3480

IGF1R

CD221|IGFIR|IGFR|JTK13;insulin-like growth factor 1 receptor;IGF1R;insulin-like growth factor 1 receptor

IGF-I receptor|insulin-like growth factor I receptor|soluble IGF1R variant 1|soluble IGF1R variant 2

15q26.3

protein-coding

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the intestinaltract that typically occur in adults over the age of 40 years. GISTs in younger patients are rare and not well characterized. The objective was to define the characteristics of GISTs in children and young adults (<30 years old). Clinicopathologic and molecular features, including KIT/PDGFRA genotype, in GISTs from 5 children and 10 young adults were analyzed. Gene expression analysis was performed on 5 gastric tumor samples from 2 children, 2 gastric tumors from young adults, and 10 gastric GISTs from older adults using an U133A Affymetrix platform (22,000 genes). ALL five pediatric GISTs occurred in girls, involved the stomachas multiple nodules, showed predominantly an epithelioid morphology, often involved lymph nodes, and lacked KIT or PDGFRA mutations. Although ALL five patients developed recurrence (four in the liver, three in the peritoneum, and two in both sites), four are still alive with disease. Of the 10 GISTs in young adults, half occurred in the small bowel and had spindle cell morphology, and one case had lymph node metastasis. KIT mutations were identified in seven cases, four in exon 11 and three in exon 9. Seven patients developed recurrence, and atlast follow-up two patients had died of disease. Gene expression analysis showedhigh expression of PHKA1, FZD2, NLGN4, IGF1R, and ANK3 in the pediatric and young adult versus older adult cases. GISTs that occur in children are a separate clinicopathologic and molecular subset with predilection for girls, multifocal gastric tumors, and wild-type KIT/PDGFRA genotype. In contrast, GISTs in young adults are a more heterogeneous group, including cases that resemble either the pediatric or the older adult-type tumors. The distinct gene expression profile suggests avenues for investigation of pathogenesis and potential therapeutic strategies.

PURPOSE OF REVIEW: We will review the recent (2006/2007) literature on pediatricgenitourinary tumors. RECENT FINDINGS: The WTX gene is now the most common knowngene mutation in Wilms' tumor. It acts as a tumor suppressor gene and may play arole in other malignancies. Current clinical trials have incorporated the loss of heterozygosity of 1p and 16q along with age, tumor size, stage, and response to therapy to risk stratify therapy. The PAX3-FOX01 gene fusion and the IGF-1R-signaling and mTOR-signaling pathways are implicated in rhabdomyosarcoma biology, and hence are promising therapeutic targets for this tumor. SUMMARY: Progress is being made in understanding the pathogenesis of genitourinary tumorsin children, and the prognosis for these children continues to improve. Current treatment strategies are focused on improving event-free survival while decreasing late effects from therapy.

BACKGROUND: Type 1 insulin like growth factor receptor (IGF-IR) is over expressed in many tumors including hematological cancers. It is a critical signaling molecule for tumor cell proliferation and survival. Data suggest that IGF-IR antibodies can effectively and specifically inhibit cancer cell growth in vitro and in vivo. Blockage of IGF-IR expression could be a promising therapeutic approach for the management of cancer patients. AIM OF WORK: To characterize theexpression pattern of IGF-IR gene in malignant lymphoblasts of children and adults suffering from ALL in relation to clinical features at diagnosis. PATIENTS AND METHODS: The expression of IGF-IR was analyzed in 60 patients with ALL, 30 childhood ALL (16 newly diagnosed and 14 in complete remission) and 30 adulthoodALL (15 newly diagnosed and 15 in complete remission) together with 20 normal age and sex matched healthy controls using a Real-Time Quantitative Reverse- Transcriptase Polymerase Chain Reaction (RTQ-PCR) to assess the possible relation, association or correlation between IGF-IR expression and ALL clinical and laboratory features at diagnosis. RESULTS: IGF-IR was expressed in ALL 60 patients with ALL; the expression levels of IGF-IR were significantly higher in newly diagnosed patients than in patients in complete remission (CR) and controls (p < 0.001). There were no statistically significant differences in the expression of IGF-IR between patients with different clinical and laboratory features. CONCLUSION: IGF-1R seems to play a crucial role in patients with ALL since it is expressed in ALL ALL cases (adulthood and childhood). Therefore, newtherapeutic agents targeting IGF-1R may provide a better chance for those patients. KEY WORDS: IGF-IR - Adult ALL - childhood ALL - RTPCRT - Prognosis.

The occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient.

MicroRNAs (miRs) are a novel class of cellular bioactive molecules with criticalfunctions in the regulation of gene expression in normal biology and disease. MiRs are frequently misexpressed in cancer, with potent biological consequences.However, relatively little is known about miRs in pediatric cancers, including sarcomas. Moreover, the mechanisms behind aberrant miR expression in cancer are poorly understood. Ewing sarcoma is an aggressive pediatric malignancy driven byEWS/Ets fusion oncoproteins, which are gain-of-function transcriptional regulators. We employed stable silencing of EWS/Fli1, the most common of the oncogenic fusions, and global miR profiling to identify EWS/Fli1-regulated miRs with oncogenesis-modifying roles in Ewing sarcoma. In this report, we characterize a group of miRs (100, 125b, 22, 221/222, 27a and 29a) strongly repressed by EWS/Fli1. Strikingly, ALL of these miRs have predicted targets in the insulin-like growth factor (IGF) signaling pathway, a pivotal driver of Ewing sarcoma oncogenesis. We demonstrate that miRs in this group negatively regulate the expression of multiple pro-oncogenic components of the IGF pathway, namely IGF-1, IGF-1 receptor, mammalian/mechanistic target of rapamycin and ribosomal protein S6 kinase A1. Consistent with tumor-suppressive functions, these miRs manifest growth inhibitory properties in Ewing sarcoma cells. Our studies thus uncover a novel oncogenic mechanism in Ewing sarcoma, involving post-transcriptional derepression of IGF signaling by the EWS/Fli1 fusion oncoprotein via miRs. This novel pathway may be amenable to innovative therapeutic targeting in Ewing sarcoma and other malignancies with activated IGFsignaling.

pediatric glioblastoma (pGBM), although rare, is one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. We have identified IGF1R to be a potential therapeutic target in pGBM due to gene amplification and high levels of IGF2 expression in some tumor samples, as well as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we havecarried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was seen in vitro, with GI(50) values of 5 to 6 mumol/L, and concurrent inhibition of receptor phosphorylation.Specific targeting of IGF1R with short interfering RNA decreased cell viability,diminished downstream signaling through phosphoinositide 3-kinase (PI3K), and induced G(1) arrest, effects mimicked by NVP-AEW541, both in the absence and presence of IGF2. Hallmarks of PI3K inhibition were observed after treatment with NVP-AEW541 by expression profiling and Western blot analysis. Phospho-receptor tyrosine kinase (RTK) arrays showed phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha/beta in pGBM cells, suggesting coactivation of an alternative RTK pathway. Treatment of KNS42 with the PDGFR inhibitor imatinib showed additional effects targeting the mitogen-activated protein kinase pathway, and cotreatment of the PDGFR inhibitor imatinib with NVP-AEW541 resulted in a highly synergistic interaction in vitro and increased efficacy after 14 days therapy in vivo compared with either agent alone. These data provide evidence that inhibition of IGF1R, in combination with other targeted agents, may be a useful and novel therapeutic strategy in pGBM.#CI- (c)2011 AACR

