bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B35: Enhanced antitumor efficacy by combining oncolytic herpes simplex virus and Aurora A kinase inhibition in models of neuroblastoma and malignant peripheral nerve sheath tumor
Authors: Currier Mark , Rizvi Tilat , Nartker Brooke , Chen Duo , Chen Chun-Yu , Wang Pin-Yi , Sprague Les , Franczek Meghan , Patel Ami , Chaney Katherine , Streby Keri , Ecsedy Jeff , Conner Joe , Ratner Nancy , Cripe Timothy 
Published: May 2016

Abstract
We previously reported xenograft models of neuroblastoma and malignant peripheral nerve sheath tumor (MPNST) are responsive to direct intratumoral injection of oncolytic Herpes Simplex Viruses (Parikh et al., Ped Blood Can 44:469, 2005; Mahller et al., Ped Blood Can 46:745, 2006; Mahller et al., Can Res 68:1170, 2008). We have confirmed these findings using an oncolytic HSV, Seprehvir (HSV1716), which is in clinical trials that include pediatric patients (NCT00931931, NCT02031965). The models showed wide variability, however, with some models having maintained complete responses and others showing only delayed growth. Because DNA viruses are highly dependent on normal nuclear machinery for DNA synthesis/replication and virus packaging/assembly, we postulated that increased transit time in mitosis may be beneficial to an oncolytic DNA virus. Aurora A Kinase is an enzyme critical for formation of centrioles and mitotic spindles during mitosis and is often dysregulated in cancer. The selective AAK inhibitor, Alisertib (MLN8237), arrests cells in G2/M and has significant activity in models of neuroblastoma (data from the Pediatric Preclinical Testing Program) and in MPNST (data from our prior study: Patel et al., Clin Can Res 18:5020, 2012). We found tumor responses in xenograft models using the combination of Seprehvir and Alisertib was more than additive. Immunohistochemical staining for HSV antigens revealed a marked difference in the extent and spread of virus as early as 24 hrs after virus injection. Our preliminary data assessing kinetics of virus infection suggest that Alisertib pretreatment enhances virus uptake and spread, accounting for the combinatorial effects. These data strongly suggest alisertib pretreatment “primes” tumor cells, making them highly susceptible to virus infection and spread and greatly accelerates the virolytic effects. Overall, our findings support clinical testing of Alisertib combined with Seprehvir in patients with refractory neurogenic tumors such as neuroblastoma and MPNST.
Citation Format: Mark Currier, Tilat Rizvi, Brooke Nartker, Duo Chen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Meghan Franczek, Ami Patel, Katherine Chaney, Keri Streby, Jeff Ecsedy, Joe Conner, Nancy Ratner, Timothy Cripe. Enhanced antitumor efficacy by combining oncolytic herpes simplex virus and Aurora A kinase inhibition in models of neuroblastoma and malignant peripheral nerve sheath tumor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B35.
Abstract B39: NQO1 as a therapeutic target for atypical teratoid/ rhabdoid tumor
Authors: Meade Julia C. , Moore Zachary R. , Stuart Sarai H. , Cholka Agnieszka , Boriack Richard L. , Xu Jingying , Erdreich-Epstein Anat , Rakheja Dinesh , Boothman David A. , Amatruda James F. , Laetsch Theodore W. 
Published: May 2016

