Diffuse intrinsic pontine gliomas: the future of combination therapy with mTORC1/2 inhibitors and radiation

DIPGs, even though rare in adults, account for 10 percent of all childhood central nervous system tumors and comprise 75–80% of brainstem tumors in children. While DIPGs are usually diagnosed when children are between the ages of 5 and 9, they can occur at any age in childhood. These tumors are currently the number one cause of brain tumor related death in children, being the median survival only 9 months post-diagnosis and with a survival rate of less than 1% in 5 years (1). DIPGs are highly aggressive and difficult to treat. They diffusely involve the pons and due to the location, the surgical intervention is not a therapeutic option thus currently, palliative radiation therapy is the standard treatment. In the past decades, over 250 clinical trials have been performed using different adjuvant chemotherapy, but there has not been any improvement in patient survival when compared to radiotherapy alone and therefore the treatment has not changed for decades (1). It is urgent to improve current therapies to reduce the mortality rate of this tumor, and the first approach may be to sensitize the tumor to the radiotherapy, making it more effective. Biological information has been missing for a long period of time, since biopsies were considered too risky for the patient’s survival and the histopathological analysis did not improve the prognosis or the therapeutic approach. After demonstrating the safety of the stereotactic surgery and together with the samples from the autopsies, a sufficient number of samples have been collected and analyzed to obtain extensive genomic profiling. This has provided important molecular information on this tumor. Among the different alterations, mutations in Histone 3 (H3K27M), mutations in TP53 and different genomic alterations such as gain of AKT and loss of PTEN have been described (2-4). In fact, the PI3K/AKT/mTOR signaling pathway has been shown to be aberrantly active in 70% of DIPGs (4)