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

• 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
• 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

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（由应用提供）：多发性骨髓瘤（MM）是浆细胞无法治愈的癌症，取决于骨髓微环境的进展。转化生长因子β（TGF- - ）是MM细胞和骨髓微环境中细胞阐述的多功能生长因子。通过促进分解代谢骨重塑，IL-6分泌和Th17 T细胞的发育，TGF- - 刺激MM进展，从而导致骨化骨病和免疫失调。尽管在MM中TGF- - 在MM中很重要，但TGF-oo拮抗剂尚无用于治疗MM的临床试验。大多数TGF-拮抗剂广泛针对配体，接收器或下游激酶，这可以拮抗稳态水平的TGF- - 并增加发生不良事件的风险。我们已经开发了一种新型的方法，可以选择性地靶向MM骨髓微环境中与疾病相关的TGF-活性，仅靶向TGF-€TSP1是一种分泌的细胞外基质蛋白，通过结合和激活延伸的TGF-®来控制TGF- - 在疾病中控制TGF-€的活性。 TSP1在mm中增加。我们的研究表明，TSP1激活由人和小鼠MM细胞在体外和重要的是，TSP1依赖性TGF-¿激活中的四肽拮抗剂（LSKL）表达的潜在TGF- - 活化减少了MM MM MM模型的小鼠模型中的MM肿瘤burnen，stromal IL-6和Ostetoltic bone病。 LSKL几乎完全阻止了处理过的MM小鼠的骨髓细胞中的活性TGF-，这表明TSP1-TGF- - 拮抗剂肽正在通过靶向骨髓微环境中的TSP1依赖性TGF-激活来靶向TSP1依赖性TGF-激活。这些数据建立，即TSP1是MM中TGF- - 活性的重要调节剂，并表明该途径的封锁代表了一种新颖而选择性的理论策略，以减少MM进展和骨骼疾病。我们的目标是开发一种口服的LSKL肽的口服“可药”形式，用于治疗MM。我们已经确定了基于LSKL的铅化合物（SRI31277），该化合物在MM的小鼠模型，改进的药代动力学和口服生物利用度中具有剂量依赖性体内活性，这将是鉴定和优化铅药物的基础。该提案将将机械研究（目标1）与药物开发工作（AIM 2）相结合，以实现我们确定用于治疗MM的口服铅化合物的目标。在AIM 1中，我们将通过使用免疫能力和TSP1 NULL模型来进一步确定TSP1-TGF- - 途径在MM中的作用，通过将SRI31277与全局TGF- - 抑制剂进行比较，并通过在药物组合中使用，以及通过辅助性在体外进行TSP1受体的细胞来激活TGF-¿细胞因子产生和成骨细胞/破骨细胞调节。 AIM 2的关键目标是鉴定SRI31277的口服活性衍生物和适用于使用肽和肽型/小分子方法的GLP-IND促进研究的备用肽模拟/小分子。