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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.

硼替佐米联合干扰素- α对黑色素瘤的免疫治疗