Abstract
Atypical Teratoid/ Rhabdoid Tumor (ATRT) is an aggressive cancer that accounts for up to 20% of infant brain tumors. Even with intense chemotherapy and radiation, approximately 75% of children die from their disease at a median of 10 months after diagnosis. We found that the pathognomonic genetic lesion of ATRTs and related malignant rhabdoid tumors (MRTs), loss of the SWI/SNF chromatin remodeling complex member INI1/hSNF5/SMARCB1, is associated with high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a two-electron oxidoreductase. Thus, we hypothesized that ATRTs will be vulnerable to drugs such as ß-lapachone (ß-lap, ARQ761 in clinical form) that selectively kill NQO1-expressing cells via mu-calpain mediated cell necrosis.
A panel of ATRT cell lines exhibited overall high NQO1 expression and sensitivity to ß-lap (IC50 1.6-4 uM). A two-hour pulse with ß-lap caused a burst of ROS-mediated DNA damage and PARP1 hyperactivation, resulting in NAD+ and ATP depletion. Lack of NQO1 expression or inhibition of NQO1 with dicoumarol abrogated sensitivity to ß-lap. Low expression of NQO1 in normal brain and other pediatric tissues suggests a wide therapeutic window for ß-lap, and a survival advantage was observed after treatment in a heterotopic mouse xenograft model with several mice achieving apparent cures. Furthermore, the mechanism of ß-lap results in synergy with standard of care agents such as ionizing radiation, increasing its potential for clinical applications.
Citation Format: Julia C. Meade, Zachary R. Moore, Sarai H. Stuart, Agnieszka Cholka, Richard L. Boriack, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch. NQO1 as a therapeutic target for atypical teratoid/ rhabdoid tumor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B39.
Abstract B42: Hope for a future: Conditional survival estimates for childhood cancer in Australia, 2002-2011
Authors: Youlden Danny , Baade Peter , Hallahan Andrew , Valery Patricia , Green Adele , Aitken Joanne 
Published: May 2016

Abstract
Purpose: Conditional survival rates provide a more realistic assessment of long-term prognosis than survival rates calculated from the date of diagnosis because they take into account the time that a patient has already remained alive following diagnosis. However, estimates of conditional survival are scarce for childhood cancer. Here we provide results from a national population-based childhood cancer registry by diagnostic group, age at diagnosis and stage of cancer.
Methods: De-identified population-based data were obtained from the Australian Paediatric Cancer Registry for children aged 0-14 years diagnosed with cancer between 1983 and 2010. Mortality status was followed up to the end of 2011. The hybrid period method was used to calculate relative survival estimates for those who were at risk during the period 2002 to 2011. Conditional survival was then obtained from the ratio of the relative survival estimates at different time points.
Results: A total of 13,537 children were eligible for inclusion in the study. Five-year survival for all childhood cancers combined improved from 82% at diagnosis (95% confidence interval = 81%-83%) to 89% (88%-90%), 95% (94%-96%) and 97% (97%-98%) conditional on surviving 1, 3 and 5 years after diagnosis, respectively. Conditional survival reached 95% within five years of diagnosis for nearly all types of cancer, regardless of age or stage at diagnosis.
Conclusions: Most children diagnosed with cancer who are alive five years after diagnosis can anticipate a similar chance of survival to children in the general population. For childhood cancer patients and their families, this information provides a more accurate and optimistic picture of long-term prognosis than has been available until now.
Citation Format: Danny Youlden, Peter Baade, Andrew Hallahan, Patricia Valery, Adele Green, Joanne Aitken. Hope for a future: Conditional survival estimates for childhood cancer in Australia, 2002-2011. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B42.
Abstract B48: The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma
Authors: Basma Hussein , Ghayad Sandra , Mancinelli Angelo , Pisano Claudio , Darwiche Nadine , Saab Raya 
Published: May 2016

Abstract
Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some anti-tumor efficacy in RMS cells in vitro, however the effects are of low magnitude. E-3-(4'-hydroxyl-3'-adamantylbiphenyl-4-yl) acrylic acid (known as ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable in vivo micromolar concentrations. ST1926 induced an early DNA damage response, which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion protein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in retarding the growth of ARMS and ERMS xenografts, and induced a prominent DNA damage response. We conclude that ST1926 has preclinical efficacy against RMS, and should be considered further investigated in clinical trials, possibly in combination therapy.
Citation Format: Hussein Basma, Sandra Ghayad, Angelo Mancinelli, Claudio Pisano, Nadine Darwiche, Raya Saab. The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B48.
Abstract IA04: Using genome editing to model MLL rearranged leukemias
Authors: Breese Erin , Buechele Corina , Cleary Michael , Porteus Matthew 
Published: May 2016

