The thrombospondin1-TGF-beta axis in multiple myeloma

多发性骨髓瘤中的血小板反应蛋白 1-TGF-β 轴

基本信息

批准号：
9324935
负责人：
JOANNE E MURPHY-ULLRICH
金额：
$ 59.83万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324935
关键词：
Address Adverse effects Adverse event Back Binding Biological Availability Bone Diseases Bone Marrow Bone Marrow Cells Bone remodeling Bortezomib Cell Line Cell Surface Receptors Cell physiology Cells Chronic Clinical Trials Coculture Techniques Data Dendritic Cells Dexamethasone Disease Dose Drug Combinations Drug Kinetics Drug Targeting Extracellular Matrix Proteins Goals Growth Factor Half-Life Hematopoietic Heterogeneity Hour Human Immune Immune System Diseases Immune System and Related Disorders Immune system Immunocompetent In Vitro Inflammation Insulin-Like Growth Factor I Interleukin-6 Lead Leu-Ser-Lys-Leu peptide Ligands Malignant Neoplasms Mediating Metabolic Modeling Modification Morbidity - disease rate Multiple Myeloma Mus Oral Osteoblasts Osteoclasts Osteolytic Pathogenesis Pathway interactions Peptides Performance Pharmaceutical Preparations Phosphotransferases Plasma Plasma Cells Pre-Clinical Model Production Property Regulation Risk Role SCID Mice Stromal Cells T-Cell Development T-Lymphocyte Subsets TNFSF11 gene Therapeutic Toxic effect Transforming Growth Factor beta Transforming Growth Factors Tumor Burden Vascular Endothelial Growth Factors angiogenesis base bone carcinogenesis cell transformation cytokine drug development improved in vivo inhibitor/antagonist mouse model novel novel strategies osteoblast differentiation peptidomimetics preclinical development public health relevance receptor small molecule synergism

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable cancer of plasma cells that is dependent on the bone marrow microenvironment for progression. Transforming growth factor-beta (TGF-ß) is a multi-functional growth factor elaborated by MM cells and by cells in the bone marrow microenvironment. TGF-ß stimulates MM progression through promotion of catabolic bone remodeling, IL-6 secretion, and Th17 T cell development, leading to osteolytic bone disease and immune dysregulation. Despite the importance of TGF-ß in MM, there are no clinical trials of TGF-ß antagonists for the treatment of MM. Most TGF-ß antagonists broadly target the ligand, receptors, or downstream kinases, which can antagonize homeostatic levels of TGF-ß and increase the risk of adverse events. We have developed a novel approach to selectively targeting disease-related TGF-ß activity in the MM bone marrow microenvironment through targeting only the TGF-ß which is activated through binding to the extracellular matrix protein, thrombospondin1 (TSP1). TSP1 is a secreted and extracellular matrix protein, which controls TGF-ß activity in disease by binding and activating latent TGF-ß. TSP1 is increased in MM. Our studies show that TSP1 activates latent TGF-ß expressed by human and mouse MM cells in vitro and importantly, a tetrapeptide antagonist (LSKL) of TSP1-dependent TGF-ß activation reduces MM tumor burden, stromal IL-6, and osteolytic bone disease in mouse models of MM. LSKL nearly completely blocks active TGF-ß in bone marrow cells of treated MM mice, indicating that the TSP1-TGF-ß antagonist peptide is working through targeting TSP1-dependent TGF-ß activation in the bone marrow microenvironment. These data establish that TSP1 is an important regulator of TGF-ß activity in MM and suggest that blockade of this pathway represents a novel and selective therapeutic strategy to reduce MM progression and bone disease. Our goal is to develop an orally available, "druggable" form of the LSKL peptide for treatment of MM. We have identified a lead compound (SRI31277) based on LSKL which has dose-dependent in vivo activity in a mouse model of MM, improved pharmacokinetics and oral bioavailability, and which will be the basis for identification and optimization of lead drugs. This proposal will combine mechanistic studies (Aim 1) with drug development efforts (Aim 2) to achieve our goal of identifying an orally active lead compound for treatment of MM. In Aim 1, we will further determine the role of the TSP1-TGF-ß pathway in MM through use of immune competent and TSP1 null models, by comparison of SRI31277 to global TGF-ß inhibitors and by use in drug combinations, and by complementary in vitro studies to define the TSP1 receptor on MM cells for TGF-ß activation and the role of this pathway in MM cell cytokine production and osteoblast/osteoclast regulation. The key goal of Aim 2 is to identify an orally active derivative of SRI31277 and a back-up peptide mimetic/small molecule suitable for GLP-IND enabling studies using both peptide and peptidomimetic/small molecule approaches.

