Local and systemic control of multiple myeloma colonization and growth by MMP-13

MMP-13 对多发性骨髓瘤定植和生长的局部和全身控制

基本信息

批准号：
10620155
负责人：
Conor C Lynch
金额：
$ 43.16万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620155
关键词：
Ablation Address Animal Disease Models Attention Automobile Driving Biological Availability Bone Diseases Bone Resorption Bone neoplasms Cell Line Cell Separation Cells Clinic Clustered Regularly Interspaced Short Palindromic Repeats Complementary DNA Data Development Diagnosis Disease Disease Progression Disease model Early identification Effectiveness Engraftment Enterobacteria phage P1 Cre recombinase Enzymes Generations Growth Growth Factor Human In Vitro Intervention Luciferases Lytic Metastatic Lesion Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Mediator Medical Melphalan Microbial Collagenase Modeling Monitor Multiple Myeloma Mus Newly Diagnosed Osteoblasts Osteoclasts Osteolysis Pain Patients Proteasome Inhibitor Proteomics Regulation Research Personnel Resolution Roentgen Rays Role Skeleton Specimen Stromal Cells Techniques Testing Time Translations Work activin receptor-like kinase 1 aspirate bisphosphonate bone bone cell cell growth chemotherapy clinically relevant collagenase 3 comparative efficacy cytokine decorin efficacy evaluation exosome experimental study high risk improved in vitro activity in vivo in vivo Model inhibitor insight mouse model novel overexpression patient subsets peripheral blood pharmacokinetics and pharmacodynamics potential biomarker pre-clinical progression risk promoter response risk mitigation skeletal skeletal tissue standard of care synergism tumor

项目摘要

SUMMARY Despite medical advances, multiple myeloma remains a fatal disease. The mechanisms underpinning how myeloma progresses in the local bone microenvironment and through which myeloma colonizes the skeleton to generate multiple painful osteolytic lesions needs to be addressed urgently. Matrix metalloproteinases (MMPs) are key regulators of tumor-bone interaction via the regulation of cytokine and growth factor bioavailability/activity. Emerging data from our group has identified that in human specimens of the disease, MMP-13 is highly expressed by both the myeloma cells and the cells of the bone microenvironment namely, bone building osteoblasts. In vivo analyses show that when MMP-13 is genetically ablated from the host compartment there is a significant increase in overall survival and a concomitant decrease in myeloma induced bone disease. We also have identified that myeloma derived exosomes can promote the skeletal colonization of myeloma and, are rich in MMP-13. Further, preliminary data with a novel highly selective MMP-13 inhibitor significantly limits myeloma growth in vitro and in vivo underscoring the role for MMP-13 activity in driving multiple myeloma. Based on these preliminary findings we hypothesize that MMP-13 contributes to multiple myeloma progression. We will test our hypothesis by; 1) Defining the role of tumor and osteoblast derived MMP-13 in multiple myeloma progression. We will use CRISPR/cDNA overexpression approaches to manipulate the levels of MMP-13 in myeloma cell lines while using specific Cre-recombinase driven promoters to eliminate MMP-13 expression by osteoblasts. We will then test whether the presence or absence of MMP-13 in one or both compartments contributes to myeloma growth and associated bone disease in two separate in vivo models (5TGM1 and U266). We will also explore MMP-13 mechanisms of action with preliminary work pointing to regulation of transforming growth factorβ (TGFβ) activity. 2) Determining the role of myeloma derived exosomes and specifically exosomal MMP-13 in the skeletal colonization of the disease. We will also examine whether exosomal MMP-13, can identify smoldering multiple myeloma patients (n=200) at high-risk of progression to active disease using proteomic techniques. 3) Identifying the efficacy of a selective MMP-13 inhibitor in limiting multiple myeloma viability using CD138 isolated myeloma cells obtained from newly diagnosed patients in a novel ex vivo high throughput platform and clinically relevant in vivo models of the disease. Based on the anticipated results, interrogating the role MMP-13 in multiple myeloma progression will reveal a number of novel insights thereby providing a strong rationale for the translation of selective MMP-13 inhibitors to the clinic that we predict would have limited off-target effects due to the restricted skeletal expression of MMP-13.

概括尽管有医疗进展，多发性骨髓瘤仍然是致命的疾病。基于如何支撑的机制骨髓瘤在局部骨微环境中进展，骨髓瘤将骨骼定居至需要紧急解决多种疼痛的溶性病变。基质金属蛋白酶（MMP）是通过细胞因子和生长因子调节的肿瘤骨相互作用的关键调节剂生物利用度/活动。来自我们小组的新兴数据已经确定，在该疾病的人类标本中 MMP-13由骨髓瘤细胞和骨微环境的细胞高度表达，即骨骼建筑成骨细胞。体内分析表明，当MMP-13从宿主遗传上消失时车厢的总生存率显着增加，骨髓瘤诱导的伴随降低骨病。我们还确定，骨髓瘤衍生的外泌体可以促进骨骼定植骨髓瘤，富含MMP-13。此外，具有新型高选择性MMP-13抑制剂的初步数据显着限制了体外骨髓瘤的生长，体内强调了MMP-13活性在驱动中的作用多发性骨髓瘤。根据这些初步发现，我们假设MMP-13有助于多个骨髓瘤进展。我们将通过测试我们的假设； 1）定义肿瘤和成骨细胞的作用多发性骨髓瘤进展中的MMP-13。我们将使用CRISPR/cDNA过表达方法在使用特定的Cre-Recombinase驱动子时，操纵骨髓瘤细胞系中MMP-13的水平通过成骨细胞消除MMP-13的表达。然后，我们将测试MMP-13的存在或不存在在一个或两个隔室中，有两个单独的骨髓瘤生长和相关的骨骼疾病体内模型（5TGM1和U266）。我们还将通过初步工作探索MMP-13动作机制指出转化生长因子β（TGFβ）活性的调节。 2）确定骨髓瘤的作用在该疾病的骨骼定植中，衍生的外泌体，特别是外体外MMP-13。我们也会检查外泌体MMP-13是否可以在高风险的使用蛋白质组学技术进展为活性疾病。 3）确定选择性MMP-13的效率使用从新近获得的CD138分离的骨髓瘤细胞限制多发性骨髓瘤活力的抑制剂在新型的离体高吞吐量平台和临床相关的体内模型中诊断出的患者疾病。根据预期的结果，询问多发性骨髓瘤进展中MMP-13的角色将揭示了许多新颖的见解，从而为选择性MMP-13的翻译提供了强大的理由我们预测的诊所的抑制剂将由于骨骼受限而受到有限的脱靶作用 MMP-13的表达。