The Role of CD86 in Multiple Myeloma

 描述(申请人提供)：多发性骨髓瘤是一种长期存活的骨髓浆细胞的恶性肿瘤。在过去的15年里，我们看到在我们对与骨髓瘤相关的基因组变化的理解以及被诊断为骨髓瘤的患者的存活率方面都取得了显着的进步。然而，患者存活率的改善不能归因于专门针对与骨髓瘤相关的基因组变化的药物的开发。相反，在骨髓瘤中最有效的两类药物(蛋白酶体抑制剂和IMiDS)的分子靶点在这种疾病中没有突变，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地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反应和自身免疫。由于浆细胞不是生存所必需的，它们的丧失可以通过静脉注射免疫球蛋白(如IVIg)进行被动免疫转移来克服，靶向正常的浆细胞生物学为治疗多发性骨髓瘤等浆细胞恶性肿瘤提供了新的机会。然而，蛋白酶体抑制剂并不是浆细胞所特有的，具有明显的毒性，因此寻找比蛋白酶体抑制剂更具选择性的浆细胞靶点对多发性骨髓瘤的治疗有重要影响。我们和其他人已经发现，CD28及其配体CD86存在于正常和骨髓瘤浆细胞上，这些分子的表达与疾病进展和预后不良有关。我们之前也证明了CD28为骨髓瘤细胞提供生存信号，是维持正常浆细胞所必需的。我们现在有证据表明，即使在已建立的细胞系的体外条件下，CD28和CD86也是骨髓瘤细胞生存所必需的，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张和骨髓外疾病的建立。此外，我们的数据表明，CD28和CD86并不是一对简单的受体-配体对。我们假设CD86既作为CD28的配体，又作为信号分子参与生存信号的传递，并提出了3个特异性靶点以确定CD86信号在骨髓瘤细胞生存和肿瘤生长中的作用和机制。确定CD86在骨髓瘤生存中的作用和机制具有重要意义，因为它将定义骨髓瘤的新生存。重要的是，由于FDA批准的针对该分子的药物已经存在，因此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.