Molecular Characterization of Pediatric Gastrointestinal Stromal Tumors
ABSTRACT Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling.
Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells.
A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT.
Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.
- SourceAvailable from: Margherita Nannini[Show abstract] [Hide abstract]
ABSTRACT: In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.Histology and histopathology 10/2013; · 2.24 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.Frontiers in Oncology 01/2013; 3:117. DOI:10.3389/fonc.2013.00117
- [Show abstract] [Hide abstract]
ABSTRACT: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and are caused by activating KIT or PDGFRA mutations. GISTs can be successfully treated with the small molecule kinase inhibitor imatinib mesylate (Gleevec, Novartis) with response rates of up to 85%. However, complete responses are rare, and most patients will develop imatinib resistance over time. Recent results have shown that although imatinib effectively stimulates apoptotic cell death in sensitive GIST cells, a considerable proportion of cells does not undergo apoptosis, but instead enters a state of quiescence. Quiescence is characterized by a reversible withdrawal from the cell division cycle, during which the cells remain alive and metabolically active. It is conceivable that quiescence not only plays a pivotal role in the emergence of residual disease but also in creating a pool of tumor cells that survive continuous small molecule therapy and may hence represent the "seeds" for the outgrowth of resistant clones. This review will summarize the current knowledge about GIST biology and treatment response to imatinib including the induction of cellular quiescence in GIST. In addition, we will highlight future strategies to design more effective treatment options to overcome these problems with an aim towards cure of this hitherto untreatable tumor entity.Biochemical pharmacology 04/2010; 80(5):575-83. DOI:10.1016/j.bcp.2010.04.006 · 4.65 Impact Factor