The insulin-like growth factor-I receptor (IGF-I-R) has been implicated in the etiology and/or progression of Wilms' tumor, a pediatric malignancy of the kidney that is often associated with deletion or mutation of the WT1 tumor suppressor gene. The expression of the IGF-I-R gene is increased in Wilms' tumor as compared with normal kidney tissue. Furthermore, the levels of IGF-I-R mRNA in individualtumors have been shown to be inversely correlated to the levels of WT1 mRNA, suggesting that the expression of the IGF-I-R gene is under the negative controlof WT1. The activity of an IGF-I-R promoter/luciferase construct in Chinese hamster ovary cells was reduced by cotransfection of a WT1 expression vector. Ananalysis of various reporter constructs containing different portions of the IGF-I-R 5'-flanking and 5'-untranslated regions suggested that the effect of WT1depends on the number of WT1 binding sites present, with sites located both upstream and downstream of the IGF-I-R transcription start site involved in mediating this effect. Using the purified zinc finger domain of WT1 in gel retardation and DNase I footprinting assays, we mapped five sites in the 5'-flanking and six sites in the 5'-untranslated regions that were involved in WT1 binding. In addition, the initiator element of the IGF-I-R gene contains a sequence that binds WT1. Thus, the repression of IGF-I-R promoter activity by the WT1 tumor suppressor gene product involves multiple interactions of its zinc finger domain with WT1 binding sites located both 5' and 3' of the transcriptioninitiation site.

Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of the gene encoding insulin-like growth factor II (IGF-II) is often elevated in these tumors. Since many of the actions of IGF-II are mediatedthrough activation of the IGF-I receptor (IGF-IR), we have measured the levels of IGF-IR mRNA in normal kidney and in Wilms tumor samples using solution hybridization/RNase protection assays. IGF-IR mRNA levels in the tumors were 5.8-fold higher than in adjacent normal kidney tissue. Among the tumors themselves, the levels of IGF-IR mRNA in those containing heterologous stromal elements were 2-fold higher (P < 0.01) than in tumors without these elements. IGF-IR gene (designated IGF1R) expression in the tumors was inversely correlatedwith the expression of the Wilms tumor suppressor gene WT1, whose inactivation appears to be a key step in the etiology of Wilms tumor. Cotransfection of Chinese hamster ovary cells with rat and human IGF-IR gene promoter constructs driving luciferase reporter genes and with WT1 expression vectors showed that the active WT1 gene product represses IGF-IR promoter activity in a dose-dependent manner. These results suggest that underexpression, deletion, or mutation of WT1may result in increased expression of the IGF-IR, whose activation by IGF-II maybe an important aspect of the biology of Wilms tumor.

THe insulin-like growth factor I receptor (IGF-I-R) has been implicated in the etiology and/or progression of Wilms' tumor, or nephroblastoma, a pediatric neoplasm of the kidney that is often associated with deletion or mutation of theWT1 tumor suppressor gene. The levels of IGF-I-R mRNA in the tumors were sixfoldhigher than in normal adjacent kidney tissue and were inversely correlated to the levels of WT1 mRNA, suggesting that the expression of the IGF-I-R gene is under inhibitory control by WT1. Cotransfection of an IGF-I-R promoter-luciferase reporter construct together with a WT1 expression vector resulted in a dose-dependent suppression of promoter activity. Multiple WT1 binding sites weremapped in the 5'-flanking and 5'-untranslated regions of the IGF-I-R gene using gel retardation and DNaseI footprinting assays. Thus, suppression of the IGF-I-Rpromoter by WT1 involves multiple interactions of its zinc finger domain with sites located both upstream and downstream of the transcription initiation site.Finally, we showed that expression of the endogenous IGF-I-R gene is decreased in G401 cells stably transfected with a WT1 expression vector. Reduction in expression of the IGF-I-R gene is associated with a decrease in a number of IGF-I-mediated biological effects. Thus, deletion or mutation of the WT1 gene inWilms' tumor and other malignancies can result in overexpression of the receptor, with enhanced autocrine/paracrine activation by locally produced or circulating IGFs.