Glioblastoma (GBM) is the most common primary brain tumor and even with surgical resection, radiation, and chemotherapy, recurrence and mortality is almost 100%. This is due in part to the cancer?s tentacle like projections that make complete surgical removal difficult. Neural stem cells can be genetically engineered to secrete tumoricidal agents. These tumoricidal neural stem cells (tNSC) have the ability to ?home? to distant GBM deposits in the brain and have been shown to significantly reduce the growth of solid and invasive human GBM xenografts. Unfortunately, as a monotherapy, tNSCs have faltered due to drug resistance and tumor heterogeneity. Combination therapies have been shown to overcome these challenges. To avoid the blood- brain barrier and therefore dose-limiting toxicities of systemically administered drugs, therapeutics administered directly into the brain after GBM resection is ideal. This can be achieved by loading drug into a biodegradable polymer allowing for controlled temporal release of drug locally as the polymer degrades. A clinical example of this is Gliadel, a biodegradable polymeric wafer that delivers carmustine into the resection cavity. However, due to its poor drug release profile and the insufficient tumoricidal activity of carmustine, Gliadel has not resulted in significantly improved patient outcomes. Recent advancement in the genomic landscape of cancer allows for more efficacious drugs to be utilized, leading to personalized chemotherapeutic selection. Additionally, alternative polymers with more optimal drug release can be applied. The most commonly used biodegradable polymers, such as polyesters, have slow and fixed degradation rates on the order of months or years. This slow degradation results in drug release rates that are too slow to achieve or maintain a therapeutic dose. Alternative biomaterials with improved degradation kinetics can be explored. For facile placement in the brain, biopolymers can be electrospun with drug into a flexible and nanofibrous scaffold. It is hypothesized that drug-loaded biopolymer scaffolds will have ideal drug release properties that when delivered concomitantly with tNSC therapy will overcome resistance mechanisms and reduce the recurrence of GBM.
Glioblastoma is a devastating disease with limited therapeutic options due to tumor location, heterogeneity and drug resistance. This project proposes that combination therapy administered locally can overcome these challenges and lead to improved outcomes.
