Browsing by Author "Boeckman, Robert K., Jr."

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    Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity
    (American Association for Cancer Research, 2021) Sabol, Hayley M.; Ferrari, Adam J.; Adhikari, Manish; Amorim, Tânia; McAndrews, Kevin; Anderson, Judith; Vigolo, Michele; Lehal, Rajwinder; Cregor, Meloney; Khan, Sharmin; Cuevas, Pedro L.; Helms, Jill A.; Kurihara, Noriyoshi; Srinivasan, Venkat; Ebetino, Frank H.; Boeckman, Robert K., Jr.; Roodman, G. David; Bellido, Teresita; Delgado-Calle, Jesus; Medicine, School of Medicine
    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.
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    The Notch pathway regulates the bone gain induced by PTH anabolic signaling
    (Wiley, 2022) Delgado-Calle, Jesus; McAndrews, Kevin; Wu, Gerald; Orr, Ashley L.; Ferrari, Adam; Tu, Xiaolin; Srinivasan, Venkatesan; Roodman, G. David; Ebetino, Frank H.; Boeckman, Robert K., Jr.; Bellido, Teresita; Anatomy, Cell Biology and Physiology, School of Medicine
    Parathyroid hormone (PTH) signaling downstream of the PTH 1 receptor (Pth1r) results in both bone anabolic and catabolic actions by mechanisms not yet fully understood. In this study, we show that Pth1r signaling upregulates the expression of several components of the Notch pathway and that Notch signals contribute to the catabolic actions of PTH in bone. We found that constitutive genetic activation of PTH receptor signaling in osteocytes (caPth1rOt ) or treatment with PTH daily increased the expression of several Notch ligands/receptors in bone. In contrast, sustained elevation of endogenous PTH did not change Notch components expression. Deletion of the PTH receptor or sclerostin overexpression in osteocytes abolished Notch increases by PTH. Further, deleting the canonical Notch transcription factor Rbpjk in osteocytes decreased bone mass and increased resorption and Rankl expression in caPth1rOt mice. Moreover, pharmacological bone-targeted Notch inhibition potentiated the bone mass gain induced by intermittent PTH by reducing bone resorption and preserving bone formation. Thus, Notch activation lies downstream of anabolic signaling driven by PTH actions in osteocytes, and Notch pharmacological inhibition maximizes the bone anabolic effects of PTH.