The thrombospondin1-TGF-beta axis in multiple myeloma

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，依赖于骨髓微环境的进展。转化生长因子- β （TGF-ß）是一种由MM细胞和骨髓微环境细胞合成的多功能生长因子。TGF-ß通过促进分解代谢骨重塑、IL-6分泌和Th17 T细胞发育，刺激MM进展，导致溶骨性骨病和免疫失调。尽管TGF-ß在MM中的重要性，但目前尚无TGF-ß拮抗剂治疗MM的临床试验。大多数TGF-ß拮抗剂广泛靶向配体、受体或下游激酶，可拮抗TGF-ß的稳态水平，增加不良事件的风险。我们已经开发了一种新的方法，通过仅靶向TGF-ß通过与细胞外基质蛋白血小板spondin1 （TSP1）结合而激活，选择性地靶向MM骨髓微环境中与疾病相关的TGF-ß活性。TSP1是一种分泌和细胞外基质蛋白，它控制

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.