Glioblastoma multiforme (GBM) is the most advanced and invasive form of brain tumor. Various issues reduce long-term survival, the most common being recurrence even after treatment. GBM invasion and metastasis (dispersal) require the degradation of extracellular matrix (ECM) which is mediated, in part, by matrix metalloproteases (MMP). Since MMP inhibition has not been shown to be clinically effective despite MMPs being shown to be greatly overactive particularly in metastatic disease, a more function-related approach is needed to exploit this therapeutic target. We will investigate a novel method of utilizing MMP expression to understand and treat GBM and other invasive brain tumors. The rationale for this study is to target MMP specificity thereby activating chemotherapeutics in a manner similar to traditional prodrugs;however, unlike traditional prodrugs, activation will take place from a polymeric device. MMP-sensitive substrates (peptides) will be incorporated into hydrogels to allow activation of chemotherapeutics and biodegradation in the presence of MMPs. Cleavage of the peptide by MMPs will release and activate the drug from the hydrogel. With this rationale and goals in mind, we have based our novel intervention on the general hypothesis that extracellular proteases can enter a hydrogel matrix and activate pendant chemotherapeutic agents.
Five specific aims have been established to investigate this hypothesis: (1) to optimize MMP-sensitivity;(2) to optimize hydrogel parameters;(3) to determine soluble MMP activity within hydrogels;(4) to determine cell association and activity;and (5) to examine glioma cell invasion within the hydrogels. Consistent with the Program Announcement to which this application was submitted (PAS-04- 079), this proposal describes an innovative approach to understanding and treating brain tumor dispersal. This work will develop a therapy targeted to the tumor's dispersive signals, specifically the invasive nature of the disease. The proposed hypothesis and specific aims are specifically designed to 1) address the localization of MMP activity during invasive behavior of brain tumor, 2) to develop a new tool for fighting this disease, and (3) to develop a new tool for examining tumor cell invasion.
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