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

总结 目前的化学治疗剂已经改善了多发性骨髓瘤（MM）患者的存活率。然而，MM仍然 由于源自对治疗有抗性休眠MM克隆的高疾病复发率而不可治愈。此外，本发明还 抗MM治疗对修复MM诱导的骨疾病（发病的主要原因）的影响较小， MM患者的死亡率。因此，疾病复发和骨病仍然是主要的未满足的医疗需求， 需要创新的方法来有效地治疗MM。该提案的总体目标是评估疗效 新型骨靶向治疗阻断MM细胞和肿瘤小生境细胞之间的关键相互作用， MM在骨中的进展。我们将重点关注Notch和Wnt信号，两个主要的信号通路 介导肿瘤-宿主微环境通信。在导致该应用的研究中，我们生成了一个 骨靶向Notch抑制剂（BT-GSI），选择性降低骨中的Notch信号传导。抑制Notch BT-GSI在肿瘤龛中的通讯减少了MM的生长，并减少了破骨细胞数量和骨密度。 杀伤性重要的是，BT-GSI规避了限制Notch抑制剂在临床中使用的肠道毒性。 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蛋白的表达， 抑制成骨细胞骨形成功能的局部Wnt信号传导拮抗剂。使用硬化素阻断 中和抗体（Scl-Ab）通过增加成骨细胞和刺激成骨细胞增殖来预防MM诱导的骨病。 新骨形成。重要的是，我们的工作导致这一应用表明，MM细胞之间的相互作用 成骨细胞维持MM细胞处于休眠状态，而与破骨细胞的相互作用促进其 再活化成增殖的MM细胞。基于这些初步的发现，我们建议联合骨- 抑制Notch和激活Wnt信号传导的定向疗法将1）减少MM生长，2）防止MM生长。 MM休眠细胞的再活化，和3）修复受损的骨，同时减少全身毒性作用。这 假设将通过追求特定的目标，采用已建立的MM诱导的小鼠模型， 骨疾病和MM休眠以及针对肿瘤小生境的新药理学工具。两个目标是 提出了目的1将确定我们的骨靶向药物的药代动力学，药效学和安全性特征。 Notch抑制剂BT-GSI。目的2将检查联合骨靶向抑制Notch信号传导的效果， （BT-GSI）和Wnt途径的激活（Scl-Ab）对肿瘤生长、骨修复和MM细胞休眠的影响。

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.