Clinically Relevant Brain Tumor Model and Device Development for Experimental Therapeutics

Abstract

This paper assesses the subcutaneous, orthotopic, and transgenic mouse models used to study glioblastomas (GBMs) as well as delineates our model to overcome the limitations of these currently used models. Subcutaneous model involves the injection of GBM cells into hind leg or back of a mouse, whereas in orthotopic model, the injection of GBM cells into the cranium of mice is required. Neither subcutaneous nor orthotopic models accurately display the infiltrative growth pattern of the tumor into the brain parenchyma characteristic of GBMs in humans. Transgenic models are achieved by pronuclear microinjection (into the male pronucleus, immediately after fertilization) or the injection of DNA into embryonic stem cells. Transgenic models are similar to human GBMs in every way, except they are not as genetically complex. To overcome the limitations in these models, we have developed a brain tumor model that exhibits all the histologic hallmarks of human GBM. We used a flank model initially to enrich a tumorigenic population of GBM cells from patient biopsies and a subsequent intracranial implantation to achieve the characteristics of tumors similar to those observed in human patients. The cells enriched by this method were then implanted and subjected to standard treatments such as chemotheraphy and radiation. Subsequently, we determined the treatment efficacy and rate of recurrence. Currently, we are using this approach to determine the treatment resistance pathways leading to recurrence and for developing a better combinatorial approach by short-circuiting the aberrant signaling pathways that are up-regulated in the treatment resistance tumors.