The Role of CD86 in Multiple Myeloma

CD86 在多发性骨髓瘤中的作用

• 批准号: 9198507
• 负责人: Lawrence H. Boise
• 金额: $ 34.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-23 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198507
• 关键词: Antibodies; Antigen-Presenting Cells; Autoimmunity; Autophagocytosis; BCL2 gene; Bone Marrow; CD28 gene; CD80 gene; CD86 gene; Cell Death; Cell Line; Cell Survival; Cells; Cellular biology; Clinic; Clinical Trials; Cytoplasmic Tail; Data; Dependence; Development; Diagnosis; Disease; Disease Progression; Drug resistance; Etiology; Event; Extramedullary; FDA approved; Genetic; Genetic Polymorphism; Genomics; Growth; Human; IgE; Immune response; In Vitro; Induction of Apoptosis; Intravenous; Kidney Transplantation; Lesion; Ligands; Maintenance; Malignant Neoplasms; Maps; Mediating; Molecular; Molecular Target; Multiple Myeloma; Mus; Mutation; Passive Transfer of Immunity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Plasma Cells; Pre-Clinical Model; Proteasome Inhibition; Proteasome Inhibitor; Quality Control; Receptor Signaling; Rheumatoid Arthritis; Role; Sampling; Secretory Cell; Signal Transduction; Signaling Molecule; Site; Surface; Tail; Testing; Toxic effect; Translations; Vertebral column; Xenograft procedure; actionable mutation; base; cancer therapy; design; drug development; established cell line; inhibitor/antagonist; multicatalytic endopeptidase complex; novel; organ transplant rejection; outcome forecast; personalized medicine; public health relevance; receptor; transcriptome sequencing; translational impact; treatment response; tumor growth

 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.

 描述（由申请人提供）：多发性骨髓瘤是一种骨髓长寿命浆细胞的恶性肿瘤。在过去 15 年中，我们对与骨髓瘤相关的基因组变化的理解以及显着的进展都取得了显着进展。然而，患者生存率的提高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，两类药物的分子靶标。在骨髓瘤中最活跃的蛋白酶体抑制剂（蛋白酶体抑制剂和 IMiD）在这种疾病中不会突变，并且在正常浆细胞中高度表达，这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相一致，蛋白酶体抑制剂已成功获得成功。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，因为浆细胞对于生存能力不是必需的，因为它们的损失可以通过免疫的被动转移来克服。通过静脉注射免疫球蛋白（例如 IVIg），靶向正常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，但是蛋白酶体抑制剂对浆细胞不具有特异性，会导致显着的毒性，因此需要识别浆细胞。比蛋白酶体抑制剂更具选择性的靶点可能对多发性骨髓瘤的治疗产生重大影响，我们和其他人发现，CD28 及其配体 CD86 存在于正常和多发性骨髓瘤中。骨髓瘤浆细胞和这些分子的表达与疾病进展和不良预后相关，我们之前也证明 CD28 为骨髓瘤细胞提供生存信号，并且是维持正常浆细胞所必需的。即使在体外条件下已建立的细胞系中，CD86 也是骨髓瘤细胞存活所必需的，这表明与疾病进展相关的表达增加可能导致骨髓瘤微环境内的扩展以及骨髓外疾病的建立。此外，我们的数据表明 CD28 和 CD86 并不是作为简单的受体-配体对发挥作用，我们研究了 CD86 作为 CD28 的配体和信号分子对生存信号传导的贡献，并提出了 3 个具体目标来确定其贡献和作用。确定 CD86 在骨髓瘤细胞存活和肿瘤生长中的作用和机制具有重要意义，因为它将定义骨髓瘤的新存活。 FDA 批准的针对该分子的药物已经存在，因此可以将这些发现快速转化为临床试验。