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

 描述（由申请人提供）：尽管医学进步，多发性骨髓瘤仍然是一种致命的疾病，迫切需要更好的治疗。多发性骨髓瘤的进展依赖于与骨微环境中正常细胞（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破坏，极大地影响患者的生活质量。我们已经表明，基质金属蛋白酶（MMP），如MMP-2是通过调节细胞因子和生长因子的生物利用度和生物活性的肿瘤-骨相互作用的关键介质。在人类中，研究已经确定， MMP-2表达存在于晚期疾病，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效应是背景和组织依赖性的，迄今为止，没有研究检查癌症或宿主来源的MMP-2是否有助于多发性骨髓瘤的进展。使用一种创新的方法，即在双膦酸骨架上产生选择性MMP-2抑制剂，以特异性靶向骨骼组织，从而靶向癌骨微环境，新的研究表明，与单独的双膦酸盐相比，我们的骨寻求MMP-2抑制剂（BMMPI）在体内预防骨髓瘤进展方面是有效的。这些观察结果进一步暗示MMP-2在促进多发性骨髓瘤生长中的作用。重要的是，我们的新型BMMPI化合物允许规避问题，例如在全身递送广谱MMP的先前临床试验中注意到的剂量限制性副作用。综上所述，我们的初步研究结果为MMP-2促进多发性骨髓瘤进展以及BMMPI选择性靶向MMP-2治疗多发性骨髓瘤有效的假设提供了依据。我们将通过以下方式检验我们的假设：1）使用遗传学方法确定肿瘤和宿主来源的MMP-2在多发性骨髓瘤进展中的作用; 2）充分评价MMP-2选择性BMMPI作为单一治疗剂对多发性骨髓瘤进展的影响。还将使用主要BMMPI进行初步药代动力学和药效学（PK/PD）研究。基于预期的结果，我们期望询问肿瘤和宿主来源的MMP-2在多发性骨髓瘤中的作用将揭示关于疾病如何在骨微环境中进展的许多新见解。令人兴奋的是，我们的研究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疗效。此外，考虑到患者对双膦酸盐的耐受性良好，我们预测BMMPI候选药物可以迅速应用于临床。

 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.