INTRAARTERIAL DELIVERY TO THE GLIOMA STEM CELL NICHE
Led by John Boockvar, MD at Cornell Universit
Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, currently has ineffective treatment strategies as evidenced by median survival rates of 12 to 15 months. Treatment resistance develops both after first line therapy with surgery and chemoradiation and after second line therapy with monoclonal antibodies such as bevacizumab and cetuximab. Glioma stem-like cells (GSCs), which reside in a tightly controlled microenvironmental niche, are believed to be responsible for GBM recurrence and therapy resistance. However, little is known about how effectively systemic drug delivery, the current standard of care delivery, penetrates the GSC niche, especially given the blood-brain barrier (BBB). We will utilize a novel strategy for eradicating the GBM GSC population by delivering bevacizumab and cetuximab intra-arterially (IA) in conjunction with two distinct methods of BBB disruption (BBBD): pharmacological disruption with mannitol and mechanical disruption with MRI-guided focused ultrasound (MRgFUS). We believe that IA drug delivery allows for highly selective delivery of a high drug dose into the tumor to effectively reach and disrupt the niche, make GSCs more vulnerable and eventually deplete the GSC pool in these lethal tumors.
GSCs from patient GBMs will be isolated and injected into a well-established rodent xenograft model to assess the impact of IA bevacizumab and cetuximab along with BBBD on GSC biology as well as progression-free and overall survival. Data from these studies could inform us about the role of GSCs on treatment resistance and quickly lead to human clinical trials combining IA drug delivery techniques with novel pharmacological or mechanical BBBD techniques such as MRgFUS. This could potentially change current treatment paradigms in individuals with GBM.
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