描述（由申请人提供）：多发性骨髓瘤 (MM) 是一种无法治愈的浆细胞癌症，其进展依赖于骨髓微环境。转化生长因子-β (TGF-ß) 是 MM 精心设计的一种多功能生长因子。 TGF-β 通过促进分解代谢骨重塑、IL-6 分泌和 Th17 T 细胞发育来刺激 MM 进展，从而导致 MM 进展。尽管 TGF-β 在 MM 中很重要，但尚无 TGF-β 拮抗剂用于治疗 MM 的临床试验，大多数 TGF-β 拮抗剂广泛靶向配体、受体或下游激酶。可以拮抗 TGF-β 的稳态水平并增加不良事件的风险。我们开发了一种新方法，通过靶向作用选择性地靶向 MM 骨髓微环境中与疾病相关的 TGF-β 活性。只有 TGF-β 通过与细胞外基质蛋白血小板反应蛋白 1 (TSP1) 结合而被激活，它是一种分泌性细胞外基质蛋白，负责控制。我们的研究表明，在 MM 中，TSP1 可以显着激活人类和小鼠 MM 细胞表达的潜在 TGF-β，从而增强疾病中的 TGF-β 活性，这是一种四肽拮抗剂 (LSKL)。在 LSKL 小鼠模型中，TSP1 依赖性 TGF-β 激活可减少 MM 肿瘤负荷、基质 IL-6 和溶骨性骨疾病，几乎完全阻断活性。接受治疗的 MM 小鼠骨髓细胞中存在 TGF-β，表明 TSP1-TGF-β 拮抗剂肽通过靶向骨髓微环境中 TSP1 依赖性 TGF-β 激活发挥作用。这些数据表明 TSP1 是 TGF-β 的重要调节因子。 -ß 活性，表明阻断该途径代表了一种新颖的选择性治疗策略，可减少 MM 进展和骨疾病。我们的目标是开发一种口服可用的“药物”形式。用于治疗多发性骨髓瘤的 LSKL 肽我们已经鉴定出一种基于 LSKL 的先导化合物 (SRI31277)，该化合物在多发性骨髓瘤小鼠模型中具有剂量依赖性体内活性，改善了药代动力学和口服生物利用度，这将成为鉴定和优化的基础。该提案将把机制研究（目标 1）与药物开发工作（目标 2）结合起来，以实现我们确定用于治疗 MM 的口服活性先导化合物的目标。 1，我们将通过使用免疫活性模型和 TSP1 无效模型、通过将 SRI31277 与全球 TGF-β 抑制剂进行比较、在药物组合中使用以及通过体外补充来进一步确定 TSP1-TGF-β 通路在 MM 中的作用研究确定 MM 细胞上用于 TGF-β 激活的 TSP1 受体，以及该途径在 MM 细胞细胞因子产生和成骨细胞/破骨细胞调节中的作用。目标 2 的关键目标。旨在鉴定 SRI31277 的口服活性衍生物和适合 GLP-IND 的备用肽模拟物/小分子，从而能够使用肽和肽模拟物/小分子方法进行研究。