Skip to main content
Top
Published in: Current Neurology and Neuroscience Reports 4/2014

01-04-2014 | Neuro-Oncology (LE Abrey, Section Editor)

Targeted Therapy in Pediatric Low-Grade Glioma

Authors: John-Paul Kilday, Ute Katharina Bartels, Eric Bouffet

Published in: Current Neurology and Neuroscience Reports | Issue 4/2014

Login to get access

Abstract

Collectively, pediatric low-grade gliomas account for most brain tumors reported in children. Surgery is typically curable for operable lesions. However, more effective therapies are required for inaccessible tumors, both to overcome refractory disease and to minimize the toxicity associated with conventional adjuvant chemotherapy and radiotherapy regimens. Recent years have witnessed rapid improvements in our understanding of the molecular pathogenesis of several childhood tumors, including low-grade gliomas. As a result, several novel compounds targeting and inhibiting critical components of molecular signaling pathways purported to be overactive in the disease have been developed. This article summarizes the most recent literature evaluating such novel targeted agents in childhood low-grade gliomas.
Literature
1.
go back to reference Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002;61:215–25. discussion 226-9.PubMed Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002;61:215–25. discussion 226-9.PubMed
2.
go back to reference Gnekow AK, Packer RJ, Kortmann RD. Astrocytic tumors, low-grade: general considerations. In: Walker DA, Perilongo G, Punt JAG, Taylor RE, editors. Brain and spinal tumors of childhood. London: Arnold; 2004. p. 245–55.CrossRef Gnekow AK, Packer RJ, Kortmann RD. Astrocytic tumors, low-grade: general considerations. In: Walker DA, Perilongo G, Punt JAG, Taylor RE, editors. Brain and spinal tumors of childhood. London: Arnold; 2004. p. 245–55.CrossRef
3.
4.
go back to reference Gnekow AK, Falkenstein F, von Hornstein S, et al. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol. 2012;14:1265–84.PubMedCentralPubMedCrossRef Gnekow AK, Falkenstein F, von Hornstein S, et al. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol. 2012;14:1265–84.PubMedCentralPubMedCrossRef
5.
go back to reference Wisoff JH, Sanford RA, Heier LA, et al. Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery. 2011;68:1548–54. discussion 1554-5.PubMedCrossRef Wisoff JH, Sanford RA, Heier LA, et al. Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery. 2011;68:1548–54. discussion 1554-5.PubMedCrossRef
6.
go back to reference Fisher PG, Tihan T, Goldthwaite PT, et al. Outcome analysis of childhood low-grade astrocytomas. Pediatr Blood Cancer. 2008;51:245–50.PubMedCrossRef Fisher PG, Tihan T, Goldthwaite PT, et al. Outcome analysis of childhood low-grade astrocytomas. Pediatr Blood Cancer. 2008;51:245–50.PubMedCrossRef
7.
8.
go back to reference Grill J, Couanet D, Cappelli C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol. 1999;45:393–6.PubMedCrossRef Grill J, Couanet D, Cappelli C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol. 1999;45:393–6.PubMedCrossRef
9.
go back to reference Taphoorn MJ, Schiphorst AK, Snoek FJ, et al. Cognitive functions and quality of life in patients with low-grade gliomas: the impact of radiotherapy. Ann Neurol. 1994;36:48–54.PubMedCrossRef Taphoorn MJ, Schiphorst AK, Snoek FJ, et al. Cognitive functions and quality of life in patients with low-grade gliomas: the impact of radiotherapy. Ann Neurol. 1994;36:48–54.PubMedCrossRef
10.
go back to reference Heath JA, Zacharoulis S, Kieran MW. Pediatric neuro-oncology: current status and future directions. Asia Pac J Clin Oncol. 2012;8:223–31.PubMedCrossRef Heath JA, Zacharoulis S, Kieran MW. Pediatric neuro-oncology: current status and future directions. Asia Pac J Clin Oncol. 2012;8:223–31.PubMedCrossRef
11.
go back to reference McCubrey JA, Steelman LS, Chappell WH, et al. Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget. 2012;3:954–87.PubMedCentralPubMed McCubrey JA, Steelman LS, Chappell WH, et al. Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget. 2012;3:954–87.PubMedCentralPubMed
12.
go back to reference Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118:1739–49.PubMedCentralPubMedCrossRef Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118:1739–49.PubMedCentralPubMedCrossRef
13.
