Tumor Treating Fields remain effective in therapy-resistant glioblastoma with kinome shifts revealing novel therapeutic opportunities

Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of less than 15 months with maximal safe surgical resection, radiation, and the chemotherapy temozolomide. Addition of Tumor Treating Fields (TTFields), or alternating electromagnet fields therapy, to temozolomide was shown to extend the survival of GBM patients by approximately 4.9 months. TTFields disrupt mitosis to inhibit cell growth, but we also determined that TTFields alter the cellular kinome. Using a PamStation, we identified kinases that are predicted to be activated and repressed by TTFields treatment in newly diagnosed and recurrent GBM models that are sensitive or resistant to temozolomide or irradiation, respectively. While the growth of all GBM cells tested was significantly decreased by TTFields, there was a relatively limited set of kinases that were commonly altered in newly diagnosed and temozolomide-resistant GBM cells with little similarly across irradiation resistant GBMs. These kinase data are reminiscent of published data demonstrating kinome variability in radioresistant GBM xenografts. We did find that TTFields were predicted to activate PDGFRalpha in both newly diagnosed and temozolomide-resistant GBM cells: when combined with TTFields, a blood brain barrier penetrant PDGFR inhibitor, crenolanib, significantly decreased GBM cell growth. Subsequent studies have identified additional kinases to be evaluated in combination with TTFields in radioresistant GBM cells. Using the Novocure inovivo system, we plan to test these novel kinase inhibitor combinations with TTFields in mouse models bearing intracranial GBMs. We hope to identify a kinase inhibitor based treatment strategy that can be translated to the clinic to further improve TTFields mediated increases in patient survival.