# Reprogramming tumor associated macrophages to induce anti-tumor immune responses in bone metastatic breast cancer.

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Despite progress in the treatment of primary breast tumors, metastatic disease remains incurable. While
metastatic breast tumors can metastasize to multiple organs, approximately 70% of women that die from
metastatic breast cancer experience serious complications from bone metastases. Once established in the bone,
tumors disrupt normal bone homeostasis leading to increased pain, fracture, and general morbidity.
Unfortunately, Veterans that develop breast cancer are at higher risk for metastatic disease and more aggressive
tumors. Our research has identified the transcription factor, Gli2, as a driver of the tumor-produced protein
parathyroid hormone related protein (PTHrP), which drives osteoclast mediated bone destruction. Inhibition of
Gli2 reduces tumor-induced bone destruction but has limited efficacy for eliminating tumors. Other studies by
our group have identified bone marrow myeloid progenitor population that expand when tumors are established
in bone. These myeloid progenitor cells differentiate into the pro-tumor/anti-immune, tumor-associated
macrophages (TAMs) and osteoclasts. Our preliminary data suggest a potential role of Gli2 in the expansion of
TAMs, demonstrating Gli2 as a potential target to inhibit myeloid expansion and improve anti-tumor immune
responses. In this application, we hypothesize that tumor expression of Gli2 induces the transcription of
cytokines leading to increased pro-tumor macrophage recruitment and increased tumor growth and
bone destruction. To address this hypothesis, we will use mouse mammary tumor models with alterations in
Gli2 expression (over expressed or inhibited) to investigate how Gli2 alters tumor-produced cytokines and
macrophage responses. In subsequent aims, we will use mouse models with macrophage alteration in NFkB
and IL-4 signaling to investigate how macrophage signaling drives tumor and bone interactions and potentially
alters pro-tumor immune responses to drive anti-tumor, immune stimulating responses that result in reduced
tumor and bone destruction. Finally, in our third aim, we will investigate pre-clinical inhibitors of Gli2 and IL-4Rα
as potential therapies for tumor-induced bone disease. These therapies will be compared to standard-of-care
therapies, including paclitaxel and zoledronic acid, for efficacy and toxicity. These studies will improve our
understanding of immune responses in tumor-induced bone disease and will help identify therapeutic
approaches to reduce pro-tumor macrophage recruitment. Improving anti-tumor immune responses will reduce
tumor burden in bone and osteoclast-mediated bone destruction. Importantly, we will investigate potential
toxicities associated with these therapies in comparison to standard-of-care approaches. Based on our
preliminary data, we expect to identify a promising therapeutic strategy from this study that can be rapidly move
to early clinical studies for patients with bone metastatic disease. This study could have high potential impact to
ident...

## Key facts

- **NIH application ID:** 10368386
- **Project number:** 2I01BX001957-09
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Julie A Rhoades (Sterling)
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2013-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368386

## Citation

> US National Institutes of Health, RePORTER application 10368386, Reprogramming tumor associated macrophages to induce anti-tumor immune responses in bone metastatic breast cancer. (2I01BX001957-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368386. Licensed CC0.

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