Abstract
MLL rearranged leukemias, particularly those associated with infant acute lymphoblastic leukemias, continue to have a generally poorer prognosis than other childhood leukemias. Improved understanding of these leukemias has been gained by using transgenic mouse models and retroviral transduction of human cells but each of these approaches has well recognized limitations. With the recent development of an expanded genome editing toolbox, it is now possible to use genome editing in primary human hematopoietic stem and progenitor cells (HSPCs) to directly re-create genomic rearrangements, including those involving the MLL gene. Using these tools we have generated MLL-AF4 and MLL-AF9 translocations in HSPCs and studied the biologic properties of these cells. Moreover, we have further used genome editing of HSPCs to knock-in the AF9 fusion partner into the MLL locus to create the MLL-AF9 fusion. When the modified HSPCs were transplanted into immunodeficient mice (NSG), these modified cells gave rise to ALL, mixed phenotype leukemias, and AML. These results now give a powerful new way to study the developmental biology and pathogenesis of MLL rearranged leukemias and provide a proof-of-concept of how genome editing of human HSPCs can be used to study a wide variety of hematologic disorders.
Citation Format: Erin Breese, Corina Buechele, Michael Cleary, Matthew Porteus. Using genome editing to model MLL rearranged leukemias. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA04.
Abstract IA05: Oncogenic signaling pathways and resistance to therapy in T-ALL
Authors: Ferrando Adolfo 
Published: May 2016

Abstract
Aberrant NOTCH1 signaling plays a major role in the pathogenesis of over 60% of T-ALLs harboring activating mutations in the NOTCH1 gene. Most notably, oncogenic NOTCH1 has been proposed as a therapeutic target in NOTCH1-mutant leukemias and small molecule γ-secretase inhibitors (GSIs), which effectively block NOTCH activation via inhibition of a critical intramembrane proteolytic cleavage required for NOTCH signaling. However, the clinical development of anti-NOTCH1 therapies in T-ALL has been hampered by the limited and delayed therapeutic response to these drugs, making the identification of highly effective and synergistic drug combinations capable of delivering strong antileukemic responses a top priority in the field. Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of clinical response to anti-NOTCH1 therapies. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, both inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapies. Moreover, Pten loss and consequent activation of the PI3K pathway induces increased glycolysis and consequently rescues leukemic cell metabolism abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL. These results highlight the fundamental importance of NOTCH1 signaling in the control of leukemia cell metabolism, extend our understanding of the prominent role of PTEN and the PI3K pathway in the control of oncogenic cell growth and provide the basis for the design of new therapeutic strategies targeting cell metabolism for the treatment of T-ALL.
Citation Format: Adolfo Ferrando. Oncogenic signaling pathways and resistance to therapy in T-ALL. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA05.
Abstract IA18: Children, adolescents, and young adult ALL: Translating novel discoveries into therapeutic opportunities
Authors: Loh Mignon L. 
Published: May 2016

Abstract
Acute lymphoblastic leukemia (ALL) is a genetically complex disease that remains a major cause of childhood cancer-related mortality. Some subsets of ALL can be successfully treated with traditional cytotoxic chemotherapy while others remain at high risk of relapse. Specifically, adolescents and young adults have higher relapse rates than younger children and also experience increased toxicity with cytotoxics. Major advances in genomic profiling through the application of next generation sequencing technologies in these high risk patients have uncovered recurrent mutations in key pathways that may be targeted with the addition of signal transduction inhibitors to chemotherapy. Such therapeutic approaches will mandate genetically precise risk stratification of patients. The Children's Oncology Group (COG) is poised to act in real time to identify these high risk subsets and will be introducing relevant signal transduction inhibitors in clinical trials shortly. Relapsed ALL remains a significant therapeutic challenge additional genomic analyses have shed light on new events that occur at relapse, but these may be difficult to individually target. Indeed, immunotherapeutic approaches are being harnessed to focus on eradicating the malignant B-cell without regard to genetic lesions, which may be useful in relapsed ALL. This discussion will review genomic data generated through large scale collaborations with the COG ALL committee and also present an overview of the clinical trials that will capitalize on these recent discoveries.
Citation Format: Mignon L. Loh. Children, adolescents, and young adult ALL: Translating novel discoveries into therapeutic opportunities. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA18.
Abstract IA19: Genome-epigenome interplay in medulloblastoma
Authors: Northcott Paul 
Published: May 2016

