bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B43: Role of activated SHP2 in high-risk neuroblastoma pathogenesis
Authors: Zhu (Jane) shizhen , Neel Benjamin G. , Look A. Thomas 
Published: May 2015

Abstract
Neuroblastoma, an embryonic tumor of peripheral sympathetic nervous system (PSNS), accounts for 10% of all childhood cancer deaths. We recently developed a robust zebrafish model of neuroblastoma and demonstrated that activated ALK synergizes with MYCN by inhibiting a developmentally-timed apoptotic response that is otherwise induced by MYCN. Genomic studies show that PTPN11 (encoding SHP2) is the second most frequently mutated genes in high-risk neuroblastoma. We have now used our zebrafish model to ask whether mutationally activated SHP2 functions as an oncogene in neuroblastoma. We developed transgenic lines in which ptpn11E69K is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase promoter. Interestingly, ptpn11E69Ksynergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland, the zebrafish analogue of the adrenal medulla. Tumors began to appear at 15 weeks in transgenic fish overexpressing MYCN alone, whereas latency was shortened to 7 weeks and the penetrance was increased more than four-fold in transgenic fish co-expressing MYCN and ptpn11E69K. Co-expression of ptpn11E69K and MYCN also induced ganglioneuroma in the sympathetic ganglia, an outcome that has not been observed in transgenic fish overexpressing MYCN and activated ALK. These results suggest that activated SHP2 can collaborate with MYCN in neuroblastoma tumorigenesis via mechanisms different from those of activated ALK. Thus, zebrafish appears to provide a robust model system for functional genomic analysis and for the investigation of the mechanisms and pathways underlying mutations identified in ongoing tumor resequencing studies.
Citation Format: (Jane) shizhen Zhu, Benjamin G. Neel, A. Thomas Look. Role of activated SHP2 in high-risk neuroblastoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B43.
Abstract B45: A novel therapeutic approach for neuroblastoma
Authors: Mokhtari Reza Bayat , Tsui Micky , Lotfi Shamim , Kumar Sushil , Baluch Narges , Islam Syed S. , Das Bikul , Yeger Herman 
Published: May 2015

Abstract
Neuroblastoma (NB), a tumor of the primitive neural crest, despite aggressive treatment regimens, portends a poor long-term survival for patients with advanced high stage NB. Here, we investigated the effects of targeting two families of critical regulatory molecules involved in cancer progression, histone deacetylases (HDACs) and carbonic anhydrases (CAs). HDACs regulate the expression and activity of various proteins involved in carcinogenesis and cancer progression, whereas carbonic anhydrases (CAs) function in tumor cell pH homeostasis and therein regulation of growth, survival, and metastasis. In this study we have used HDAC inhibitor (HDACi), pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) and CA inhibitor acetazolamide (AZ). We report that MS-275, at nanomolar concentrations, significantly reduced the tumor initiating cell fraction (TIC) in NB cell lines in reference to NT2/D1, a teratocarcinoma cell line, exhibiting a stem cell like phenotype in-vitro. Stemness genes Oct-5, SOX2 and nanog, assessed by flow cytometry and western blot were found to be significantly down-regulated after MS-275 treatment. Overall, the tumor growth inhibitory effect of MS-275 was demonstrated by cytotoxicity assays, FACs analysis, and “In cell Western” assay. In-vivo treatment with MS-275 (20 mg/Kg) in human NB SH-SY5Y subcutaneous NOD/SCID xenograft model significantly reduced the tumor weight after 21 days treatment compared to the control (AZ 30%; MS-275 85%; AZ+MS-275 90%); (AZ p&lt;0.05; MS-275 and MS-275+AZ p&lt;0.0001). The efficacy of MS-275 was further enhanced by co-administration of AZ (40 mg/Kg) without causing morbidity in mice. Electron microscopy and H&E staining revealed higher numbers of apoptotic cells in MS-275 and AZ+MS-275 treated tumors. Upon re-implantation of tumor cells from primary xenografts in mice, the MS-275+AZ treated cells did not produce palpable tumors after two months whereas untreated cells produced large tumors. This significant reduction in initial tumorigenicity and subsequent abrogation suggests potential elimination of NB tumor initiating cells. Thus MS-275 combined with AZ shows promise as a potent novel anti-NB therapeutic strategy given their current clinical utility.
Citation Format: Reza Bayat Mokhtari, Sr., Micky Tsui, Sr., Shamim Lotfi, Sr., Sushil Kumar, Sr., Narges Baluch, Syed S. Islam, Bikul Das, Herman Yeger. A novel therapeutic approach for neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B45.
Abstract B57: Modeling human metastatic neuroblastoma in immunodeficient mice
Authors: Bexell Daniel , Braekeveldt Noémie , Beckman Siv , Mohlin Sofie , Gisselsson David , Påhlman Sven 
Published: May 2015

