Inhibition of Brain Tumor Stem Cell Tumorigenicity using Self-assembling Nanogels

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DESCRIPTION (provided by applicant): Glioblastoma is the most common brain tumor in adults and carries a poor prognosis, due in part to a propensity for tumor recurrence despite aggressive treatment strategies. Such relapse may be due to the persistence of brain tumor stem cells (BTSCs), a small subset of glioma cells with stem-like characteristics that have recently been proposed to underlie tumor initiation and progression. It is likely that modulation of pathways normally involved in neural stem cell (NSC) differentiation will be of clinical relevance in the targeting of these cells. Activation of betal-integrin after binding of the laminin-derived epitope IKVAV is one such pathway of particular interest, as it has been shown to promote neuronal differentiation as well as inhibit tumorigenesis. Furthermore, the use of self-assembling peptide amphiphile (PA) nanogels as a vehicle as described in this proposal would maximize the density of epitope presentation in addition to providing a novel method of drug delivery unparalleled by current tools. The enclosed aims will comprehensively evaluate the potential differentiation induction and anti-tumorigenic effect of the IKVAV PA on BTSCs, both in vitro as well as in xenograft models. In addition, the mechanisms underlying this effect, such as signaling via betal-integrin, will be investigated. These studies will further our current understanding of brain tumor stem cells and stand to significantly contribute to the application of nanotechnology to the treatment of glioblastoma. PUBLIC HEALTH RELEVANCE: Current treatments for the most malignant primary brain tumor (glioblastoma) are woefully inadequate, and the average survival is just over one year. The proposed research aims to develop more effective therapies for this devastating disease by targeting the cells responsible for tumor relapse using nanotechnology. If successful, this work stands to significantly improve the care of glioblastoma patients.