Bone-Targeted Therapies to Improve Bone Health and Prevent Relapse in Multiple Myeloma

摘要 目前的化疗药物已经提高了多发性骨髓瘤(MM)患者的存活率。然而，MM仍然 由于疾病复发率高而无法治愈，这种疾病源于对治疗有抵抗力的休眠MM克隆。此外， 抗多发性骨髓瘤疗法在修复多发性骨髓瘤引起的骨病方面效果不大，骨病是发病和死亡的主要原因 多发性骨髓瘤患者的死亡率。因此，疾病复发和骨病仍然是未得到满足的主要医疗需求。 需要创新的方法来有效治疗多发性骨髓瘤。本提案的总体目标是评估疗效。 阻止MM细胞和肿瘤巢细胞之间关键相互作用的新型骨靶向疗法的研究 多发性骨髓瘤在骨骼中的进展。我们将重点介绍Notch和Wnt信号，这是两条主要的信号通路 调节肿瘤-宿主微环境通讯。在导致这一应用的研究中，我们生成了一个 骨靶向Notch抑制剂(BT-GSI)，选择性地减少骨骼中的Notch信号。凹槽的抑制 BT-GSI在肿瘤巢内的通讯减少了MM的生长，减少了破骨细胞数量和骨质 毁灭。重要的是，BT-GSI避免了限制Notch抑制剂在临床使用的肠道毒性。 此外，我们发现MM细胞和骨细胞之间的相互作用增加了硬化素的表达，a 局部Wnt信号拮抗剂，抑制成骨细胞成骨功能。阻断硬化素的使用 中和抗体(scl-Ab)通过增加成骨细胞和刺激骨质疏松症而预防MM引起的骨病 新骨形成。重要的是，我们导致这一应用的工作表明多发性骨髓细胞之间的相互作用 成骨细胞维持MM细胞的休眠状态，而与破骨细胞的相互作用促进其 重新激活为增殖的多发性骨髓瘤细胞。基于这些初步发现，我们提出了组合骨- 抑制Notch和激活Wnt信号的定向治疗将1)减少MM的生长，2)防止 重新激活MM休眠细胞，以及3)修复受损的骨骼，同时减少全身毒性影响。这 通过追求特定的目标，利用已建立的MM诱导的小鼠模型，将提出假设 骨病和多发性骨髓瘤休眠，以及针对肿瘤利基的新药理工具。两个目标是 建议。目标1将确定我们的骨靶向药物的药代动力学、药效学和安全性 缺口抑制剂BT-GSI。目的2将研究联合骨靶向抑制Notch信号的效果 (BT-GSI)和Wnt途径的激活(scl-Ab)在肿瘤生长、骨修复和MM细胞休眠中的作用。

Summary Current chemotherapeutic agents have improved multiple myeloma (MM) patient survival. However, MM remains incurable due to high rate of disease relapse that originate from dormant MM clones resistant to therapy. Further, anti-MM therapies have minor effects on repairing MM-induced bone disease, a leading cause of morbidity and mortality in MM patients. Thus, disease relapse and bone disease remain major unmet medical needs that require innovative approaches to effectively treat MM. The overall goal of this proposal is to evaluate the efficacy of novel bone-targeted therapies blocking key interactions between MM cells and cells of the tumor niche to stop the progression of MM in bone. We will focus on Notch and Wnt signaling, two major signaling pathways mediating tumor-host microenvironment communication. In studies leading to this application, we generated a bone-targeted Notch inhibitor (BT-GSI) that selectively decreases Notch signaling in bone. Inhibition of Notch communication in the tumor niche with BT-GSI reduced MM growth and decreased osteoclast number and bone destruction. Importantly, BT-GSI circumvented the gut toxicity that limits the use of Notch inhibitors in the clinic. Further, we found that interactions between MM cells and osteocytes increase the expression of Sclerostin, a local Wnt signaling antagonist that inhibits osteoblast bone forming function. Blockade of Sclerostin using neutralizing antibodies (Scl-Ab) prevented MM-induced bone disease by increasing osteoblasts and stimulating new bone formation. Importantly, our work leading to this application showed that interactions between MM cells and osteoblasts maintain MM cells in a dormant state, while interactions with osteoclasts promote their reactivation into proliferating MM cells. Based on these preliminary findings, we propose that combined bone- directed therapies inhibiting Notch and activating Wnt signaling will 1) decrease MM growth, 2) prevent reactivation of MM dormant cells, and 3) repair damaged bone, while reducing systemic toxic effects. This hypothesis will be advanced by pursuing specific aims that employ established mouse models of MM-induced bone disease and MM dormancy and new pharmacologic tools targeted to the tumor niche. Two aims are proposed. Aim 1 will determine the pharmacokinetic, pharmacodynamic, and safety profiles of our bone-targeted Notch inhibitor BT-GSI. Aim 2 will examine the effects of combined bone-targeted inhibition of Notch signaling (BT-GSI) and activation of the Wnt pathway (Scl-Ab) on tumor growth, bone repair, and MM cell dormancy.