GARRETT BRODEUR

..Future therapies will focus increasingly on the genes and biological pathways that contribute to malignant transformation or progression...

..Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites...

..CONCLUSIONS: These data support the hypothesis that inactivation of a tumor suppressor gene within 1p36.3 is associated with an increased risk for disease relapse...

..These results suggest that for neuroblastoma, large HDs do not occur within 1p36, most known TSGs are not homozygously deleted, and biallelic inactivation of CDKN2A may contribute to tumorigenicity in a subset of cases...

..These findings suggest that a tumor suppressor gene involved in the initiation or progression of neuroblastoma is located within distal 14q...

..04). The redundancy in angiogenic factor expression suggests that inhibition of VEGF bioactivity alone might not be a sufficient approach for antiangiogenic therapy of human NB...

..This suggests differences from TrkA pathways identified in PC12 cells...

..We conclude that HKR3 is a novel zinc finger gene that maps to a region of the genome commonly rearranged or deleted in neuroblastoma and other human cancers...

..HKR3 is a novel zinc finger gene that maps to a region of the genome commonly rearranged or deleted in human cancers...

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..Neuroblastoma tumorigenesis may involve the differential inactivation of multiple tumor suppressor genes. Recent data have suggested that a neuroblastoma suppressor gene may be located on the long arm of chromosome 11 (11q)...

..The compound CEP-751 (KT-6587), a potent and selective inhibitor of the Trk family of tyrosine kinases, has been shown to inhibit the growth of human neuroblastoma (NB) xenografts in nude mice [1]...

..Several lines of evidence es tablish that chromosome band 1p36 is frequently deleted in neuroblastoma primary tumors and cell lines, suggesting that a tumor suppressor gene within this region is involved in the development of this tumor...

..2-36.3. Indirect evidence suggests the presence of an imprinted neuroblastoma suppressor gene within this region, as well as an additional nonimprinted, proximal suppressor gene, inactivation of which correlates with MYCN amplification...

..Conversely, TrkBtrunc expression is associated with excellent outcome, perhaps as a result of a dominant negative effect...

..We hypothesized that BIN1, a MYC interacting protein capable of inducing apoptosis, may be an important regulator of MYCN in neuroblastoma...

..This information should facilitate the mapping of tumor suppressor and genetic disease loci that have been localized to this region...

..In addition, neuroblastoma has been described in children with constitutional deletions within 1p36, supporting the existence of one or more neuroblastoma suppressor genes within this region...

..01). Expression of Apo-3 was significantly associated with survival in PNET/medulloblastomas (P=0.03). Thus, the Apo-3 receptor/ligand system might be involved in the regulation of apoptosis in neuroblastomas and PNET...

..Hereditary predisposition to develop neuroblastoma segregates as an autosomal dominant Mendelian trait...

..Moreover, MYCN expression was correlated with TrkA expression (P < 0.01) in the low-stage NBs. CONCLUSIONS: This observation points to the possibility that MYCN expression might contribute to favorable outcome of low-stage NBs...

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..Since the NET mRNA expression in human brain is developmentally regulated and is induced during neuronal differentiation, NET potentially plays important roles in human neurogenesis...

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..Because many cytotoxic drugs induce caspase-dependent apoptosis, failure to express caspase-8 and/or caspase-10 might be an important mechanism of resistance to chemotherapy in NB...

..5-kb band encodes the full-length TRK-B mRNA and the 8.0-kb band encodes the truncated form of TRK-B mRNA. By fluorescence in situ hybridization and somatic cell hybrid mapping, the human TRK-B gene was localized to chromosome 9q22.1...

..Taken together, the data suggest that ECK maps to 1p36.1, a region that is frequently deleted in neuroblastoma, melanoma, and other neuroectodermal tumors...

..Thus, the DRT gene may play a part in neuroblastoma and SCLC tumorigenesis...

..These results suggest that the EPHB subgroup receptor kinases may modulate the biological behavior of SCLC through autocrine and/or juxtacrine activation by ephrin-B ligands that are expressed in the same or neighboring cells...

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

..The goal of Pediatric Oncology Group 9243 was to improve outcomes for children with intermediate-risk neuroblastoma (NB)...

..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...

..To determine the clinical significance of MYCN amplification in children with favorable-stage NB, we performed a retrospective review of data from the Pediatric Oncology Group (POG) biology study 9047...

..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...

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

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

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

..Fine-tuning of the malignant phenotype may be achieved by additional ligand stimulation with subsequent activation of a few specific genes...

..The biologically different behavior of TrkA- and TrkB-expressing NBs may be explained in part by their effects on angiogenesis...

..Activation of PI3K/AKT survival pathway may contribute to the increased drug resistance in TrkB-expressing neuroblastomas...

..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...

..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...

..These findings suggest that this gene may play a role in the development of the nervous system, and it may also play a role in the pathogenesis of neural tumors...

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..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...

..This annotation of a putative tumor suppressor locus provides a resource for further analysis of meningioma candidate genes...

..Given the increasing evidence for a role of Trk receptors in a variety of pediatric and adult tumors, these data would argue strongly for the utility of Trk receptor inhibition in therapy, alone or in combination. ..

..Finally, deletions of 1p36 are found in many other cancers, so the identification of this TSG could have broad implications for many forms of neoplasia. ..

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..P75 and Trk in Neuroblastoma Differentiation and Death (Garrett Brodeur, Leader). Project 2. Antiangiogenic Strategies for Neuroblastoma Therapy (John Maris, Leader) Project 3...

..We will also determine the optimum Trk inhibitor (agent, dose, schedule) to incorporate into future clinical trials, and we will determine which tumors express Trk receptors to identify who would benefit from Trk inhibitor therapy. ..

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..We will also determine the optimum Trk inhibitor (agent, dose, schedule) to incorporate into future clinical trials, and we will determine which tumors express Trk receptors to identify who would benefit from Trk inhibitor therapy. ..

..They will be extended to all samples studied, and they should allow us to address issues of tumor heterogeneity and progression within and between primary and metastatic lesions...

..The final specific aim is to clone and characterize the neuroblastoma TSG and use transgenic mice experiments to determine gene function. ..

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