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

基本信息

项目摘要

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.
NF-kappaB包括一系列信号激活的转录因子,这些转录因子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,NF-kappaB参与肿瘤发生、进展和转移过程中的细胞存活、炎症、血管生成、扩散和治疗抵抗。抑制NF-kappaB的非特异性天然和合成药物已证明在预防或治疗方面具有活性和安全性。nf - kappab活化激酶和蛋白酶体正在研究用于癌症的靶向预防和治疗。

项目成果

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CARTER VAN WAES其他文献

CARTER VAN WAES的其他文献

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{{ truncateString('CARTER VAN WAES', 18)}}的其他基金

GENE AND IMMUNOTHERAPY OF NEOPLASMS AFFECTING HUMAN COMMUNICATION
影响人类交流的肿瘤基因和免疫治疗
  • 批准号:
    6289632
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
Molecular Therapy Of Neoplasms Affecting Human Communica
影响人类通讯的肿瘤的分子治疗
  • 批准号:
    6966643
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
NIDCD Core for Clinical Research and Care
NIDCD 临床研究和护理核心
  • 批准号:
    10470081
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
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:
    9147422
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
Gene And Immunotherapy Of Neoplasms Affecting Human Comm
影响人类通讯的肿瘤的基因和免疫治疗
  • 批准号:
    6690276
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
Molecular Therapy Of Neoplasms Affecting Human Communication
影响人类交流的肿瘤的分子治疗
  • 批准号:
    7593327
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
NIDCD Core for Clinical Research and Care
NIDCD 临床研究和护理核心
  • 批准号:
    10249876
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
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:
    10688908
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:
Genomics and Proteomics of Head and Neck Cancer
头颈癌的基因组学和蛋白质组学
  • 批准号:
    7967002
  • 财政年份:
  • 资助金额:
    $ 69.92万
  • 项目类别:

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