Spatial and Temporal Tracking of Neural Stem Cells Migration to Brain Metastases of Breast Cancer using High Resolution Imaging - PROJECT SUMMARY Patients diagnosed with breast cancer brain metastases (BM) have a poor prognosis, and their therapeutic options are minimal. Surgical intervention is limited to a single lesion, whereas most women present with multiple metastases, and most chemotherapeutic drugs are not effective due to the blood-brain barrier. Whole-brain radiation therapy is often the only available therapeutic option for patients with multiple and larger brain metastases. However, it is associated with potentially devastating side effects; therefore, there is an urgent need to develop new targeted therapies. Stem cell-based therapies have the potential to fulfill this need. The inherent tropism of neural stem cells (NSCs) towards solid and metastatic brain tumors after a local and systemic injection has been demonstrated by multiple studies. This specific property, along with the low immunogenicity of NSCs, has generated substantial interest in therapeutic applications using NSCs as carriers for targeted delivery of anti-tumor therapies in experimental animal models and translation to clinical trials for patients with glioblastoma. We have recently generated NSCs secreting therapeutic antibodies and tested NSCs' therapeutic properties in a BM model in pre-clinical studies. However, there has been no reliable methodology to monitor the intracranial behaviors of therapeutic NSCs in the complex in vivo brain environment. Therefore, it is imperative to devise non-invasive imaging modalities for tracking NSCs in the brain to ensure the quality of tailored development of NSC-based brain tumor therapies. Here, we propose to take advantage of a multimodal imaging approach combining an integrated single-photon emission microscope (SPEM) and magnetic resonance system that utilizes the inverted compound eye camera to track NSCs in the brain with high sensitivity and resolution. We hypothesize that this multimodal imaging platform will generate well-validated pre-clinical data necessary for successfully applying therapeutic NSCs to treat BM of breast cancer. The nanoparticle-based approach developed in our laboratory will be utilized for cell labeling with imaging agents. Three interrelated aims are designed to cover the scope of proposed studies. Specific Aim 1 will optimize SPEM/MR imaging for in vivo tracking of NSCs within the brain parenchyma. Specific Aim 2 will investigate the migration of NSCs within the brain of mice bearing BM using a multimodal imaging approach. Finally, Specific Aim 3 will investigate the influence of whole-brain irradiation on the distribution of NSCs within the brain of mice bearing BM. This system will provide an ultra-sensitive, non-invasive imaging platform for tracking NSCs in the pre-clinical model of BM of breast cancer and can be widely applied for imaging stem cell behavior in the context of other brain malignancies and solid tumors.
