Molecular Neurotherapy and Imaging
Successful treatment of brain tumors remains one of the greatest challenges in oncology. The recognition that different stem cell types, including mesenchymal and neural stem cells, can integrate appropriately throughout the mammalian brain following transplantation has unveiled new possibilities for their use in neural transplantation. Our laboratory has shown that different stem cell types home to sites of cerebral pathology and thus can be armed with therapeutic transgenes, a strategy that can be used to inhibit tumor growth by targeting angiogenesis or selectively inducing apoptosis in proliferating tumor cells in the brain.
Our research is based on developing clinically translatable models of both primary and metastatic brain tumors, and stem cell based therapeutics that simultaneously target cell death and proliferation pathways in an effort to eradicate brain tumors. We have engineered different stem cells types (i) to secrete therapeutic protein, S-TRAIL (secreted tumor necrosis factor receptor-apoptosis inducing ligand) to specifically induce apoptosis in tumor cells and (ii) anti-angiogenic TSP-1 (thrombospondin-1) to inhibit tumor angiogenesis. These stem cells are then used to populate primary tumors and their secondary micro-invasive deposits in the brain. Recently, our laboratory has also focused on targeting tumors that are resistant to TRAIL and different oncolytic viruses. Resultantly, we have developed stem cell deliverable bi-modal therapeutic molecules, such as EGFR targeting nanobody (ENb)-TRAIL and oncolytic herpes virus (oHSV) bearing TRAIL (oHSV-TRAIL), and shown their efficacy in mouse models of aggressive and invasive brain tumors. Inherently linked to the brain tumor therapy paradigm are imaging techniques, thus we employ fluorescent/bioluminescent imaging markers and optical imaging techniques to track stem cells, image apoptosis and changes in tumor volumes in real time in vivo. We also explore the use of microRNA inhibitors to target brain tumor specific microRNAs; and the combination of clinically approved drugs, microRNA inhibitors and shRNAs with therapeutic stem cells in a variety of brain tumor models.
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