bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A14: Checkpoinblockade enhances oncolytic herpes virotherapy in immunosuppressive sarcoma models
Authors: Chun Chun-yu , Wang Pin-Yi , Hutzen Brian , Haworth Kellie , Conner Joe , Cripe Timothy 
Published: May 2016

Abstract
Most solid tumors are characterized by an immunosuppressive microenvironment, limiting the effectiveness of antitumor immunotherapeutics. Programmed cell death protein (PD)-1-mediated T cell suppression via engagement of its ligand, PD-L1, is of particular interest due to recent successes in selected adult cancers. The utility of PD1-directed therapy for pediatric cancers is unknown, especially given the paucity of mutations and thus infrequent neoantigens in many types of childhood tumors. Oncolytic virotherapy induces tumor shrinkage via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines, and induction of anti-tumor T cell responses. We recently demonstrated that intratumoral injection of an oncolytic herpes virus induced growth delays and in some cases durable remissions in several mouse models of rhabdomyosarcoma. The effects were T cell mediated, rendering surviving mice resistant to tumor rechallenge and being absent in athymic nude hosts (Leddon et al., Mol Ther-Oncolytics 1, Article number: 14010, 2015). We found these tumor models express PD-L1, suggesting that T cell checkpoints may in part limit virus-induced antitumor immunity. Here we show the implantable C57Bl/6 rhabdomyosarcoma model, M3-9-M, showed a moderate response to single-agent Seprehvir (HSV1716), a virus currently in pediatric clinical trials (NCT00931931, NCT02031965). Single-agent PD-1 blockade also showed moderate but significant tumor growth delay with no complete responses. Strikingly, combining these two therapies together substantially prolonged overall survival with several complete responses post 40 days treatment. We hypothesize that virotherapy-induced chemokine secretion increases the recruitment of antitumor T cells, while PD-1 blockade increases their effectiveness. Overall, our data suggest the combination of PD-1 and oncolytic herpes virotherapy may be an effective treatment strategy for some cancers.
Citation Format: Chun-yu Chun, Pin-Yi Wang, Brian Hutzen, Kellie Haworth, Joe Conner, Timothy Cripe. Checkpoinblockade enhances oncolytic herpes virotherapy in immunosuppressive sarcoma models. [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 A14.
Abstract A34: EWS/FLI regulates transcriptional activation in Ewing sarcoma via length dependent GGAA microsatellites
Authors: Johnson Kirsten M. , Gangwal Kunal , Robertson James , Cheatham Thomas E. , Lessnick Stephen L. 
Published: May 2016

Abstract
The purpose of this study is to investigate how EWS/FLI transcriptionally activates gene targets via polymorphic GGAA microsatellites. Ewing Sarcoma is a pediatric bone malignancy initiated by a t(11;22) chromosomal translocation that produces the EWS/FLI oncoprotein. EWS/FLI transcriptionally activates and represses its target genes to mediate oncogenic reprogramming. Expression of its up-regulated targets correlates with EWS/FLI binding to associated GGAA microsatellites. These microsatellites show length polymorphisms, suggesting that microsatellite polymorphisms may have critical effects on EWS/FLI-responsiveness of key gene targets. For example, NR0B1 is necessary for EWS/FLI mediated oncogenic transformation, and we found a “sweet-spot” of 24-25 repeat length as optimal for EWS/FLI mediated transcriptional activity at NR0B1. The mechanism underlying this optimal length is unknown. We therefore explored the stoichiometry and binding affinity of EWS/FLI for different repeat lengths through biochemical studies combined with molecular modeling simulation. Our data demonstrate a complex relationship between microsatellite length and transcriptional activity. Fluorescence anisotropy studies demonstrate that FLI binding affinity is independent of GGAA microsatellite length. In contrast, the stoichiometry of protein to DNA binding increases in specific incremental patterns with increasing microsatellite repeats. Gel shift binding assays elucidate the minimal microsatellite length critical for binding. Overall our data suggests a model in which the DNA binding domain of multiple monomers of FLI function as independent binding units to facilitate transcriptional activity in a length-dependent fashion. We propose that GGAA microsatellites are necessary and sufficient for EWS/FLI-mediated oncogenic transformation and that repeat length affects optimal DNA binding stoichiometry and transcriptional activity.
Citation Format: Kirsten M. Johnson, Kunal Gangwal, James Robertson, Thomas E. Cheatham, Stephen L. Lessnick. EWS/FLI regulates transcriptional activation in Ewing sarcoma via length dependent GGAA microsatellites. [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 A34.
Abstract A47: Unusual suspects identified in neuroblastoma: An unexpected tumor suppression pathway
Authors: Choo Zhang'e , Koh Rachel Yu Lin , Wallis Karin , Koh Timothy Jia Wei , Kuick Chik Hong , Sobrado Veronica , Loh Amos Hong Pheng , Soh Shui Yen , Schlisio Susanne , Chang Kenneth Tou En , Chen Zhi Xiong 
Published: May 2016