go back to reference Sievert AJ, Jackson EM, Gai X, et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 2009;19:449–58.PubMedCentralPubMedCrossRef Sievert AJ, Jackson EM, Gai X, et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 2009;19:449–58.PubMedCentralPubMedCrossRef
14.
go back to reference Jones DT, Kocialkowski S, Liu L, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68:8673–7.PubMedCentralPubMedCrossRef Jones DT, Kocialkowski S, Liu L, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008;68:8673–7.PubMedCentralPubMedCrossRef
15.
go back to reference Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. 2008;67:878–87.PubMedCrossRef Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. 2008;67:878–87.PubMedCrossRef
16.
go back to reference Forshew T, Tatevossian RG, Lawson AR, et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 2009;218:172–81.PubMedCrossRef Forshew T, Tatevossian RG, Lawson AR, et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 2009;218:172–81.PubMedCrossRef
17.
go back to reference Jacob K, Albrecht S, Sollier C, et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer. 2009;101:722–33.PubMedCentralPubMedCrossRef Jacob K, Albrecht S, Sollier C, et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer. 2009;101:722–33.PubMedCentralPubMedCrossRef
18.
go back to reference Hawkins C, Walker E, Mohamed N, et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res. 2011;17:4790–8.PubMedCrossRef Hawkins C, Walker E, Mohamed N, et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res. 2011;17:4790–8.PubMedCrossRef
19.
go back to reference Basu TN, Gutmann DH, Fletcher JA, et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature. 1992;356:713–5.PubMedCrossRef Basu TN, Gutmann DH, Fletcher JA, et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature. 1992;356:713–5.PubMedCrossRef
20.
go back to reference Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Nuero Oncol. 2012;14:777–89.CrossRef Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Nuero Oncol. 2012;14:777–89.CrossRef
21.
go back to reference Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol. 2010;119:641–9.PubMedCrossRef Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol. 2010;119:641–9.PubMedCrossRef
22.
go back to reference Lin A, Rodriguez FJ, Karajannis MA, et al. BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol. 2012;71:66–72.PubMedCrossRef Lin A, Rodriguez FJ, Karajannis MA, et al. BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol. 2012;71:66–72.PubMedCrossRef
23.
go back to reference Cin H, Meyer C, Herr R, et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 2011;121:763–74.PubMedCrossRef Cin H, Meyer C, Herr R, et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 2011;121:763–74.PubMedCrossRef
24.
go back to reference Janzarik WG, Kratz CP, Loges NT, et al. Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics. 2007;8:61–3.CrossRef Janzarik WG, Kratz CP, Loges NT, et al. Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics. 2007;8:61–3.CrossRef
25.
26.•
go back to reference Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405. This large-sequencing CNS tumor analysis identified that the BRAF V600E point mutation occurred with increased frequency in certain low-grade glioma histological subgroups. PubMedCrossRef Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121:397–405. This large-sequencing CNS tumor analysis identified that the BRAF V600E point mutation occurred with increased frequency in certain low-grade glioma histological subgroups. PubMedCrossRef
27.
go back to reference Eisenhardt AE, Olbrich H, Roring M, et al. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer. 2011;129:2297–303.PubMedCrossRef Eisenhardt AE, Olbrich H, Roring M, et al. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer. 2011;129:2297–303.PubMedCrossRef
28.
go back to reference Schiffman JD, Hodgson JG, VandenBerg SR, et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010;70:512–9.PubMedCentralPubMedCrossRef Schiffman JD, Hodgson JG, VandenBerg SR, et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010;70:512–9.PubMedCentralPubMedCrossRef
29.
go back to reference Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 2010;12:621–30.PubMedCentralPubMedCrossRef Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 2010;12:621–30.PubMedCentralPubMedCrossRef
