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：
8761464
负责人：
JOANNE E MURPHY-ULLRICH
金额：
$ 60.82万
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/8761464
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 Development Dexamethasone Disease Dose Drug Combinations Drug Kinetics Drug Targeting Extracellular Matrix Proteins Goals Growth Factor Growth Factor Inhibition Half-Life Hematopoietic Heterogeneity Hour Human Immune Immune System Diseases 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 Work angiogenesis base bone cell carcinogenesis cytokine drug development improved in vivo inhibitor/antagonist mimetics mouse model novel novel strategies osteoblast differentiation peptidomimetics pre-clinical public health relevance receptor small molecule

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-¿) is a multi-functional growth factor elaborated by MM cells and by cells in the bone marrow microenvironment. TGF-¿ 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-¿ in MM, there are no clinical trials of TGF-¿ antagonists for the treatment of MM. Most TGF-¿ antagonists broadly target the ligand, receptors, or downstream kinases, which can antagonize homeostatic levels of TGF-¿ and increase the risk of adverse events. We have developed a novel approach to selectively targeting disease-related TGF-¿ activity in the MM bone marrow microenvironment through targeting only the TGF-¿ which is activated through binding to the extracellular matrix protein, thrombospondin1 (TSP1). TSP1 is a secreted and extracellular matrix protein, which controls TGF-¿ activity in disease by binding and activating latent TGF-¿. TSP1 is increased in MM. Our studies show that TSP1 activates latent TGF-¿ expressed by human and mouse MM cells in vitro and importantly, a tetrapeptide antagonist (LSKL) of TSP1-dependent TGF-¿ activation reduces MM tumor burden, stromal IL-6, and osteolytic bone disease in mouse models of MM. LSKL nearly completely blocks active TGF- ¿ in bone marrow cells of treated MM mice, indicating that the TSP1-TGF-¿ antagonist peptide is working through targeting TSP1-dependent TGF-¿ activation in the bone marrow microenvironment. These data establish that TSP1 is an important regulator of TGF-¿ 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-¿ pathway in MM through use of immune competent and TSP1 null models, by comparison of SRI31277 to global TGF-¿ inhibitors and by use in drug combinations, and by complementary in vitro studies to define the TSP1 receptor on MM cells for TGF-¿ 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-¿）是MM精心设计的一种多功能生长因子。细胞和骨髓微环境中的细胞。尽管 TGF-¿ 很重要，但它通过促进骨分解代谢、IL-6 分泌和 Th17 T 细胞发育来刺激 MM 进展，导致溶骨性骨疾病和免疫失调。在 MM 中，尚无 TGF-¿ 的临床试验大多数 TGF-¿ 拮抗剂。拮抗剂广泛针对配体、受体或下游激酶，可以拮抗 TGF-¿我们开发了一种新方法来选择性地靶向疾病相关的 TGF-¿通过仅靶向 TGF-¿ 在 MM 骨髓微环境中发挥活性它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，TSP1 是一种分泌性细胞外基质蛋白，控制 TGF-¿通过结合和激活潜在的 TGF-¿我们的研究表明，TSP1 会激活潜在的 TGF-¿由人类和小鼠 MM 细胞在体外表达，重要的是，它是 TSP1 依赖性 TGF-¿ 的四肽拮抗剂 (LSKL) LSKL 的激活可减少 MM 小鼠模型中的 MM 肿瘤负荷、间质 IL-6 和溶骨性骨病，几乎完全阻断活性 TGF-¿在接受治疗的 MM 小鼠的骨髓细胞中，表明 TSP1-TGF-¿拮抗肽通过靶向 TSP1 依赖性 TGF-¿这些数据表明 TSP1 是 TGF-¿ 的重要调节因子。 MM 中的活性，表明阻断该途径代表了一种减少 MM 进展和骨疾病的新型选择性治疗策略，我们的目标是开发一种口服的“可药用”形式的 LSKL 肽来治疗 MM。基于 LSKL 的先导化合物 (SRI31277)，在 MM 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，这将成为先导化合物鉴定和优化的基础该提案将机制研究（目标 1）与药物开发工作（目标 2）相结合，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。在目标 1 中，我们将进一步确定 TSP1-TGF-的作用。 ¿通过使用免疫活性和 TSP1 无效模型，通过 SRI31277 与全球 TGF-¿抑制剂并用于药物组合，并通过补充体外研究来定义 MM 细胞上 TGF-¿ 的 TSP1 受体激活以及该途径在 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 的关键目标是鉴定 SRI31277 的口服活性衍生物和适合 GLP-IND 研究的备用肽模拟物/小分子。使用肽和拟肽/小分子方法。