kB RELA transactivation were completed and manuscripts were published or in preparation.