Have we considered all barriers to mammalian target of rapamycin inhibition as treatment for diffuse intrinsic pontine glioma?

Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal primary pediatric brain tumor (1,2). Surgical resection is impossible due to its location in the brainstem and invasive nature. Radiotherapy provides just a minor incremental extension in overall survival, whereas chemotherapy is largely ineffective (3-5). There is thus a high unmet need for better therapies. Importantly, several recent studies have characterized the genomic landscape of DIPG, revealing common genetic alterations in ACVR1, histone H3, ATRX and TP53 (6-9). Unfortunately, these are mostly not yet appreciable druggable targets. Next to these alterations, a fraction of DIPGs is characterized by increased receptor tyrosine kinase-RAS-PI3K-AKT signaling, e.g., as a result of AKT gain or phosphatase and tensin homolog (PTEN) loss, making this pathway a potentially attractive target for therapy (10,11). Researchers from the lab of Dr. Raabe at Johns Hopkins University School of Medicine in Baltimore have therefore investigated targeting the PI3K-AKT-mTOR pathway as a potential therapeutic strategy for DIPG. In a recent study in Cancer Letters, Miyahara and colleagues demonstrate that the mammalian target of rapamycin complex 1 and 2 (mTORC1/2) inhibitor TAK228 (INK128, sapanisertib) delayed tumor formation of an orthotopic murine model of DIPG (12) and conclude that mTOR inhibition may be a promising therapeutic strategy for treatment of DIPG