30.
go back to reference Dias-Santagata D, Lam Q, Vernovsky K, et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011;6:e17948.PubMedCentralPubMedCrossRef Dias-Santagata D, Lam Q, Vernovsky K, et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications. PLoS One. 2011;6:e17948.PubMedCentralPubMedCrossRef
31.•
go back to reference Rush S, Foreman N, Liu A. Brainstem ganglioglioma successfully treated with vemurafenib. J Clin Oncol. 2013;31:e159–60. This was the first report of therapeutic response to targeted inhibitor therapy for a glial tumor harboring the BRAF V600E mutation. PubMedCrossRef Rush S, Foreman N, Liu A. Brainstem ganglioglioma successfully treated with vemurafenib. J Clin Oncol. 2013;31:e159–60. This was the first report of therapeutic response to targeted inhibitor therapy for a glial tumor harboring the BRAF V600E mutation. PubMedCrossRef
32.
go back to reference Karajannis M, Fisher MJ, Milla SS, Cohen KJ, Legault G, Wisoff JH, et al. Phase II Study of sorafenib in children with recurrent/progressive low-grade astrocytomas. Neuro Oncol. 2012;14(6):vi101–5. Karajannis M, Fisher MJ, Milla SS, Cohen KJ, Legault G, Wisoff JH, et al. Phase II Study of sorafenib in children with recurrent/progressive low-grade astrocytomas. Neuro Oncol. 2012;14(6):vi101–5.
33.
go back to reference Sievert AJ, Lang SS, Boucher KL, et al. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A. 2013;110:5957–62.PubMedCentralPubMedCrossRef Sievert AJ, Lang SS, Boucher KL, et al. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A. 2013;110:5957–62.PubMedCentralPubMedCrossRef
34.
go back to reference Lang S, Sievert AL, Boucher KL, Madsen PJ, Slaunwhite E, Brewington D, et al. Development of pediatric glioma models for BRAF-targeted therapy. Neurosurgery. 2012;71:E575.CrossRef Lang S, Sievert AL, Boucher KL, Madsen PJ, Slaunwhite E, Brewington D, et al. Development of pediatric glioma models for BRAF-targeted therapy. Neurosurgery. 2012;71:E575.CrossRef
35.
go back to reference Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010;55:668–77.PubMedCentralPubMedCrossRef Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2010;55:668–77.PubMedCentralPubMedCrossRef
36.
go back to reference Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol. 2004;63:1236–42.PubMed Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol. 2004;63:1236–42.PubMed
39.
go back to reference Adriaensen ME, Schaefer-Prokop CM, Stijnen T, et al. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol. 2009;16:691–6.PubMedCrossRef Adriaensen ME, Schaefer-Prokop CM, Stijnen T, et al. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol. 2009;16:691–6.PubMedCrossRef
40.
go back to reference Lam C, Bouffet E, Tabori U, et al. Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors. Pediatr Blood Cancer. 2010;54:476–9.PubMedCrossRef Lam C, Bouffet E, Tabori U, et al. Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors. Pediatr Blood Cancer. 2010;54:476–9.PubMedCrossRef
41.
go back to reference Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006;59:490–8.PubMedCrossRef Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006;59:490–8.PubMedCrossRef
42.
go back to reference Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11.PubMedCrossRef Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11.PubMedCrossRef
43.••
go back to reference Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381:125–32. This international randomized placebo-controlled study revealed significant tumor shrinkage using the mTOR inhibitor everolimus for SEGAs in TSC patients. PubMedCrossRef Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381:125–32. This international randomized placebo-controlled study revealed significant tumor shrinkage using the mTOR inhibitor everolimus for SEGAs in TSC patients. PubMedCrossRef
44.
go back to reference Jentoft M, Giannini C, Cen L, et al. Phenotypic variations in NF1-associated low grade astrocytomas: possible role for increased mTOR activation in a subset. Int J Clin Exp Pathol. 2010;4:43–57.PubMedCentralPubMed Jentoft M, Giannini C, Cen L, et al. Phenotypic variations in NF1-associated low grade astrocytomas: possible role for increased mTOR activation in a subset. Int J Clin Exp Pathol. 2010;4:43–57.PubMedCentralPubMed
45.