Abstract
Neuroblastoma is a childhood tumor located in the sympathetic nervous system and most often found in the adrenal gland. Half of the patients have metastases already at diagnosis. There is a need for improved preclinical in vivo models of human high-stage neuroblastoma. Aims: 1) To establish relevant xenograft in vivo models for studying neuroblastoma orthotopic growth and metastatic growth in bone marrow, 2) to detect tumor growth by the two imaging modalities utilized in the clinic, i.e. magnetic resonance imaging (MRI) and I-123-metaiodobenzylguanidine (MIBG)-Single photon emission computed tomography (SPECT), and 3) to characterize orthotopic and bone marrow tumor growth at a pathohistological level. Methods: SK-N-Be2c and KCN-69 neuroblastoma cells were injected into adrenal gland of immunodeficient NSG mice to establish orthotopic tumors. SK-N-Be2c cells were injected directly into femur bone marrow of NSG mice to model bone marrow metastatic growth in a reproducible way. Tumor growth was monitored by MRI or by MIBG-SPECT. Histopathological assessment was performed on formalin-fixed paraffin-embedded tissue sections. Conclusion: We have established a model for orthotopic neuroblastoma growth and characterized the model by MRI and MIBG-SPECT. Orthotopic tumors grow infiltratively into surrounding tissues and resemble the histopathological hallmarks of patient neuroblastoma. We also describe a reproducible in vivo model for neuroblastoma bone marrow metastatic growth. The in vivo models will be important tools for studying mechanisms of neuroblastoma growth and for preclinical drug testing.
Citation Format: Daniel Bexell, Noémie Braekeveldt, Siv Beckman, Sofie Mohlin, David Gisselsson, Sven Påhlman. Modeling human metastatic neuroblastoma in immunodeficient mice. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B57.
Abstract B6: Epigenetic regulation of Hedgehog pathway transcriptional output by BET bromodomain proteins
Authors: Tang Yujie , Schubert Simone , Qi Jun , Nguyen Brian , Masoud Sabran , Vue Nujsaunusi , Balansay Brianna , Yu Furong , Atwood Scott X. , Whitson Ramon J. , Ponnuswami Anitha , Chen Spencer , Gholamin Sharareh , Pamelyn Woo J. , Monje-Diesseroth Michelle , Oh Sekyung , Lee Alex , Tang Jean Y. , Wechsler-Reya Rob , Oro Anthony E. , Bradner James E. , Cho Yoon-Jae 
Published: May 2015

Abstract
Aberrant activation of Hedgehog signaling drives oncogenesis in several types of cancer. As a result, there has been significant interest in developing therapeutic strategies targeting this pathway, most notably through inhibition of Smoothened. Though Smoothened inhibitors have shown efficacy in several cancer clinical trials, the initial enthusiasm for these inhibitors has been tempered by emergence of resistance and a priori resistance, often via mutation of Smoothened itself or through dysregulation of downstream components of the Hedgehog signaling axis. Here we reveal a strategy that overcomes these resistance mechanisms by targeting the far downstream transcriptional mediators of Hedgehog signaling through inhibition of the BET bromodomain protein, BRD4. We show that knockdown of BRD4 or treatment with the BET bromodomain inhibitor, JQ1, dramatically inhibits transcription of GLI1 and other Hedgehog target genes upon ligand-mediated or genetic activation of the Hedgehog pathway. We confirm the inhibitory effect of JQ1 occurs downstream of SMO and SUFU and verify by chromatin immunoprecipitation that Brd4 directly occupies the GLI1 and GLI2 promoters, with a substantial decrease in the engagement of these genomic sites upon treatment with JQ1. We observe a corresponding downregulation of genes associated with medulloblastoma-specific GLI1 binding sites upon exposure to JQ1, confirming the direct regulation of GLI1 by BET bromodomain proteins. Finally, using patient- and GEMM-derived cell lines of Hedgehog-driven cancer (basal cell carcinoma, medulloblastoma and ATRT), we show that JQ1 decreases Hh pathway output and proliferation, even in cell lines resistant to Smoothened inhibitors. These results expand the role of BET bromodomain inhibitors to targeting Hedgehog-driven cancers and highlight a strategy that overcomes the limitation of Hedgehog pathway inhibitors currently in clinical use.
Citation Format: Yujie Tang, Simone Schubert, Jun Qi, Brian Nguyen, Sabran Masoud, Nujsaunusi Vue, Brianna Balansay, Furong Yu, Scott X. Atwood, Ramon J. Whitson, Anitha Ponnuswami, Spencer Chen, Sharareh Gholamin, Woo J. Pamelyn, Michelle Monje-Diesseroth, Sekyung Oh, Alex Lee, Jean Y. Tang, Rob Wechsler-Reya, Anthony E. Oro, James E. Bradner, Yoon-Jae Cho. Epigenetic regulation of Hedgehog pathway transcriptional output by BET bromodomain proteins. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B6.
Abstract IA05: Targeting the oxidative stress pathway in rhabdomyosarcoma
Authors: Dyer Michael A. 
Published: May 2015

