Benefits, limitations and opportunities of NOTCH inhibitors for treatment of glioma

High grade gliomas are associated with worse prognosis and treatment failure. In glioma, the anti-tumor effect of Notch inhibition in combination with the standard care of treatment has been shown in vitro and in pre-clinical research. Now, a phase 0/1 trial by Xu et al., evaluated for the first time the efficacy of a previously available NOTCH inhibitor (RO4929097) in combination with standard treatment consisting of radiation therapy (RT) with daily temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma (GBM) or anaplastic astrocytoma (AA). Quite impressively the authors also studied the in vivo pharmacokinetics of RO4929097 and tumor perfusion in glioma prior to RT + TMZ and in resections using contrast-enhanced MRI and noted tumor progression in several patients during treatment. However, defining disease progression versus pseudoprogression (psPD) as a result of therapy-induced alteration of blood-brain-barrier (BBB) can be difficult. While sufficient drug target inhibition was achieved in the initial tumor, recurrence occurred. Surprisingly, recurrent tumors exhibited increased expression of angiogenesis markers despite low NOTCH activity contrasting the pro-angiogenic role of NOTCH. While the authors concluded a NOTCH-independent form of angiogenesis, it is possible that therapy-induced inflammation and necrosis resulted into break down of the BBB causing the upregulation of pro-angiogenic markers. Given the disappointing outcome of the sustained NOTCH inhibition, their effect could potentially be enhanced when used in conjunction with angiogenesis inhibitors. Importantly, in this study it was not stated if GBM tumors originated de novo (primary) or progressed from low grade glioma (secondary). This is crucial due to their different cell of origin and molecular profile, which can lead to different treatment response and outcome. Further investigating different scheduling to allow normal tissue recovery, optimizing the sequence of multimodal treatments, combined with patient selection and monitoring seems necessary to move NOTCH therapeutics forward.