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

> **NIH NIH R37** · UNIV OF ARKANSAS FOR MED SCIS · 2021 · $349,984

## Abstract

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.

## Key facts

- **NIH application ID:** 10246469
- **Project number:** 5R37CA251763-02
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Jesus Delgado-Calle
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,984
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246469

## Citation

> US National Institutes of Health, RePORTER application 10246469, Bone-Targeted Therapies to Improve Bone Health and Prevent Relapse in Multiple Myeloma (5R37CA251763-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246469. Licensed CC0.

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