# Macrophage and osteoclast specific targeting for the prevention and treatment of breast cancer bone metastasis

> **NIH NIH K01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $126,738

## Abstract

Project Summary/Abstract: I have completed DVM, MS, and PhD degrees, a surgical residency, and am now
a Post-Doctoral Research Fellow in cancer and bone genetics and biology. This K01 award will facilitate my
transition into an independent position as a tenure-track clinician-scientist studying bone metastasis and primary
bone tumors. My clinical and research training will benefit both human and veterinary clinicians and researchers
and promote the development of essential translational and comparative collaborations. Advancement towards
independence will occur by many mechanisms during this K01 award. I will obtain knowledge and skills central
to this award’s research strategy and my career goals. I will continue to hone previously learned techniques but
also receive training in new methods to study cancer biology and genetics, the tumor microenvironment, bone
biology, and metastasis. I will receive training in essential non-laboratory research skills such as grantsmanship,
scientific writing, responsible conduct of research, and mentoring. Metastatic disease is the leading cause of
breast cancer-related deaths and bone metastases occur in ~75% of patients with metastasis. In bone, cancer
cells secrete factors that 1) stimulate macrophages (MPs) to differentiate into osteoclasts (OCs) and 2) increase
osteoclastic bone resorption (lysis), leading to bone loss, pain, and fracture. Therefore, preventing the
establishment of and treating existing bone metastasis is the goal of therapy. Colony stimulating factor 1 receptor
(CSF1R) regulates the expression of the transcription factor (TF) PU.1. Our preliminary data demonstrate that
the CSF1R/PU.1 axis is a key regulator of 1) tumor-associated MP (TAM) function and 2) normal MP and OC
differentiation and function. In addition, several TFs and genes essential for OC differentiation and function have
a strong enhancer binding pattern by PU.1 resembling “superenhancers”. These enhancers are enriched for BET
proteins which bind to PU.1 to regulate key osteoclastogenic TFs. The objective of this award is to 1) investigate
the role of the CSF1R/PU.1 axis and 2) determine if superenhancers play a role, in breast cancer bone
metastasis. Our hypothesis is that the CSF1R/PU.1 axis is essential for bone metastasis and this occurs in the
context of superenhancers. We will initially assess the effects of MP-specific deletion of PU.1 on breast cancer
bone metastasis and determine genes regulated by PU.1 in both primary tumor MPs and bone metastasis MPs
and OCs (Aim 1). We will then evaluate if BET inhibition can reduce the development of, and growth of
established, bone metastasis and determine if increasing its specificity to specifically target MPs and OCs will
increase its therapeutic efficacy (Aim 2). Lastly, we will evaluate if combination therapy with the most efficacious
BET inhibitor preparation from Aim 2 and a CSF1R inhibitor targeting the CSF1R/PU.1 axis is more efficacious
against the development and gro...

## Key facts

- **NIH application ID:** 9996808
- **Project number:** 5K01OD026527-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Blake Eason Hildreth
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $126,738
- **Award type:** 5
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996808

## Citation

> US National Institutes of Health, RePORTER application 9996808, Macrophage and osteoclast specific targeting for the prevention and treatment of breast cancer bone metastasis (5K01OD026527-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996808. Licensed CC0.

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