Abstract
The recent application of genomics to large series of primary human medulloblastomas has dramatically improved our perspective of the genes, pathways, and molecular processes underpinning this highly malignant pediatric brain tumor. Transcriptionally defined molecular subgroups have emerged, changing the fundamental definition of medulloblastoma from a single histologically recognized entity, to four distinct subtypes: WNT, SHH, Group3, and Group4. These subgroups exhibit highly discriminatory genomic landscapes, patient demographics, and clinical phenotypes. Next-generation sequencing has identified and implicated recurrently altered somatic drivers, many of which are affected in a subgroup-restricted manner. In contrast, somatic variants affecting chromatin-modifying genes, including histone writers, erasers, and readers are prevalent in medulloblastoma and occur across subgroups, suggesting that deregulation of the epigenome is an essential step during medulloblastoma development. Integrative omics-based strategies have begun to dissect the fascinating genome-epigenome interplay underlying medulloblastoma, revealing previously undisclosed oncogenic mechanisms and drivers of disease. Furthermore, new insights into the biology and putative origins of the poorly understood Group3 and Group4 medulloblastomas have likewise been revealed. This talk will summarize these recent discoveries afforded through genomics and discuss their potential implications, both in the lab and in the clinic, going forward.
Citation Format: Paul Northcott. Genome-epigenome interplay in medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA19.
Abstract PR10: The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy
Authors: Marques Joana , Boehm Maria , Wachtel Marco , Schaefer Beat 
Published: May 2016

Abstract
Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is a paediatric tumour driven by an oncogenic fusion transcription factor, PAX3-FOXO1. Conventional chemotherapy is only effective for low risk patients which carry no metastasis, achieving a 5-year overall survival of 65%. The unique presence of this fusion protein in FP-RMS as well as the tumour cell survival dependency on PAX3-FOXO1 make this transcription factor a promising target for therapy. However, due to the difficulties associated with drug development targeting transcription factors, we performed a combined proteomic and genetic screen to identify new druggable co-regulators of PAX3-FOXO1 transcriptional activity.
Interactor candidates were defined by mass spectrometry analysis of proteins co-purified with the fusion protein and individually validated for their relevance for PAX3-FOXO1 activity through siRNA silencing. The chromodomain-DNA-binding protein 4 (CHD4), a nucleosome remodeler and core member of the NuRD complex (Nucleosome Remodelling and Deacetylase), was identified as an essential positive co-regulator of PAX3-FOXO1 transcriptional activity. ChIP-qPCR experiments demonstrated that CHD4 not only co-localizes with PAX3-FOXO1 in the FP-RMS genome but also it is necessary for the binding of the fusion protein to cis-regulatory sites for a subset of its target genes. Consequently, CHD4 silencing affected the expression of more than 50% of PAX3-FOXO1 regulated target genes. Additionally, depletion of CHD4 impaired FP-RMS cell proliferation and caused a complete regression of xenograft tumours in mice. Moreover, CHD4 silencing had no effect in cell proliferation of human myoblasts or fibroblasts, suggesting a unique tumour dependency on this chromatin remodeler.
In summary, our data propose that CHD4 has a crucial role as a co-regulator of PAX3-FOXO1 driven gene expression whose presence is required for FP-RMS cell viability. To our knowledge, CHD4 is the first identified chromatin remodeler associated with PAX3-FOXO1 transcriptional activity, thus highlighting the relevance of epigenetic regulation in FP-RMS tumour development. Collectively, our findings suggest CHD4 as a potential novel therapeutic target in this childhood malignancy, and are motivating ongoing work aimed at finding first-in-class small molecules to inhibit CHD4.
This abstract is also presented as Poster A20.
Citation Format: Joana Marques, Maria Boehm, Marco Wachtel, Beat Schaefer. The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr PR10.