(507f) Predicting Progression-Free Survival and Recurrence Time of Primary Glioblastoma Using a Microfluidic Invasion Network Device

Authors: 
Wong, B. S., Johns Hopkins University
Yankaskas, C. L., Johns Hopkins University
Konstantopoulos, K., Johns Hopkins University
Shah, S. R., Johns Hopkins University
Quiñones-Hinojosa, A., Mayo Clinic
Glioblastoma (GBM) is the most common and aggressive form of primary brain cancer in adults, accounting for about 15-20% of all brain malignancies. Owing to their highly proliferative and infiltrative nature, GBMs are capable of invading surrounding brain parenchyma and spreading to the contralateral hemisphere through the corpus callosum, thus confounding local therapy and rendering gross total resection nearly impossible. As a result, despite aggressive radical surgical resection coupled with concurrent chemo- and radio- therapy, GBMs remain incurable and recur frequently with a median patient survival on only approximately 14.6 months.

While traditional genetic and proteomic characterizations have contributed considerably to personalized GBM care, these techniques unfortunately suffer from the inability to discern inter- and intra- tumor heterogeneity and accurately predict complex cellular phenotypic behaviors resulting from an amalgamation of multiple genetic alterations. The heterogeneous and complex nature of GBMs therefore necessitate the development of more direct, faster, inexpensive, high throughput and unbiased in vitro testing platform for GBM prognosis at single cell resolution capable of dissecting the heterogeneity among the cancer cells derived from individual patients.

Here, we developed and fabricated a novel and proprietary in vitro testing platform, Microfluidic Invasion Network Device (MIND) from polydimethylsiloxane with standard photolithography and replica molding techniques. MIND consists of microchannels of defined dimensions aiming to recapitulate aspects of the complex topography and confining longitudinal pores or perivascular tracks of the brain parenchyma formed between glial cells and the basement membrane of vascular smooth muscle cells. A panel of 22 patient-derived primary GBM specimens was screened in MIND in a blind manner. We evaluated the ability of GBM cells to navigate and squeeze through confined microchannels, as well as the proliferative capacity of these highly motile subpopulations. By combining migratory- and proliferative-based indices, MIND predicts individual patient progression-free survival (p=0.008) and time to recurrence (p=0.006) retrospectively with high sensitivity (85%), specificity (89%), and accuracy (86%). Furthermore, in a pilot prospective study, MIND classified all patients accurately based on their survival outcomes.

Overall, our study reveals that invasive growth is intimately associated with disease progression and overall patient outcomes. By quantitatively evaluating both migratory and proliferative behaviors of patient-derived primary GBM cells in a physiologically relevant confining microenvironment that mimics the natural invasive routes of native GBM cells, MIND can precisely determine prognosis in a patient-specific manner both retrospectively and prospectively. We believe that this in vitro testing platform will provide a useful prognostic tool that can be translated into the clinics to improve personalized management of GBM patients.