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

 描述(申请人提供)：尽管医学上取得了进步，但多发性骨髓瘤仍然是一种致命的疾病，强调了对更好的治疗方法的迫切需要。多发性骨髓瘤的进展依赖于与骨微环境中正常细胞的相互作用，包括成骨细胞和破骨细胞。这些相互作用导致广泛的骨骼破坏，极大地影响了患者的生活质量。我们已经证明，基质金属蛋白酶(MMPs)，如基质金属蛋白酶-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。在人类身上，研究已经确定 在晚期疾病中存在基质金属蛋白酶-2的表达，而我们对临床标本的初步分析表明，基质金属蛋白酶-2在骨髓瘤和宿主间隔室中高表达。重要的是，基质金属蛋白酶的作用是已知的上下文和组织依赖的，到目前为止，还没有研究检查癌症或宿主来源的基质金属蛋白酶-2是否有助于多发性骨髓瘤的进展。使用一种创新的方法，产生建立在双膦主干上的选择性基质金属蛋白酶-2抑制剂，以便特异性地靶向骨骼组织，从而癌症-骨微环境，新兴的研究表明，我们的骨寻找基质金属蛋白酶-2抑制剂(BMMPIs)在体内比单独使用双膦酸盐在防止骨髓瘤进展方面有效。这些观察进一步暗示了基质金属蛋白酶-2在促进多发性骨髓瘤生长中的作用。关键的是，我们的新型BMMPI化合物允许规避先前的临床试验中注意到的剂量限制副作用等问题，在这些临床试验中，广谱MMPs被系统地输送。综上所述，我们的初步发现为以下假设提供了理论基础，即基质金属蛋白酶-2促进多发性骨髓瘤的进展，并且通过BMMPIs选择性靶向基质金属蛋白酶-2对多发性骨髓瘤的治疗将是有效的。我们将通过1)使用遗传学方法确定肿瘤和宿主来源的基质金属蛋白酶-2在多发性骨髓瘤进展中的作用以及2)充分评估基质金属蛋白酶-2选择性BMMPIs作为单一治疗剂对多发性骨髓瘤进展的影响来检验我们的假设。还将进行以BMMPI为主导的初步药代动力学和药效学(PK/PD)研究。基于预期的结果，我们预计，询问肿瘤和宿主来源的基质金属蛋白酶-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骼微环境中进展的新见解。令人兴奋的是，我们的结果也将阐明一种新型的骨骼靶向基质金属蛋白酶-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很好，我们预测BMMPI候选药物有望迅速转化为临床应用。

 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.