John Maris

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..Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity...

..Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known...

..This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP)...

..Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, FLT3, and KIT...

..report that Aurora A interacts with MYCN, a potent oncogene in human neuroblastoma, and sequesters it from proteolytic degradation. This surprising finding further enhances Aurora A's potential as a therapeutic target...

..MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis...

..These data suggest that transcriptional regulation of ID2 by the MycN oncoprotein is unlikely to be a seminal molecular event resulting in a highly malignant neuroblastoma phenotype...

..Taking all of this together indicates that aCGH can accurately measure CNAs in the neuroblastoma genome and facilitate gene discovery efforts by high-throughput refinement of candidate loci...

..31 that encodes 23 genes. Based on mutation analysis, expression pattern, and putative function, we identified CHD5 as the best tumor suppressor gene candidate...

..Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies...

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..002 and P=0.02, respectively). CONCLUSIONS: Unb11q LOH and 1p36 LOH are independently associated with a worse outcome in patients with neuroblastoma...

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..These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer...

..BCL2 and MYCN were identified as miR-34a targets and likely mediators of the tumor suppressor phenotypic effect. These data support miR-34a as a tumor suppressor gene in human neuroblastoma...

..We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans...

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..DNA signature patterns embed important prognostic information in diagnostic neuroblastoma samples, and can identify candidate cancer-related genes...

..We conclude that STAC is a powerful tool for identifying nonrandom genomic amplifications and deletions across multiple experiments. A Java version of STAC is freely available for download at http://cbil.upenn.edu/STAC...

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..This phase II study was conducted to determine the response rate associated with use of irinotecan and temozolomide for children with relapsed/refractory neuroblastoma...

..In summary, the low-calcemic hybrid analog QW showed significant anti-tumor activity in vivo and thus exhibits potential as a novel cancer therapeutic...

..Increased availability and experience with 131I-MIBG therapy would benefit a large number of children with end-stage neuroblastoma and no realistic hope for cure...

..It requires the installation of the free Java Runtime Environment 1.4.1 (or more recent) (http://www.java.sun.com)...

..Together, these results suggest that one or more genes involved in neuroblastoma tumorigenesis or tumor progression are likely contained within this region...

..Taken together, these data suggest that a hereditary neuroblastoma predisposition gene (HNB1) is located at 16p12-13 and that disruption of this gene may contribute to the pathogenesis of nonfamilial neuroblastomas...

..To evaluate (131)I-MIBG scintigraphic localization of xenotransplanted and spontaneously arising neuroblastomas in murine models of high-risk neuroblastoma...

..This review will describe the genetic and biologic basis for the diverse clinical phenotypes observed in neuroblastoma patients. It will also discuss the current approach to risk classification and how this may change in the future...

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..58). These data strongly refute a parent-of-origin effect for 1p deletions in NB and exclude the existence of an imprinted NB suppressor locus in this region...

..With the wide application of whole-genome SNP genotyping techniques, our wave adjustment method will be important for taking full advantage of genotyped samples for CNV analysis...

..The hypoventilation in CHS is more severe during NREM than REM sleep. We speculate that this may be due to increased excitatory inputs to the respiratory system during REM sleep...

..We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma...

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..We demonstrate the application of the proposed HMRF model using data from a case-control GWAS of neuroblastoma and identify 1 new SNP that is potentially associated with neuroblastoma...

..Our results also indicate that ZD1839 is a potent inhibitor of neuroblastoma cell proliferation; therefore, it may be a useful, biologically based therapeutic agent for these tumors...

..We wanted to determine if the Trk-selective inhibitor lestaurtinib had therapeutic efficacy in a preclinical neuroblastoma model...

..131)I-MIBG imaging following high therapeutic doses often reveals sites of occult metastatic disease that may be clinically relevant...

..Efforts to develop novel therapies that increase T-cell trafficking into tumor nests are warranted...

..While highly expressed on neuroblastoma cells, the relative contribution of the three major NCAM isoforms (120, 140, and 180 kDa) to neuroblastoma biology has not been investigated...

..The identification of the downstream effector pathways controlled by ALK should pave the way for the rational design of ALK-inhibition therapies for the treatment of a subset of human cancers that harbor ALK aberrations...

..The ability of patients with central hypoventilation syndrome (CHS) to produce and process mechanoreceptor signals is unknown...

..In such patients, we recommend brain, neck, and chest magnetic resonance imaging (MRI) with and without contrast as well as urinary catecholamine metabolite testing. However, imaging is more sensitive than urine testing in this setting...

..These data affirm that MetAP2 plays a pivotal role in cell growth and establish that reversible MetAP2 inhibitors are promising novel cancer therapeutic agents...

..Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes...

..CONCLUSIONS: These data support that reduced BIN1 expression contributes to the malignant phenotype of childhood NB. As we reported previously, BIN1 may function to circumvent MycN-mediated apoptosis in NBs with MYCN amplification...

..The aim of this study was to determine whether children with neuroblastoma in which MYCN oncogene amplification is manifested as HSRs at diagnosis have a worse prognosis than those whose tumors exhibit dmins...

..These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma...

..To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma...

..Bone marrow tumor at time of treatment was the most useful predictor of hematotoxicity, whereas whole-body radiation dose was the most useful predictor of failure to recover platelets after AHSCT...

..The long-term survival of children between age 12 and 24 months with stage 4 neuroblastoma and nonamplified MYCN (MYCN-NA) has not been defined previously...

..To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma...

..Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide...

..The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds...

..Such treatment would have selectivity by virtue of the acidic milieu surrounding tumors, because MCT is increasingly active as extracellular pH decreases below 7.0 and lactic acid production increases...

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..The most frequent microdeletion involved the PTPRD locus, indicating a possible tumor suppressor function for this gene...

..The reproducibility and high inter-observer concordance makes mIBG score an important component of overall response criteria in patients with recurrent neuroblastoma...

..To determine predictive strength of tumor cell ploidy and MYCN gene amplification on survival of children older than 12 months with disseminated neuroblastoma (NB)...

..The purpose of the current study was to evaluate the antitumor activity of bortezomib against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP)...

..Cisplatin is one of the most widely used drugs for the treatment of solid tumors in adults and children. Here, we report the activity of cisplatin against the PPTP panels of childhood cancer xenografts...

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..Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy...

..Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP)...

..More effective therapy might be given using consecutive doses in rapid succession with early stem cell support...

..Dasatinib, a dual inhibitor of the src and abl tyrosine kinases, was recently approved by the Federal Drug Administration for the treatment of imatinib mesylate-resistant chronic myeloid leukemia...

..The activity of SCH 717454 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP)...

..Alvespimycin (17-DMAG, KOS-1022), a potent small-molecule inhibitor of the protein chaperone Hsp90, is being developed as an anticancer agent because of the multiple Hsp90 client proteins involved in cancer cell growth and survival...

..Our findings provide evidence for a previously undescribed mechanism by which oncogenic tyrosine kinases can block TGF-beta tumor suppressor activity...

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..These insights will lead to new molecular diagnostic assays and/or new treatments for this frequently devastating malignancy of young children. ..

..It is expected that these will be of prognostic importance and serve as specific targets for developmental therapeutics. ..

..Ultimately, these experiments should lead to the identification of a common pathway to neuroblastoma tumorigenesis that will be an outstanding target for rationally designed therapeutics. ..

..The successful completion of these studies should have considerable impact on the diagnosis and management of all children with neuroblastoma, a malignancy for which no causal genetic alterations have been identified. ..

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