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

• 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
• 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

 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，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方法的迫切需要。多发性骨髓瘤的进展取决于与骨微环境正常细胞（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质破坏，极大地影响患者的生活质量。我们已经证明，基质金属蛋白酶 (MMP)（例如 MMP-2）通过调节细胞因子和生长因子的生物利用度和生物活性，是肿瘤-骨相互作用的关键介质。在人类中，研究表明 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，MMP 的作用已知与环境和组织相关，迄今为止，还没有研究检验癌症或宿主衍生的 MMP-2 是否会导致多发性骨髓瘤的进展。采用创新方法生成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，从而靶向癌骨微环境，新兴研究表明，与单独使用双磷酸盐相比，我们的寻骨 MMP-2 抑制剂 (BMMPI) 可有效预防体内骨髓瘤进展。这些观察结果进一步表明 MMP-2 在促进多发性骨髓瘤生长中的作用。至关重要的是，我们的新型 BMMPI 化合物可以避免一些问题，例如之前全身递送广谱 MMP 的临床试验中注意到的剂量限制副作用。总而言之，我们的初步研究结果为以下假设提供了理论依据：MMP-2 有助于多发性骨髓瘤进展，并且用 BMMPI 选择性靶向 MMP-2 将有效治疗多发性骨髓瘤。我们将通过以下方式检验我们的假设：1) 使用遗传方法定义肿瘤和宿主衍生的 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。还将针对先导 BMMPI 进行试点药代动力学和药效学 (PK/PD) 研究。根据预期结果，我们预计，探讨肿瘤和宿主衍生的 MMP-2 在多发性骨髓瘤中的作用将揭示许多关于疾病如何在骨微环境中进展的新见解。令人兴奋的是，我们的结果还将揭示一种新型骨骼靶向 MMP-2 抑制剂治疗和根除多发性骨髓瘤的功效。此外，鉴于患者对双磷酸盐的耐受性良好，我们预测领先的 BMMPI 候选药物可以快速转化为临床环境。