Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas
| Autor: | David H. Harter, Judith D. Goldberg, Adam C. Resnick, David T.W. Jones, Angela J. Sievert, Girish Dhall, Jeffrey H. Wisoff, Geneviève Legault, Stefan M. Pfister, Matthias A. Karajannis, Charles G. Eberhart, Kenneth J. Cohen, David Zagzag, Sarah Milla, Michael C. Bloom, Jeffrey C. Allen, Amanda Merkelson, Tsivia Hochman, Andrey Korshunov, Michael Fisher |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Sorafenib
MAPK/ERK pathway Male Niacinamide Cancer Research Platelet-derived growth factor Adolescent MAP Kinase Signaling System Antineoplastic Agents Kaplan-Meier Estimate Astrocytoma chemistry.chemical_compound Mice Medicine Animals Humans neoplasms Protein Kinase Inhibitors biology Pilocytic astrocytoma business.industry Brain Neoplasms Phenylurea Compounds medicine.disease Neurofibromin 1 Magnetic Resonance Imaging Vascular endothelial growth factor Treatment Outcome Oncology chemistry Child Preschool Immunology biology.protein Cancer research NIH 3T3 Cells Female Neurology (clinical) business Pediatric Neuro-Oncology Platelet-derived growth factor receptor V600E medicine.drug |
| Popis: | Recurrent pediatric low-grade astrocytoma (PLGA) represents a major clinical problem in neuro-oncology, and novel, less toxic and more effective therapies are needed.1 Recently, our increased understanding of the key molecular pathways driving PLGA growth and the increasing availability of targeted therapies for those pathways have led to great interest in exploring molecular targeted therapies for PLGA. Pilocytic astrocytoma (PA) is the most common histological subtype of PLGA. Patients with neurofibromatosis type 1 (NF1) are predisposed to developing PAs, predominantly in the optic tract (ie, optic pathway gliomas [OPGs]).2 NF1 is characterized by the loss of the NF1 gene product neurofibromin, resulting in activation of the RAS/RAF/MEK/ERK signaling pathway.3 The majority of sporadic PAs harbor a unique tandem duplication at chromosome 7q34, which produces a fusion gene between KIAA1549 and the kinase domain of BRAF that result in constitutive BRAF and ultimately MAPK activation. In recent genomic studies, almost all PAs that do not harbor KIAA-BRAF have been shown to harbor other genetic lesions that also result in constitutive MAPK pathway activation, such as activating genetic hits in FGFR1, NTRK2, and RAF1.4,5 PLGAs express pro-angiogenic factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF]), and their receptors (VEGFR and PDGFR).6–8 Bevacizumab, a VEGF inhibitor, has recently shown very encouraging activity in PLGA.9,10 Sorafenib is an oral, small-molecule multikinase inhibitor with potent in vitro activity against both wild-type and mutant (V600E) BRAF.11 Recent preclinical data showed that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with sorafenib.12 Sorafenib also exerts anti-angiogenic activity via inhibition of VEGFR-1/2/3, PDGFRβ, Flt-3, and c-kit, which has been studied in a variety of preclinical models13,14 as well as in clinical studies using dynamic, contrast-enhanced MRI.15 Because sorafenib is a potent inhibitor of several key molecular pathways that are relevant in PLGAs and encouraging preclinical data,12 we conducted this prospective phase II clinical trial to assess the objective response rate to sorafenib in patients with PLGA. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|