CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

CD28 介导的多发性骨髓瘤细胞增殖和存活的调节

• 批准号: 8692668
• 负责人: KELVIN P. LEE
• 金额: $ 30.03万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-12 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692668
• 关键词: Antibodies; Antibody Formation; Autoimmune Diseases; Biology; Bone Marrow; Bone Marrow Neoplasms; CD28 gene; CD80 gene; Cell Communication; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular biology; Cessation of life; Clinical; Disease Progression; Disease Resistance; Drug resistance; Funding; Gap Junctions; Gene Expression; Goals; Graft Rejection; Hematologic Neoplasms; Immunosuppressive Agents; In Vitro; Lead; Life; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Molecular Profiling; Molecular Target; Multiple Myeloma; Neoplasms; Non-Hodgkin' s Lymphoma; Organ Transplantation; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma Cells; Play; Production; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Stromal Cells; Structure of germinal center of lymph node; Subgroup; T-Cell Activation; T-Lymphocyte; Treatment Failure; Work; chemotherapeutic agent; chemotherapy; clinically significant; in vivo; lenalidomide; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; prototype; public health relevance; receptor; therapeutic development; treatment strategy

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident plasma cells (PC) that comprises 20% of all hematologic malignancies, and despite new chemotherapeutic agents remains incurable. Myeloma cells are critically dependent on interactions with BM stromal niches for their survival, just like their normal counterparts the BM-resident long-lived PC (LLPC). It is also becoming evident that these interactions play a major role in MM resistance to chemotherapy, the primary cause of treatment failure in this cancer. Despite their central importance however, the specific molecular and cellular components involved in these interactions remain poorly characterized. Although it is primarily characterized as the prototype T cell costimulatory receptor involved in T cell activatio and survival, CD28 is also expressed on normal and malignant PC - and in myeloma its overexpression correlates significantly with poor prognosis, disease progression and shorter survival. Over the last funding cycle, we have shown in patient gene expression profiles that CD28 overexpression is associated with disease progression and poor prognosis patient subgroups, and that activation of CD28 on MM cells protects against chemotherapy-induced death. We have now found that blocking CD28 activation leads to MM cell death in vitro and in vivo, and sensitizes the myeloma to chemotherapy. In addition, we have made the novel observation that PC-intrinsic CD28 function also plays an essential role in sustaining the survival of normal BM LLPC. Thus it appears that CD28 regulates fundamental aspects of normal PC biology that are conserved in myeloma biology due to their essential role in survival. We have subsequently determined that the Vav pathway downstream of CD28 activation transduces CD28's pro-survival signal in BM LLPC. This pathway upregulates expression of the transcriptional regulator BLIMP-1, the "master regulator" of normal PC identity - but whose role in MM biology has been largely unexplored. We now hypothesize that the CD28Vav pathway regulates a central transcriptional nexus that is required to maintain PC identity, and that this identity is necessary for MM survival and resistance to chemotherapy. The overall goal of this proposal is to define the signaling pathways and molecular targets downstream of CD28 activation that support myeloma cell survival. This understanding is likely to lead to the identification of new therapeutic targets and development of novel treatment strategies for MM, especially chemotherapy resistant disease. The Specific Aims are: 1). Define the signaling pathways downstream of CD28 activation that intrinsically regulate myeloma cell survival, 2). Define the molecular targets of CD28Vav signaling that regulate myeloma cell survival, and 3). Determine the anti-myeloma efficacy of blocking CD28 activation in vivo.

描述(申请人提供)：多发性骨髓瘤(MM)是一种骨髓(BM)驻留浆细胞(PC)的肿瘤，占所有血液系统恶性肿瘤的20%，尽管有新的化疗药物，但仍无法治愈。骨髓瘤细胞严重依赖于与骨髓基质的相互作用才能生存，就像它们的正常对应细胞--BM驻留的长寿命PC(LLPC)一样。同样明显的是，这些相互作用在多发性骨髓瘤对化疗的抵抗中发挥了重要作用，化疗是导致这种癌症治疗失败的主要原因。然而，尽管它们具有核心重要性，但参与这些相互作用的特定分子和细胞成分仍然缺乏特征。尽管CD28主要被认为是参与T细胞活化和存活的T细胞共刺激受体原型，但CD28在正常和恶性PC中也有表达，在骨髓瘤中其过度表达与预后不良、疾病进展和生存期缩短密切相关。在上一个资金周期中，我们已经在患者基因表达谱中表明，CD28的过度表达与疾病进展和预后不良的患者亚组有关，并且激活MM细胞上的CD28可以预防化疗诱导的死亡。我们现在发现，阻断CD28的激活在体外和体内都会导致MM细胞死亡，并使骨髓瘤对化疗敏感。此外，我们还发现PC固有的CD28功能在维持正常BM LLPC的生存中也起着至关重要的作用。因此，CD28似乎调节正常PC生物学的基本方面，这些方面在骨髓瘤生物学中是保守的，因为它们在生存中扮演着重要的角色。我们随后确定CD28激活通路下游的Vav通路在BM LLPC中传递CD28‘S促生存信号。这一途径上调了转录调节因子BLIMP-1的表达，BLIMP-1是正常PC身份的“主调节因子”--但它在多发性骨髓瘤生物学中的作用在很大程度上尚不清楚。我们现在假设，CD28Vav通路调节维持PC身份所需的中央转录联系，并且这种身份对于MM生存和化疗耐药是必要的。该提案的总体目标是确定支持骨髓瘤细胞存活的CD28激活下游的信号通路和分子靶点。这一认识可能导致确定新的治疗靶点和开发新的治疗策略，特别是对化疗耐药的疾病。具体目标是：1)。定义CD28激活下游内在调节骨髓瘤细胞存活的信号通路，2)。确定调控骨髓瘤细胞存活的CD28Vav信号的分子靶点，3)。体内测定阻断CD28活化的抗骨髓瘤作用。