go back to reference Hutt-Cabezas M, Karajannis MA, Zagzag D, et al. Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target. Neuro Oncol. 2013;15:1604–14.PubMedCrossRef Hutt-Cabezas M, Karajannis MA, Zagzag D, et al. Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target. Neuro Oncol. 2013;15:1604–14.PubMedCrossRef
46.
go back to reference Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 2005;65:2755–60.PubMedCrossRef Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 2005;65:2755–60.PubMedCrossRef
47.
go back to reference Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH. Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev. 2012;26:2561–6.PubMedCentralPubMedCrossRef Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH. Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev. 2012;26:2561–6.PubMedCentralPubMedCrossRef
48.
go back to reference Kieran M, Yao X, Macy M, Geyer R, Kohen K, MacDonald T, et al. A prospective multi-institutional phase II study of everolimus (RAD001), an MTOR inhibitor, in pediatric patients with recurrent or progressive low-grade glioma. A POETIC consortium trial. Pediatr Blood Cancer. 2013;60:19. Kieran M, Yao X, Macy M, Geyer R, Kohen K, MacDonald T, et al. A prospective multi-institutional phase II study of everolimus (RAD001), an MTOR inhibitor, in pediatric patients with recurrent or progressive low-grade glioma. A POETIC consortium trial. Pediatr Blood Cancer. 2013;60:19.
49.
go back to reference Yalon M, Rood B, MacDonald TJ, et al. A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low-grade glioma (LGG). Pediatr Blood Cancer. 2013;60:71–6.PubMedCrossRef Yalon M, Rood B, MacDonald TJ, et al. A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low-grade glioma (LGG). Pediatr Blood Cancer. 2013;60:71–6.PubMedCrossRef
51.
go back to reference Hwang EI, Jakacki RI, Fisher MJ, et al. Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas. Pediatr Blood Cancer. 2013;60:776–82.PubMedCrossRef Hwang EI, Jakacki RI, Fisher MJ, et al. Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas. Pediatr Blood Cancer. 2013;60:776–82.PubMedCrossRef
52.
go back to reference Couec ML, Andre N, Thebaud E, et al. Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. Pediatr Blood Cancer. 2012;59:34–8.PubMedCrossRef Couec ML, Andre N, Thebaud E, et al. Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. Pediatr Blood Cancer. 2012;59:34–8.PubMedCrossRef
53.•
go back to reference Gururangan S, Fangusaro J, Poussaint TY, et al. Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study. Neuro Oncol. 2013. doi:10.1093/neuonc/not154. This recent PBTC trial is now the largest reported study of children with recurrent low-grade gliomas treated with bevacizumab and irinotecan. The results suggested that the combination is generally well tolerated, with an effect on progression-free survival that is comparable with that of current regimens. Gururangan S, Fangusaro J, Poussaint TY, et al. Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study. Neuro Oncol. 2013. doi:10.​1093/​neuonc/​not154. This recent PBTC trial is now the largest reported study of children with recurrent low-grade gliomas treated with bevacizumab and irinotecan. The results suggested that the combination is generally well tolerated, with an effect on progression-free survival that is comparable with that of current regimens.
54.
go back to reference Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 2012;30:2641–7.PubMedCentralPubMedCrossRef Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 2012;30:2641–7.PubMedCentralPubMedCrossRef
55.
go back to reference Bouffet E, Jakacki R, Goldman S, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol. 2012;30:1358–63.PubMedCrossRef Bouffet E, Jakacki R, Goldman S, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol. 2012;30:1358–63.PubMedCrossRef
56.
go back to reference Dubois SG, Shusterman S, Ingle AM, et al. Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study. Clin Cancer Res. 2011;17:5113–22.PubMedCentralPubMedCrossRef Dubois SG, Shusterman S, Ingle AM, et al. Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children's oncology group study. Clin Cancer Res. 2011;17:5113–22.PubMedCentralPubMedCrossRef
57.•
