Specific skeletal targeting of MMP-2 for the treatment of multiple myeloma

MMP-2 的特异性骨骼靶向治疗多发性骨髓瘤

基本信息

批准号：
8959015
负责人：
Lori A Hazlehurst
金额：
$ 21.99万
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：
2015
资助国家：
美国
起止时间：
2015-07-02 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8959015
关键词：
Adverse effects Biological Availability Biopsy Bone Diseases Bone neoplasms Cell Line Cells Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Diagnosis Disease Disease Progression Dose-Limiting Drug Kinetics Enzymes Gelatinase A Genes Genetic study Growth Growth Factor Human Image Immunofluorescence Immunologic In Vitro Knockout Mice Lead Light Luciferases Malignant Bone Neoplasm Malignant Neoplasms Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediator of activation protein Medical Modeling Monitor Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Normal Cell Osteoblasts Osteoclasts Osteolysis Patients Pharmacodynamics Play Prevalence Quality of life Refractory Disease Regulation Roentgen Rays Role Skeleton Specimen Staging Staining method Stains Technology Testing Therapeutic Agents Time Tissue Microarray Tissues Toxic effect Translating Translational Research Treatment Efficacy Vertebral column Zoledronate base bisphosphonate bone bone turnover clinically relevant comparative efficacy cytokine effective therapy efficacy testing genetic approach human disease in vivo inhibitor/antagonist innovation insight novel prevent public health relevance recombinase skeletal skeletal tissue tumor

项目摘要

DESCRIPTION (provided by applicant): Despite medical advances, multiple myeloma remains a fatal disease underscoring the urgent need for better therapies. Multiple myeloma progression is dependent on interactions with normal cells of the bone microenvironment including osteoblasts and osteoclasts. These interactions lead to extensive bone destruction that greatly impact the patient's quality of life. We have shown that matrix metalloproteinases (MMPs) such as MMP-2 are key mediators of tumor-bone interaction via the regulation of cytokine and growth factor bioavailability and bioactivity. In humans, studies have identified that MMP-2 expression is present in late stage disease while our preliminary analyses of clinical specimens have demonstrated that MMP-2 is highly expressed in the myeloma and host compartments. Importantly, MMP effects are known to be context and tissue dependent and to date, no studies have examined whether cancer or host derived MMP-2 contribute to the progression of Multiple Myeloma. Using an innovative approach of generating selective MMP-2 inhibitors built on a bisphosphonic backbone in order to specifically target the skeletal tissue, hence the cancer-bone microenvironment, emerging studies indicate that our bone seeking MMP-2 inhibitors (BMMPIs) are efficacious in preventing myeloma progression in vivo compared to bisphosphonates alone. These observations further implicate a role for MMP-2 in promoting multiple myeloma growth. Critically, our novel BMMPI compounds allow for the circumvention of issues such as dose limiting side effects noted in previous clinical trials in which broad-spectrum MMPs were systemically delivered. Taken together, our preliminary findings provide rationale for the hypothesis that MMP-2 contributes to multiple myeloma progression and that the selective targeting of MMP-2 with BMMPIs will be therapeutically effective for the treatment of multiple myeloma. We will test our hypothesis by 1) defining the role of tumor and host derived MMP-2 in multiple myeloma progression using genetic approaches and; 2) fully evaluating the impact of MMP-2 selective BMMPIs as a single therapeutic agent on the progression of multiple myeloma. Pilot pharmacokinetic and pharmacodynamics (PK/PD) studies with the lead BMMPI will also be performed. Based on the anticipated results, we expect that interrogating the role of tumor and host derived MMP-2 in multiple myeloma will reveal a number of novel insights as to how the disease progresses in the bone microenvironment. Excitingly, our results will also shed light on the efficacy of a novel skeletal targeting MMP-2 inhibitor agent for the treatment and eradication of multiple myeloma. Furthermore, given that bisphosphonates are well tolerated by patients, we predict that the lead BMMPI candidate could be rapidly translated to the clinical setting.

描述（由申请人提供）：尽管医学取得了进步，但多发性骨髓瘤仍然是一种致命的疾病，这凸显了对更好治疗的迫切需要。多发性骨髓瘤的进展取决于与骨微环境中的正常细胞（包括成骨细胞和破骨细胞）的相互作用。这些相互作用导致广泛的骨形成。我们已经证明，基质金属蛋白酶 (MMP)（例如 MMP-2）是通过细胞因子的调节实现肿瘤与骨相互作用的关键介质。研究表明，生长因子在人体中的生物利用度和生物活性。 MMP-2 表达存在于疾病晚期，而我们对临床标本的初步分析表明，MMP-2 在骨髓瘤和宿主区室中高度表达。重要的是，已知 MMP 效应具有环境和组织依赖性，但迄今为止，尚无这种效应。研究使用一种创新方法来检测癌症或宿主衍生的 MMP-2 是否会导致多发性骨髓瘤的进展，该方法产生基于双磷酸骨架的选择性 MMP-2 抑制剂，以特异性靶向骨骼组织。癌症骨微环境，新兴研究表明，与单独使用双磷酸盐相比，我们的骨寻找 MMP-2 抑制剂 (BMMPI) 可有效预防体内骨髓瘤进展。这些观察进一步表明 MMP-2 在促进多发性骨髓瘤生长中的作用。我们的新型 BMMPI 化合物可以避免先前系统性递送广谱 MMP 的临床试验中注意到的剂量限制副作用等问题。综上所述，我们的初步研究结果表明。 MMP-2 促进多发性骨髓瘤进展以及 BMMPI 选择性靶向 MMP-2 对多发性骨髓瘤的治疗有效的假设的基本原理我们将通过 1) 定义肿瘤和宿主的作用来检验我们的假设。使用遗传方法衍生 MMP-2 在多发性骨髓瘤进展中的作用；2) 全面评估 MMP-2 选择性 BMMPI 作为单一治疗药物对多发性骨髓瘤进展的影响。基于预期的结果，我们也将进行主要 BMMPI 的 (PK/PD) 研究，我们预计，探究肿瘤和宿主衍生的 MMP-2 在多发性骨髓瘤中的作用将揭示许多关于该疾病如何发生的新见解。令人兴奋的是，我们的研究结果还将揭示新型骨骼靶向 MMP-2 抑制剂治疗和根除多发性骨髓瘤的功效。由于患者能够耐受，我们预测主要的 BMMPI 候选药物可以快速转化为临床环境。