Therapy of Melanoma with Bortezomib and Interferon-alpha

硼替佐米和干扰素-α 治疗黑色素瘤

• 批准号: 7230025
• 负责人: WILLIAM E. CARSON
• 金额: $ 25.77万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230025
• 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; New Agents; 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; Velcade; Week; activating transcription factor; cancer cell; cohort; cytokine; day; inhibitor/antagonist; melanoma; multicatalytic endopeptidase complex; neoplastic cell; novel; research study; response; tumor

DESCRIPTION (provided by applicant): 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%. New agents 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.

描述（由申请方提供）：硼替佐米和干扰素-α对黑色素瘤的免疫治疗对细胞毒性治疗的抗性是恶性黑色素瘤的标志。目前治疗转移性疾病的标准是单药达卡巴嗪，其总体缓解率仅为15%。因此，必须探索具有新作用机制的新药剂。硼替佐米（Velcade，以前称为PS-341）是一种新型抗肿瘤化合物，是26 S蛋白酶体的特异性和选择性抑制剂，26 S蛋白酶体是降解细胞蛋白的泛素-蛋白酶体途径的中心组分。用硼替佐米治疗恶性细胞通过多种机制导致生长停滞和凋亡性细胞死亡，包括改变细胞周期蛋白的周转和阻断促存活信号。我们注意到，硼替佐米诱导的黑色素瘤细胞凋亡在干扰素-α（IFN-α）的存在下协同增强，干扰素-α是一种自身具有独特促凋亡作用的药物。进一步的分析表明，细胞凋亡与bcl-2水平的降低和caspase蛋白的激活有关。使用恶性黑色素瘤的鼠模型，我们还证明，与单独使用任一种药剂相比，用硼替佐米和IFN-α的组合治疗后，荷瘤小鼠的存活率显著提高（p = 0.02）。我们也有初步的数据表明，用硼替佐米预处理外周血单核细胞导致响应IFN-α的Jak-STAT信号转导途径的延长激活。这些是第一次检查蛋白酶体抑制剂与细胞因子结合时的抗肿瘤作用的实验。我们现在建议在转移性恶性黑色素瘤患者中进行一项硼替佐米和IFN-a2 b的促凝剂启动的临床试验。我们假设IFN-α将增强硼替佐米诱导的晚期恶性黑色素瘤患者肿瘤细胞凋亡。在治疗前后对肿瘤进行活检，以便进行相关的免疫组化染色。还将使用新的流式细胞术测定法对患者免疫细胞中IFN-α诱导的信号传导途径进行仔细分析。这些研究将有助于确定由硼替佐米和IFN-α 2b的组合调节的特定凋亡和免疫刺激途径。