Therapy of Melanoma with Bortezomib and Interferon-alpha

硼替佐米联合干扰素-α免疫治疗黑色素瘤 对细胞毒治疗的抵抗是恶性黑色素瘤的一个标志。目前的护理标准是 转移性疾病是单药达卡巴肼，其总体应答率仅为15%。新代理商 因此，必须探索新的行动机制。波特佐米(VELCADE，前身为PS-341)是一种 新型抗肿瘤化合物，是26S蛋白酶体的特异性和选择性抑制剂，26S蛋白酶体是一种中央 泛素-蛋白酶体途径的组成部分，用于降解细胞蛋白质。治疗 硼替佐米通过多种机制诱导恶性细胞生长停滞和细胞凋亡 包括改变细胞周期蛋白的周转和阻断有利于生存的信号。我们注意到 干扰素协同增强硼替佐米诱导的黑色素瘤细胞凋亡 α(干扰素-a)，一种本身具有独特的促凋亡作用的试剂。进一步的分析显示， 细胞凋亡与bcl-2水平降低和caspase蛋白活化有关。用一只老鼠 恶性黑色素瘤模型的建立，我们还证明了荷瘤小鼠的存活时间 博替佐米和干扰素-a联合治疗后显著增强 两种药物单独作用(p=0.02)。我们也有初步数据表明，外周血肿的预治疗 加入硼替佐米的单个核细胞可延长JAK-STAT信号转导通路的激活时间 干扰素-a的反应途径。这是第一次检测一种抗肿瘤药物的实验。 蛋白酶体抑制剂，当与细胞因子结合时。我们现在建议进行一项由调查人员发起的 硼替佐米联合干扰素-a2b治疗转移性恶性黑色素瘤的临床研究。我们假设 干扰素-α增强硼替佐米诱导晚期恶性肿瘤患者肿瘤细胞的凋亡 黑色素瘤。治疗前后将对肿瘤进行活检，以便相关的免疫组织化学 可以进行染色。仔细分析干扰素-a在患者免疫细胞中诱导的信号通路将 也可以使用一种新的流式细胞仪进行检测。这些研究将有助于确定具体的 硼替佐米和联合用药调控的细胞凋亡和免疫刺激通路 干扰素-a2b。

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.