PMID- 23717811
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20130530
LR  - 20231104
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 3
DP  - 2013
TI  - The combination of novel targeted molecular agents and radiation in the treatment 
      of pediatric gliomas.
PG  - 110
LID - 10.3389/fonc.2013.00110 [doi]
LID - 110
AB  - 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-gamma, TNF-alpha, 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.
FAU - Dasgupta, Tina
AU  - Dasgupta T
AD  - Department of Radiation Oncology, University of California San Francisco San 
      Francisco, CA, USA.
FAU - Haas-Kogan, Daphne A
AU  - Haas-Kogan DA
LA  - eng
PT  - Journal Article
DEP - 20130510
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC3650671
OTO - NOTNLM
OT  - BRAFV600E
OT  - PI3K/AKT/mTOR
OT  - angiogenesis inhibitors
OT  - bevacizumab
OT  - lenalidomide
OT  - low-grade glioma
OT  - pediatric gliomas
EDAT- 2013/05/30 06:00
MHDA- 2013/05/30 06:01
PMCR- 2013/01/01
CRDT- 2013/05/30 06:00
PHST- 2013/01/21 00:00 [received]
PHST- 2013/04/22 00:00 [accepted]
PHST- 2013/05/30 06:00 [entrez]
PHST- 2013/05/30 06:00 [pubmed]
PHST- 2013/05/30 06:01 [medline]
PHST- 2013/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2013.00110 [doi]
PST - epublish
SO  - Front Oncol. 2013 May 10;3:110. doi: 10.3389/fonc.2013.00110. eCollection 2013.