Overcoming Resistance to BRAF-targeted Therapies in Low Grade Gliomas
As with high-grade tumors, treatment of low grade gliomas is complicated by inherent and acquired resistance mechanism. Standard chemotherapy, while initially producing stable disease and, less often response, has a high rate of failure in low grade tumors of the brain except in children with neurofibromatosis (Ater et al, 2012; Raabe et al, 2013). The V600E BRAF and FGFR1 mutations may impart inherent resistance to standard chemotherapy and radiotherapy although further study is needed. (Donson et al, Becker et al). Deletion or silencing of the p16INK4a locus may allow the most aggressive pediatric low grade gliomas to bypass the oncogene-induced senescence seen in high-level activation of the MAPK/ERK kinase pathway.(Horbinski et al 2012; Raabe et al, 2011). Stem-lie cells have been identified in low grade gliomas of childhood and may play a role in the remitting and relapsing course seen in many of these tumors. (Gong et al, 2011). However molecular characterization of a large series of relapsed low grade gliomas is lacking and understanding of the mechanism of resistance to standard therapies is limited. Moreover, unlike in most tumors, relapse after a standard chemotherapy does not necessarily mean the tumor is resistant and it may respond to the same therapy. (Raabe et al, 2013) Understanding of this disconnect between relapse/progression and resistance is essential if we are not to subject a number of children to round after round of therapy.
Perhaps the most worrying of all resistance mechanisms to novel therapies in low grade gliomas is paradoxical ERK activation. Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to this paradoxical ERK activation. (Karajannis et al, 2014).
Our team at Children’s spearheaded by Dr Mulcahy-Levy has identified a resistance mechanism, known as autophagy which is a normal biological process that functions to help cell survive in high stress conditions, in BRAF mutated gliomas that can be therapeutically targeted. Our results provide proof of concept for a fundamentally different way to circumvent resistance mechanisms in BRAF mutant gliomas and suggest a strategy for improved treatment of a large proportion of children’s brain tumors that could be rapidly tested in clinical trials. A publication based on this study, funded in part by the Olivia Caldwell Foundation, is currently in preparation.
Perhaps the most worrying of all resistance mechanisms to novel therapies in low grade gliomas is paradoxical ERK activation. Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to this paradoxical ERK activation. (Karajannis et al, 2014).
Our team at Children’s spearheaded by Dr Mulcahy-Levy has identified a resistance mechanism, known as autophagy which is a normal biological process that functions to help cell survive in high stress conditions, in BRAF mutated gliomas that can be therapeutically targeted. Our results provide proof of concept for a fundamentally different way to circumvent resistance mechanisms in BRAF mutant gliomas and suggest a strategy for improved treatment of a large proportion of children’s brain tumors that could be rapidly tested in clinical trials. A publication based on this study, funded in part by the Olivia Caldwell Foundation, is currently in preparation.