The Combination of Novel Targeted Molecular Agents and Radiation in the Treatment of Pediatric Gliomas

Abstract

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.

Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors

“…BRAF inhibitors targeted to the mutant V600E protein have shown efficacy in inhibition of mutant cells in vitro (34) and in murine xenografts (33). Phase I trials for BRAF V600E inhibition are currently under way (83). Conversely, Sievert et al (35) showed that cells expressing KIAA1549-BRAF are resistant to vemurafenib (PLX4032; Plexxikon, Berkeley, CA), a small molecule inhibitor of BRAF V600E.…”

Pediatric Brain Tumors

“…Targeted inhibitors with radiation are currently under investigation. 47 Aggressive surgery, if possible, has been associated with better survival of high-grade gliomas, although it is not clear whether this is owing to surgery alone or biological differences between tumors that can be ''totally'' resected and those that cannot. In the Children's Cancer Group (CCG) 945 clinical trial, children with high-grade glioma who underwent gross total resection had 5-year progression-free survival of 35%, compared to 17% for patients with subtotal resection.…”

Molecular characteristics of pediatric high-grade gliomas

“…The serine/threonine kinase BRAF is a member of the RAS/RAF/MEK/ERK kinase pathway, which plays a key role in cellular division, survival and metabolism [53]. A missense mutation at amino acid position 600 of BRAF ( BRAF V600E ) leads to overactivation of the gene and, consequently, uncontrolled cell proliferation.…”

“…A missense mutation at amino acid position 600 of BRAF ( BRAF V600E ) leads to overactivation of the gene and, consequently, uncontrolled cell proliferation. BRAF V600E was initially associated with melanoma and medullary thyroid carcinoma but later found in several types of low- and high-grade glial brain tumors [53–55]. Among the low-grade gliomas in children, BRAF V600E was most frequently detected in pleomorphic xanthoastrocytomas (66%), followed by gangliogliomas (18%) and pilocytic astrocytoma (9%) [55].…”