Abstract
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Histologically, there are two major subtypes of rhabdomyosarcoma, embryonal and alveolar, which have distinct clinical, molecular, and genetic features. Patients with resected localized disease are highly curable, but patients with recurrent, metastatic or large unresectable tumors have a poor clinical outcome. In this study, we performed whole-genome sequencing, exome sequencing, RNA-sequencing and DNA methylation profiling of embryonal and alveolar rhabdomyosarcomas. The embryonal tumors had more structural and copy number variations than did alveolar tumors and those lesions result from the accumulation of chromosomal lesions over time. Mutations in the RAS/NF1 pathway were significantly associated with intermediate- and high-risk embryonal rhabdomyosarcoma. In contrast, alveolar rhabdomyosarcoma had fewer genetic lesions overall and there were no known cancer consensus genes that were recurrently mutated other than the PAX3/7-FOXO1translocation that is a hallmark of alveolar rhabdomyosarcoma. DNA methylation profiling and RNA-seq analysis showed that embryonal and alveolar rhabdomyosarcomas are distinct and the alveolar tumors more closely resemble normal myoblasts and myotubes. To identify novel therapeutics for embryonal rhabdomyosarcomas, we developed and characterized 6 orthotopic xenografts of tumors in our discovery cohort. High throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for embryonal rhabdomyosarcoma.
Citation Format: Michael A. Dyer. Targeting the oxidative stress pathway in rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA05.
Abstract IA07: Genetic predispositions to pediatric cancers
Authors: Loh Mignon L. 
Published: May 2015

Abstract
Fortunately, childhood cancer remains a rare entity in the United States, with only 13,500 new cancers diagnosed per year in patients under the age of 19 years. However, an important component of the workup for the child who presents with cancer is obtaining a detailed family history of malignancy, which may provide clues to the frequently asked question posed by parents about “How did this happen to us?” Correctly identifying families who suffer from cancer predisposition syndromes provides critically important information for affected family members with respect to future prevention and screening. In addition, certain congenital syndromes are associated with an increased risk of malignancy and the altered genes identified in these syndromes have provided important clues about the pathogenesis of human cancer and cellular functions, which have also provided opportunities to identify new therapeutic approaches. This education session will provide a broad overview of the most common familial cancer risk syndromes that practicing oncologists should be familiar with as well as the types of cancers that most frequently occur in children with common congenital syndromes. In addition, emerging targeted therapeutic options will be discussed, where relevant.
Citation Format: Mignon L. Loh. Genetic predispositions to pediatric cancers. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA07.
Abstract IA08: Ataxia-telangiectasia: Broad implications from the study of a rare disease
Authors: Kastan Michael B. 
Published: May 2015

Abstract
DNA damage signaling pathways are critical mediators of both tumor development and tumor responses to chemotherapy and radiation therapy. Significant progress has been made in recent years in elucidating the molecular controls of cellular responses to DNA damage in mammalian cells. Much of what we have learned about damage signaling pathways has come from the study of human diseases, particularly cancer predisposition syndromes. Ataxia-Telangiectasia (A-T) is a pleiotropic disorder with multiple phenotypic abnormalities, including progressive neurodegeneration, immunodeficiencies, cancer predisposition, insulin resistance, telangiectasia development, infertility, and extreme radiosensitivity. ATM, the gene mutated in A-T, is a central mediator of responses to DNA double strand breaks in cells. Once activated, ATM phosphorylates numerous substrates in the cell that modulate the cell's response to the DNA damage. Though ATM clearly plays a central role in mediating cellular responses to DNA breakage, some of the clinical abnormalities in A-T are difficult to attribute directly to alterations in DNA damage signaling. The broad-based symptoms in A-T and recently acquired data suggest that ATM may have roles that extend beyond its regulation of DNA damage responses. In particular, ATM appears to affect insulin signaling pathways and evidence has been generated supporting a direct role for ATM in mitochondrial function. These new insights suggest that Ataxia-Telangiectasia should be considered, at least in part, as a mitochondrial dysfunction disease and provide links between cancer-related DNA damage signaling and more general metabolic signaling pathways. Some of these new insights are also providing opportunities for considerations of novel ways to modulate ATM function for clinical benefit.
Citation Format: Michael B. Kastan. Ataxia-telangiectasia: Broad implications from the study of a rare disease. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA08.
Abstract IA11: The St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project: Lessons learned
Authors: Downing James R. 
Published: May 2015

