Therapeutic Targets in Pilocytic Astrocytoma Based on Genetic Analysis

摘要

Pilocytic astrocytoma (PA) is the most common astrocytic neoplasm of childhood. Patients have an extremely favorable prognosis after surgical resection, qualifying tumors for a grade I designation by the World Health Organization. The molecular data on PA support a key role for the BRAF oncogene in the pathogenesis of these tumors, with the KIAA1549-BRAF fusion being the most common alteration identified in sporadic cases, particularly those occurring in the posterior fossa. Constitutive activation of BRAF leads to downstream activation of the MEK/MAPK/ERK/p16 pathway, which interestingly is also used by cells to activate oncogene-induced senescence (OIS). In fact, the presence of an active OIS pathway might explain the periods of dormancy or spontaneous regression or both, that can be seen in PA. In addition to reviewing the historical evolution, clinicopathologic, predictive, prognostic, and molecular features of PA, we discuss current therapeutic strategies and the caveats that should be considered for the development of therapies that could be used to more effectively treat challenging cases. Individualized treatment requires identification of the type of MAPK alteration, as several alterations in BRAF have been described in addition to the KIAA1549-BRAF fusion. Combination regimens would also appear crucial to achieve tumor eradication and prevent the development of drug resistance. Balancing mitogen-activated protein kinases (MAPK) pathway inhibition with abrogation of an active OIS should be carefully considered as well to preserve any existing protective pathways. Importantly, PAs are largely indolent tumors, and care should be taken to avoid overtreatment, as aggressive therapy could cause more harm than good. (C) 2015 Elsevier Inc. All rights reserved.