Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease. Significance: Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch.

中文翻译：

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将 Notch 抑制剂靶向骨髓瘤骨髓腔可减少肿瘤生长和骨骼破坏，而不会产生肠道毒性

用 γ-分泌酶抑制剂 (GSI) 全身抑制 Notch 可减少多发性骨髓瘤肿瘤的生长，但由于其严重的胃肠道毒性，GSI 的临床应用受到限制。在这项研究中，我们产生了一种专门针对骨骼的 GSI Notch 抑制剂 (BT-GSI)。BT-GSI 给药降低了骨髓中 Notch 靶基因的表达，但它没有改变肠道组织中的 Notch 信号传导或诱导肠道毒性。在患有人或鼠多发性骨髓瘤的小鼠中，与等摩尔剂量的未结合 GSI 相比，BT-GSI 治疗通过更有效地抑制骨吸收来降低肿瘤负荷并防止多发性骨髓瘤诱导的溶骨性疾病的进展。这些发现表明 BT-GSI 具有双重抗骨髓瘤和抗吸收特性，支持骨靶向 Notch 抑制治疗多发性骨髓瘤和相关骨病的治疗方法。意义：开发一种骨靶向 Notch 抑制剂可减少多发性骨髓瘤的生长并减轻癌症引起的骨破坏，而不会引起通常与 Notch 抑制相关的胃肠道毒性。