Monday April 20, 2015   
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Led by Xandra Breakefield, PhD at Harvard University

Brain tumors remain a challenge for treatment with the current standard of care – surgery,
radiation and chemotherapy frequently only temporarily halting the tumor surge and sometimes having a high level of co-morbidity. New types of therapy need to be developed which will have sustained long-term effects and reduced toxicity to normal cells. Recent discoveries reveal that tumor and normal cells release extracellular membrane vesicles containing bioactive molecules into the extracellular space which are avidly taken up by surrounding cells. This project will focus on harnessing these vesicles by developing methods to load them with therapeutic mRNA/protein and to have them be continuously released within the tumor by interdigitated microglia and/or by the tumor cells themselves. Initial studies will focus on deliver of an activating enzyme for a precursor chemotherapeutic agent that can cross the blood-brain barrier and when activated selectively kill dividing tumor cells. Thus, the tumor cells and/or microglia intimately associated with them will provide a “production facility” for vector-like vesicles which
will infiltrate into the tumor core and invasive surrounds. These vesicles will deliver an enzyme that can convert the precursor delivered systemically to an active chemotherapeutic agent locally within the tumor and its environs, killing tumor cells over an extended area. It is envisioned that a single rounds of drug activation will spare some non-dividing tumor cells, as well as associated microglia, so that these surviving cells will continue to deliver these therapeutic vesicles, thus allowing later drug treatment to continue to be effective. In this scenario the tumor can be genetically modified “to be its own worst enemy” capable of delivering an infectious-like agent to surrounding tumor cells that can ultimately be filled with multiple therapeutic biomolecules.

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