Abstract
In January of 2010, St. Jude Children's Research Hospital and The Genome Institute at the Washington University announced the launch of the Pediatric Cancer Genome Project (PCGP), a three year, $65 million privately funded initiative. The stated goal of this effort was to obtain 30-fold haploid coverage of the whole genome of 600 pediatric tumors and matched non-tumor germ line DNA samples (1200 total genomes), and to analyze these data in order to define the landscape of somatic mutations that underlie the major subtypes of pediatric leukemia, brain tumors, and solid malignancies. The initial phase of this project was completed in February of this year with over 700 pediatric cancers analyzed (1400 genomes). This effort has produced fundamental insights into each of the pediatric cancer subtypes sequenced. Not only has the data defined the spectrum of mutations that underlying specific pediatric cancers, but for some of the diseases analyzed, we have identified new prognostic markers and/or therapeutic targets. The effort has led to the generation of an incredibly rich data source that should serve the scientific community for years to come.
Based on the success of PCGP, we have begun a $30 million second phase of the project (PCGP Phase II) that will be completed in a two year timeframe. In this second phase, we will focus not only on discovery science, but also on the establishing the technologies, analytical tools, and medical interface needed to move genome-wide sequence analyses into the diagnostic work up of pediatric cancer patients. In this talk, I will present an overview of this project and highlight some of the important results that have emerged.
Citation Format: James R. Downing. The St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project: Lessons learned. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA11.
Abstract IA18: Mapping cancer origins
Authors: Gilbertson Richard J. 
Published: May 2015

Abstract
Histologically similar cancers respond differently to treatment. Consequently, significant populations of cancer patients continue to suffer morbidity and mortality while others with apparently similar tumors are cured. Understanding the biology that drives this heterogeneity is crucial if we are to develop effective treatments for all patients. Advanced genomic technologies have enabled us to divide cancer patients into distinct subgroups, often with different prognoses. However unmasking the mechanisms that generate these molecular subgroups has proven difficult, since their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. This talk will describe a series of recent and ongoing studies in which cross-species genomics approaches have been used to define the cellular and molecular origins of subgroups of brain tumors. By mapping regional and developmental patterns of human brain tumor subgroup gene expression in the developing mouse nervous system, it has been possible to identify variants of normal neural stem cells that share remarkably similar transcriptomes. These similarities in transcriptome reveal candidate cells of origin with a biologic ‘groundstate’ that is highly susceptible to transformation into the corresponding tumor type. Introduction of gene mutations into transcriptome-matched, but not other, normal mouse NSCs generated accurate tumor models of the corresponding human brain tumor subgroup. These models can then be used in high-throughput drug screens to identify subgroup specific treatments.
Citation Format: Richard J. Gilbertson. Mapping cancer origins. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA18.
Abstract IA23: The genomic landscape of acute lymphoblastic leukemia
Authors: Mullighan Charles 
Published: May 2015

Abstract
Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and a leading cause of cancer related death in young people. The last decade has witnessed intense activity in the field of ALL genomics, initially with microarrays and more recently with next generation sequencing, with the goal of comprehensively identifying all genetic alterations contributing to leukemogenesis, treatment failure and relapse. These studies have defined new entities of ALL, and have shown that each ALL subtype is typically defined by constellations of recurring chromosomal alterations and sequence mutations that target key cellular pathways including lymphoid maturation, cellular proliferation, tumor suppression, and chromatin modification. Genomic profiling has also identified genetic alterations that have clear implications for leukemia diagnosis and therapy in several subtypes of high-risk leukemia, including early T-cell precursor ALL, hypodiploid ALL, and BCR-ABL1-like ALL. Several genetic alterations are associated with an increased risk of leukemia relapse, including IKZF1, CREBBP, and NT5C2. Moreover, studies interrogating germline genetic variation have identified common variants associated with leukemia susceptibility, including risk of specific subtypes of ALL and ALL in different ethnic groups, and inherited mutations in familial ALL. Ongoing efforts are completing the genomic characterization of the spectrum of ALL cases, dissecting the genetic basis of clonal heterogeneity of ALL, and expanding these studies into integrated analysis of structural variation with the leukemia epigenome and transcriptome.
Citation Format: Charles Mullighan. The genomic landscape of acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA23.