Simultaneous Imaging of Tumor and Host Cells in the Microenvironment

Proposal Summary/Abstract While there have been significant advances in the detection and treatment of breast cancer, mortality due to metastatic disease recurrence remains unacceptably high and a leading cause of death. Furthermore, chemotherapies with intolerable side effects remain the standard of care for metastatic breast cancer patients, which is highly detrimental to quality of life. Advances in molecular targeting cancer imaging offer a window into underlying tumor biology and support the use of individualized targeted therapies that can spare patients over- treatment with harsh chemotherapies. However, most molecular imaging probes typically target either cancer cells or, more recently, a single cell type in the tumor microenvironment. These approaches are inherently limited in the information they can provide. Optimal treatment planning relies on a complete picture of disease state, including microscopic regions of residual disease and understanding the potential for recurrence based on a lesion’s specific molecular traits. As such, the goal of this proposal is to provide the foundation for a clinically useful means to image and understand disease status before, during, and after treatment of primary breast cancer and metastatic disease. We postulate that molecular imaging of both the microenvironment and cancer cells simultaneously will provide more complete detection of diseased regions and an understanding of dynamic changes in tumor microenvironment that are needed to support personalized therapy. We propose: (Aim1) A bispecific strategy targeting both breast cancer cells and cancer-associated fibroblasts in the tumor microenvironment to enhance tumor detection. (Aim 2) Differentially targeting cancer cells and cancer-associated fibroblasts with near-infrared molecular probes with similar spectral properties but different fluorescent lifetime values to extract tumor-stroma ratio noninvasively, which is a prognostic indicator in breast cancer. This non-invasive method of determining the relative abundance of malignant cells and cancer- associated fibroblasts will be compared with the traditional histologic determination of tumor-stroma ratio. At the completion of this study, we expect to have established a signal amplification method to detect small cancerous lesions and a non-invasive approach to map cancer-stromal ratio to understand how the dynamic changes in the tumor microenvironment affect cancer biology.