The Role of CD86 in Multiple Myeloma

 描述（由申请方提供）：多发性骨髓瘤是骨髓中长寿命浆细胞的恶性肿瘤。在过去的15年中，我们已经看到了我们对与骨髓瘤相关的基因组变化的理解以及诊断患有这种疾病的患者的生存率的显着改善的显着进步。然而，患者生存率的改善不能归因于特异性靶向与骨髓瘤相关的基因组变化的药物的开发。相反，在骨髓瘤中最活跃的两类药物（蛋白酶体抑制剂和IMiD）的分子靶标在这种疾病中没有突变，并且在正常浆细胞中高度表达。与高活性骨髓瘤药物部分通过靶向正常浆细胞生物学发挥作用的可能性一致，蛋白酶体抑制剂已成功用于临床前模型以及临床，用于治疗浆细胞介导的器官移植排斥和自身免疫。由于浆细胞对于生存力不是必需的，因为它们的损失可以通过静脉内添加免疫球蛋白（例如IVIg）被动转移免疫力来克服，因此靶向正常浆细胞生物学为治疗浆细胞恶性肿瘤（如多发性骨髓瘤）提供了新的机会。然而，蛋白酶体抑制剂对浆细胞不是特异性的，并且导致显著的毒性，因此鉴定比蛋白酶体抑制剂更具选择性的浆细胞靶标可能对多发性骨髓瘤的治疗具有显著影响。我们和其他人已经发现，CD 28及其配体CD 86存在于正常和骨髓瘤浆细胞上，并且这些分子的表达与疾病进展和不良预后相关。我们以前也证明了CD 28为骨髓瘤细胞提供了生存信号，并且是维持正常浆细胞所必需的。我们现在有证据表明，即使在体外条件下，在已建立的细胞系中，骨髓瘤细胞存活也需要CD 28和CD 86，这表明与疾病进展相关的表达增加可能允许骨髓微环境内的扩增和骨髓微环境外髓外疾病的建立。此外，我们的数据表明，CD 28和CD 86不是作为一个简单的受体-配体对发挥作用。我们假设CD 86作为CD 28的配体和信号分子参与了生存信号传导，并提出了3个具体目标来确定CD 86信号传导对骨髓瘤细胞生存和肿瘤生长的贡献和机制。确定CD 86在骨髓瘤生存中的作用和机制是重要的，因为它将定义骨髓瘤的新生存。重要的是，由于已经存在FDA批准的靶向该分子的药剂，因此将这些发现快速转化为临床试验是可能的。

 DESCRIPTION (provided by applicant): Multiple Myeloma is a malignancy of the long-lived plasma cells of the bone marrow. During the last 15 years we have seen remarkable advances in both our understanding of the genomic changes associated with myeloma as well as a significant improvement in the survival of patients who are diagnosed with this disease. However the improvement in patient survival cannot be attributed to the development of drugs that specifically target the genomic changes associated with myeloma. To the contrary the molecular targets of the two classes of drugs that are most active in myeloma (proteasome inhibitors and IMiDs) are not mutated in this disease and are highly expressed in normal plasma cells. Consistent with the possibility that highly active myeloma agents function in part by targeting normal plasma cell biology, proteasome inhibitors have been successfully used in preclinical models, as well as in the clinic, for the treatment of plasma cell-mediated organ transplant rejection and autoimmunity. Since plasma cells are not essential for viability as their loss can be overcome by passive transfer of immunity through the intravenous addition of immunoglobulin (e.g. IVIg), targeting normal plasma cell biology provides a novel opportunity for the treatment of plasma cell malignancies like multiple myeloma. However proteasome inhibitors are not specific to plasma cells and result in significant toxicity, therefore identifyig plasma cell targets that are more selective than proteasome inhibitors could have a significant impact on the treatment of multiple myeloma. We and others have found that, CD28 and it ligand CD86 are found on normal and myeloma plasma cells and the expression of these molecules is associated with disease progression and poor prognosis. We have also previously demonstrated that CD28 provides a survival signal to myeloma cells and is required for the maintenance of normal plasma cells. We now have evidence that CD28 and CD86 are required for myeloma cell survival, even under in vitro conditions in established cell lines, suggesting tha the increased expression associated with disease progression may allow for the expansion within, and the establishment of extramedullary disease outside the bone marrow micro- environment. Moreover our data suggest that CD28 and CD86 are not functioning as a simple receptor-ligand pair. We hypothesize that CD86 contributes to the survival signaling as both a ligand for CD28 as well as a signaling molecule and propose 3 Specific Aims to determine the contribution and mechanism of CD86 signaling to myeloma cell survival and tumor growth. Determining the role and mechanism of CD86 in myeloma survival is significant, as it will define a novel survival in myeloma. Importantly, since an FDA- approved agent already exists that targets this molecule, thus rapid translation of these findings to a clinical trial is possible.