Glioblastoma Multiforme (GBM) are aggressive brain tumors with poor prognosis. Therapeutic management for GBM is currently limited; with Temozolomide currently being the standard of treatment for GBM. However, even when combined with radiotherapy only up to 20 percent of patients show a favorable response to Temozolomide. Importantly, due to their requirements for potency and efficacy, oncology drugs can be quite toxic. In this study, the U87 GBM cell line was tagged with mCherry to serve as a traceable model for GBM. To study their growth behavior in a physiologically relevant system amenable to drug discovery, U87-mCherry cells were co-cultured with human induced pluripotent stem cell-derived cortical neurospheroids in a high throughput based screening platform. The neurospheroids are composed of a balanced co-culture of cortical neurons and astrocytes with mature functional neuronal circuitry evidenced by spontaneous calcium oscillations. Previously, the model has been successfully utilized in independent neurotoxicity and drug discovery studies. Thus, by combining U87-mCherry and the high throughput neurospheroids, the proliferation and infiltration patterns of the GBM cells, as well as the preservation of cortical functionality, can be analyzed within the same high throughput platform. Proof-of-principle studies focused on Temozolomide, Carmustin, Paclitaxel and Cisplatin to identify and profile compound efficacy versus its toxicity with the ultimate goal of providing a platform that can separate safe and effective compounds from those that have minimal efficacy and deleterious toxicity. In summary, the work described herein suggests a novel framework approach for combining human induced pluripotent stem cell-derived cortical neurospheres with GBM, enabling more streamlined drug discovery of compounds against aggressive brain cancers.