go back to reference Warren KE, Goldman S, Pollack IF, et al. Phase I trial of lenalidomide in pediatric patients with recurrent, refractory, or progressive primary CNS tumors: Pediatric Brain Tumor Consortium study PBTC-018. J Clin Oncol. 2011;29:324–9. This early-phase study of the antiangiogenic agent lenalidomide in 51 children with a variety of recurrent brain tumors reported that either objective responses or long-term disease stability occurred primarily in patients with low-grade gliomas. A follow-on phase II study is now under way as a result of this work. PubMedCentralPubMedCrossRef Warren KE, Goldman S, Pollack IF, et al. Phase I trial of lenalidomide in pediatric patients with recurrent, refractory, or progressive primary CNS tumors: Pediatric Brain Tumor Consortium study PBTC-018. J Clin Oncol. 2011;29:324–9. This early-phase study of the antiangiogenic agent lenalidomide in 51 children with a variety of recurrent brain tumors reported that either objective responses or long-term disease stability occurred primarily in patients with low-grade gliomas. A follow-on phase II study is now under way as a result of this work. PubMedCentralPubMedCrossRef
58.
go back to reference Doolittle ND, Anderson CP, Bleyer WA, et al. Importance of dose intensity in neuro-oncology clinical trials: summary report of the sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium. Neuro Oncol. 2001;3:46–54.PubMedCentralPubMed Doolittle ND, Anderson CP, Bleyer WA, et al. Importance of dose intensity in neuro-oncology clinical trials: summary report of the sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium. Neuro Oncol. 2001;3:46–54.PubMedCentralPubMed
59.
go back to reference Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–86.PubMed Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–86.PubMed
60.
go back to reference Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000;105:R15–24.PubMedCentralPubMedCrossRef Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000;105:R15–24.PubMedCentralPubMedCrossRef
61.
go back to reference Robison NJ, Campigotto F, Chi SN, et al. A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer. 2013. doi:10.1002/pbc.24794. Robison NJ, Campigotto F, Chi SN, et al. A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer. 2013. doi:10.​1002/​pbc.​24794.
62.
63.
64.
go back to reference Ramkissoon LA, Horowitz PM, Craig JM, et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A. 2013;110:8188–93.PubMedCentralPubMedCrossRef Ramkissoon LA, Horowitz PM, Craig JM, et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A. 2013;110:8188–93.PubMedCentralPubMedCrossRef
65.
go back to reference Jones DT, Kocialkowski S, Liu L, et al. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene. 2009;28:2119–23.PubMedCentralPubMedCrossRef Jones DT, Kocialkowski S, Liu L, et al. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene. 2009;28:2119–23.PubMedCentralPubMedCrossRef
66.
go back to reference Katoh M. Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. Expert Rev Anticancer Ther. 2010;10:1375–9.PubMedCrossRef Katoh M. Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. Expert Rev Anticancer Ther. 2010;10:1375–9.PubMedCrossRef
67.
go back to reference Ren M, Hong M, Liu G, et al. Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncol Rep. 2013;29:2181–90.PubMed Ren M, Hong M, Liu G, et al. Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncol Rep. 2013;29:2181–90.PubMed
68.
go back to reference Ren M, Qin H, Ren R, Cowell JK. Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities. Leukemia. 2013;27:32–40.PubMedCentralPubMedCrossRef Ren M, Qin H, Ren R, Cowell JK. Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities. Leukemia. 2013;27:32–40.PubMedCentralPubMedCrossRef
69.
Metadata
Title
Targeted Therapy in Pediatric Low-Grade Glioma
Authors
John-Paul Kilday
Ute Katharina Bartels
Eric Bouffet
Publication date
01-04-2014
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 4/2014
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-014-0441-0

Other articles of this Issue 4/2014

Current Neurology and Neuroscience Reports 4/2014 Go to the issue

Headache (R Halker, Section Editor)

Migraine in Pregnancy and Lactation

Neuro-Oncology (LE Abrey, Section Editor)

Microenvironmental Clues for Glioma Immunotherapy

Neuro-Oncology (LE Abrey, Section Editor)

The Role of Brain Tumor Advocacy Groups

Headache (R Halker, Section Editor)

Thunderclap Headache