A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy

Abstract

Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade’s complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance.

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

“…Further studies of ribociclib in combination with other active agents in patients with MRT and neuroblastoma are ongoing, such as the AcS e-ESMART multi-arm trial (NCT02813135), which includes ribociclib in combination with everolimus (a PI3K/ AKT/mTOR pathway inhibitor) or chemotherapy in patients prescreened for specific molecular alterations. The combination with everolimus was based on the observation that the PI3K/AKT/ mTOR pathway, for example, via MYCN, ALK, or RAS activation, may be implicated in the pathogenesis of neuroblastoma and MRT (30,31). Other ribociclib-based combinations with other targeted therapies, such as MAPK/ERK inhibitors, may be considered in future trials.…”

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[109] Therefore, new therapeutic approaches should be based on increasing the therapeutic window by targeting two different routes, namely the PAM and ERK pathways, or on combining PAM inhibitors with chemotherapeutic agents. [110] MicroRNAs have also been shown to play an important role in various CNS malignancies, and miR-142-5p and miR-25 are upregulated in all of them. [111] In MB, miR-21 suppression inhibited tumor migration.…”

Individualized therapy in neuroblastoma

“…Более того, патологический путь RAS/ MAPK играет важную роль в росте опухоли, в частности при рецидиве НБ [17, 70,71]. Лечение с использованием выбранных ингибиторов, завершающих элементов па-тологического пути, расценивается как многообещаю-щий подход в контексте таргетной терапии [70,[72][73][74][75][76][77]. Однако клинические данные по данному виду терапии, в частности в комбинации с ХТ, в настоящее время крайне ограничены [78,79].…”