Therapy of Melanoma with Bortezomib and Interferon-alpha

硼替佐米和干扰素-α 治疗黑色素瘤

基本信息

批准号：
7418854
负责人：
WILLIAM E. CARSON
金额：
$ 0.45万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418854
关键词：
26S proteasome Apoptosis Apoptotic Biological Assay Biopsy Blood Bortezomib Caring Caspase Cell Cycle Proteins Cell Death Cell Line Cells Charge Clinical Trials Combined Modality Therapy Comprehensive Cancer Center Correlative Study Cytotoxic Chemotherapy Dacarbazine Data Degradation Pathway Disease Disease regression Dose Dose-Limiting Funding Growth Heterogeneity Hour Human Immune Immunotherapy In Vitro Injection of therapeutic agent Interferon-alpha Journals Laboratory Study Length Measurement Mediating Melanoma Cell Metastatic Melanoma Modeling Monitor Mus Ohio PS341 cpd Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Pharmacologic Substance Pre-study Proteasome Inhibition Proteasome Inhibitor Proteins Rate Research Personnel Resistance Rest Safety Signal Pathway Signal Transduction Signal Transduction Pathway Staining method Stains Standards of Weights and Measures Stimulus Therapeutic Toxic effect Treatment Efficacy Treatment Protocols Ubiquitin Universities Week activating transcription factor cancer cell cohort cytokine day inhibitor/antagonist melanoma multicatalytic endopeptidase complex neoplastic cell novel research study response tumor

项目摘要

Immunotherapy of Melanoma With Bortezomib and Interferon-Alpha Resistance to cytotoxic therapy is a hallmark of malignant melanoma. The current standard of care for metastatic disease is single-agent dacarbazine which has an overall response rate of just 15%. Newagents with new mechanisms of action must therefore be explored. Bortezomib (Velcade¿, formerly PS-341) is a novel anti-tumor compound that is a specific and selective inhibitor of the 26S proteasome, a central component of the ubiquitin-proteasome pathway for the degradation of cellular proteins. Treatment of malignant cells with bortezomib leads to growth arrest and apoptotic cell death via multiple mechanisms including altered turnover of cell cycle proteins and blockade of pro-survival signals. We noted that bortezomib-induced apoptosis of melanoma cells was synergistically enhanced in the presence of interferon- alpha (IFN-a), an agent that has unique pro-apoptotic effects of its own. Further analysis revealed that apoptosis was associated with reduced levels of bcl-2 and activation of caspase proteins. Using a murine model of malignant melanoma, we also demonstrated that the survival of tumor-bearing mice was significantly enhanced following treatment with the combination of bortezomib and IFN-a as compared to either agent alone (p = 0.02). We also have preliminary data to suggest that pre-treatment of peripheral blood mononuclear cells with bortezomib leads to prolonged activation of the Jak-STAT signal transduction pathway in response to IFN-a. These are the first experiments to examine the anti-tumor effects of a proteasome inhibitor when combined with a cytokine. We now propose to conduct an investigator-initiated clinical trial of bortezomib and IFN-a2b in patients with metastatic malignant melanoma. We hypothesize that IFN-a will enhance bortezomib-induced tumor cell apoptosis in patients with advanced malignant melanoma. Tumors will be biopsied before and after therapy in order that correlative immunohistochemical stains can be performed. A careful analysis of IFN-a-induced signaling pathways in patient immune cells will also be conducted using a novel flow cytometric assay. These studies will help to define the specific apoptotic and immunostimulatory pathways that are being modulated by the combination of bortezomib and IFN-a2b.

硼替佐米和干扰素-α对黑色素瘤的免疫治疗对细胞毒治疗的抵抗是恶性黑色素瘤的一个标志。目前的治疗标准。转移性疾病采用单药达卡巴嗪，其总体缓解率仅为 15%。因此，必须探索具有新作用机制的硼替佐米（Velcade¿，以前的 PS-341）。新型抗肿瘤化合物，是 26S 蛋白酶体（26S 蛋白酶体的中枢）的特异性和选择性抑制剂。用于降解细胞蛋白质的泛素蛋白酶体途径的组成部分。硼替佐米通过多种机制导致恶性细胞生长停滞和细胞凋亡我们注意到，包括细胞周期蛋白周转的改变和促生存信号的阻断。硼替佐米诱导的黑色素瘤细胞凋亡在干扰素存在下协同增强 α（IFN-a），一种本身具有独特的促凋亡作用的药物。细胞凋亡与 bcl-2 水平降低和 caspase 蛋白激活相关。在恶性黑色素瘤模型中，我们还证明荷瘤小鼠的存活率与 bortezomib 和 IFN-a 联合治疗后相比，显着增强单独使用任一药物（p = 0.02）我们也有初步数据表明外周预处理。硼替佐米作用于血液单核细胞会导致 Jak-STAT 信号转导的激活时间延长 IFN-a 的反应途径这是第一个检验 IFN-a 抗肿瘤作用的实验。我们现在建议进行一项由研究者发起的研究。硼替佐米和 IFN-a2b 在转移性恶性黑色素瘤患者中的临床试验。 IFN-a 会增强硼替佐米诱导的晚期恶性肿瘤患者的肿瘤细胞凋亡治疗前和治疗后将对肿瘤进行活检，以便进行相关的免疫组织化学检查。可以对患者免疫细胞中 IFN-α 诱导的信号通路进行仔细分析。也可以使用新型流式细胞术进行测定，这些研究将有助于确定具体的情况。通过硼替佐米和硼替佐米的组合来调节细胞凋亡和免疫刺激途径干扰素-a2b。