Project Funding Details

With a 5-year survival rate of only 5%, glioblastoma (GBM) has the poorest prognosis among cancers. Targeted therapies, immunotherapy, image-guided surgery and radiotherapy have not improved survival, largely due to GBM's biological heterogeneity and impermeable blood brain barrier (BBB). The most common intervention remains maximal safe resection of the malignant mass followed by adjuvant radiochemotherapy. Recent data have highlighted the role of tumor cell connectivity in feeding biological diversity, protecting the cancer stem cell niche, repopulating areas of surgical resection, and evading molecular therapies. Several authors have demonstrated that inhibiting the gap-junction connexin 43 (Cx43) and neuronal growth-associated protein 43 (GAP-43) facilitates the isolation of GBM cells and synergies with radiochemotherapy. However, poor bioavailability and insufficient brain penetrance have hindered the development of multitargeted therapies combining Cx43 and GAP-43 inhibitors with potent chemotherapeutic molecules. Given the confinement of the malignant GBM mass within a 'closed' environment - the central nervous system, it is hypothesized that intracranial drug delivery systems can be designed, developed, and tested for the sustained delivery of potent chemotherapeutic agents and 'disconnecting agents' inhibiting Cx43 and GAP-43. Moreover, it is hypothesized that the vicious GBM intercellular network can be disrupted by locally delivering small inhibitors of intercellular gap-junctions (meclofenamate - MFA) and lipid nanoparticles carrying siRNA for Cx43 and GAP-43. The combination of 'disconnecting agents' and potent chemotherapeutic drugs - docetaxel (DTXL) - is expected to first isolate the tumor cells and then eradicate them, ultimately, eliminating the malignancy. GlioERASE will be articulated around 3 major objectives: i. develop an intracranial biodegradable and flexible implant (microGRID) for the sustained delivery of small molecules and siRNA-loaded lipid nanoparticles; ii. determine the optimal combination of DTXL and disconnecting agents with the lowest neurotoxicity and highest cancer cell killing efficacy; iii. validate the safety and therapeutic efficacy of microGRID in preclinical models of GBM. Over 5 years, an interdisciplinary team of bioengineers, biotechnologists, pharmaceutical scientists, and cancer biologists, with the external guidance of neurosurgeons and neurooncologists, will address the above 3 aims. First, soft lithography and microscopy techniques will be used to generate and characterize a library of microGRID with different geometrical and material features. The implant configuration with optimal drug release and tissue integration will be selected. Second, employing co-cultures of patient-derived GBM stem cells and healthy brain cells, the therapeutic combination with the lowest neurotoxicity and highest potential in disconnecting and killing the tumor cells will be selected. Finally, a microGRID integrating the selected combination therapy will be validated in orthotopic GBM models assessing disease progression via bioluminescence and magnetic resonance imaging and comparing survival across the different treatment groups. Preclinical toxicological studies will conclude the microGRID validation process. Identification of the best microGRID configuration and therapeutic combination for the successful treatment of GBM. GlioERASE will elucidate the role of intercellular network in cancer resistance and validate a novel therapeutic approach against GBM.