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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：
10349508
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 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349508
关键词：
Ablation Address Animal Disease Models Aspirate substance Attention Automobile Driving Biological Availability Bone Diseases Bone Resorption Bone neoplasms Cell Line 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 of activation protein Medical Melphalan Microbial Collagenase Modeling Monitor Multiple Myeloma Mus Newly Diagnosed Osteoblasts Osteoclasts Osteolysis Pain Patients Proteasome Inhibitor Proteomics Regulation Research Personnel Resolution Risk Roentgen Rays Role Skeleton Specimen Stromal Cells Techniques Testing Time Translations Work activin receptor-like kinase 1 base bisphosphonate bone bone cell cell growth chemotherapy clinically relevant collagenase 3 comparative efficacy cytokine decorin 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 promoter response 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.

总结