Brain tumors are the most common solid pediatric
malignancy. For high-grade, recurrent, or refractory pediatric
brain tumors,
radiation therapy (XRT) is an integral treatment modality. In the era of personalized
cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to
tumorigenesis. Our evolving knowledge of genetic aberrations in pediatric
gliomas is being exploited with the use of specific targeted inhibitors. These agents are additionally being combined with XRT to increase the efficacy and duration of local control. In this review, we discuss novel agents targeting three different pathways in
gliomas, and their potential combination with XRT. BRAF is a
serine/threonine kinase in the RAS/RAF/
MAPK kinase pathway, which is integral to cellular division, survival, and metabolism. Two-thirds of
pilocytic astrocytomas, a low-grade pediatric
glioma, contain a translocation within the BRAF gene called KIAA1549:BRAF that causes an overactivation of the
MEK/MAPK signaling cascade. In vitro and in vivo data support the use of
MEK or
mammalian target of rapamycin (
mTOR) inhibitors in low-grade
gliomas expressing this translocation. Additionally, 15-20% of high-grade pediatric
gliomas express BRAF V600E, an activating mutation of the BRAF gene. Pre-clinical in vivo and in vitro data in BRAF V600E
gliomas demonstrate dramatic cooperation between XRT and small molecule inhibitors of BRAF V600E. Another major signaling cascade that plays a role in pediatric
glioma pathogenesis is the
PI3-kinase (PI3K)/mTOR pathway, known to be upregulated in the majority of high- and low-grade pediatric
gliomas. Dual PI3K/
mTOR inhibitors are in clinical trials for adult high-grade
gliomas and are poised to enter studies of pediatric
tumors. Finally, many
brain tumors express potent stimulators of angiogenesis that render them refractory to treatment. An analog of
thalidomide, CC-5103 increases the secretion of critical
cytokines of the tumor microenvironment, including
IL-2, IFN-γ, TNF-α, and
IL-10, and is currently being evaluated in clinical trials for the treatment of recurrent or refractory pediatric
central nervous system tumors. In summary, several targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. This review article summarizes the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-
cancer agents and XRT in pediatric
gliomas. In many cases, parallels are drawn to molecular mechanisms and targeted inhibitors of adult
gliomas. We additionally discuss the potential mechanisms underlying the efficacy of these agents.