Current research projects, disease, and focus areas include:
i) Transcriptional Regulation of Macrophage Activity
Macrophages are classified on a spectrum between “M1” pro-inflammatory macrophages and “M2” anti-inflammatory macrophages. Tumor associated macrophages (TAMs) are typically thought of as “M2-like” in that they tend to display an immunosuppressive, pro-neoplastic phenotype. We are investigating how differential expression and targeting of transcription programs affects macrophage activity and the overall immune response in both health and disease using mouse models of breast cancer and models using other immune-stimulating agents.
ii) The Role of Osteoclasts and Macrophages in Bone Metastasis
Up to 70% of breast cancer patients will develop metastatic disease, with bone being the most frequent site of metastasis in these patients. In bone, cancer cells (1) stimulate macrophages to differentiate into osteoclasts and (2) increase osteoclastic bone resorption (lysis), leading to bone loss, pain, and fracture. We are working on delineating the role of, and genetically and therapeutically targeting, both of these populations in the breast cancer bone metastatic niche.
iii) Targeting the Tumor Microenvironment
The use of CSF1R inhibitors alone to target TAMs in breast cancer has shown less than desirable results clinically. However, growing evidence exists that combination therapy of CSF1R inhibitors with other therapeutic agents can have additive or synergistic effects, overcoming the limitations of CSF1R inhibitor monotherapy. Our goal is to indirectly target cancer cells by directly targeting tumor-supportive macrophages (in primary tumors and metastasis) and osteoclasts (in bone metastasis) in the tumor microenvironment with a goal of constraining tumor growth. For this project, we are working with Dr. Kharlampieva and her laboratory within the UAB Department of Chemistry to develop and validate novel microparticle formulations for targeted drug delivery of anti-macrophage and anti-osteoclast drugs we are investigating. This system will be used to target macrophages within the tumor microenvironment and both macrophages and osteoclasts in bone.