Abstract
Developmental apoptosis of neural crest precursors is crucial in determining the final number of terminally differentiated cells such as sympathetic neurons. During neural development, cells undergo apoptosis as NGF becomes limiting. Aberrant developmental apoptosis is implicated in pediatric sympathetic nervous system tumors. When NGF becomes limiting, a developmental apoptotic pathway is activated which requires KIF1Bbeta. KIF1Bbeta is necessary and sufficient for apoptosis during NGF withdrawal. KIF1Bbeta maps to 1p36.2, a frequently deleted region in neuroblastomas, and a neural crest-derived cancer. We identified that KIF1Bbeta-induced apoptosis requires RNA/DNA helicase DHX9. KIF1Bbeta interacts with DHX9 to enhance translocation and accumulation of cytoplasmic DHX9 in the nucleus, resulting in transcription of apoptotic XAF1. Transcription-incompetent DHX9 is unable to potentiate KIF1Bbeta-induced cell death. Knockdown of DHX9 also protects from KIF1Bbeta-induced cell death whereas KIF1Bbeta loss-of-function domains or patient-associated point mutants are unable to translocate and accumulate cytoplasmic DHX9 in the nucleus, impairing XAF1 expression. Furthermore, XAF1 silencing protects from KIF1Bbeta-induced and NGF withdrawal-mediated apoptosis in vitro as well as promotes tumor growth in vivo whereas XAF1 overexpression is necessary and sufficient to induce apoptosis in vitro and delays tumor growth in vivo. Conditional knockout of KIF1Bbeta in the superior cervical ganglia neurons of mouse pups also specifically ablates XAF1 expression in vivo and ex vivo, suggesting that KIF1Bbeta and XAF1 are tightly regulated and act along the same pathway. Clinically, tissue microarray analysis of pre-treatment or post-treatment neuroblastoma patients who are 1p-intact or 1p-deleted, revealed strong prognostic significance of XAF1 expression in disease stratification. Our findings provide a mechanistic understanding on the development of neuroblastoma through unexpected candidates of tumorigenesis.
Citation Format: Zhang'e Choo, Rachel Yu Lin Koh, Karin Wallis, Timothy Jia Wei Koh, Chik Hong Kuick, Veronica Sobrado, Amos Hong Pheng Loh, Shui Yen Soh, Susanne Schlisio, Kenneth Tou En Chang, Zhi Xiong Chen. Unusual suspects identified in neuroblastoma: An unexpected tumor suppression pathway. [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 A47.
Abstract A52: Investigation of p53 restoration therapy in a mouse model of pineoblastoma
Authors: Harajly Mohammad , Zalzali Hassan , Nawaz Zafar , Saab Raya 
Published: May 2016

Abstract
Background: Pineoblastoma is a malignant childhood tumor with poor outcomes. We have previously characterized a mouse model of pineoblastoma induced by transgenic expression of Cyclin D1 in a p53 null background. We showed that Cyclin D1 expression in the setting of intact p53 results in pineal hyperplasia, but no onset of invasive tumors, reminiscent of pineal enlargement seen in a subset of children with RB haploinsufficiency. In the setting of p53 loss, pineoblastoma occurs with 100% penetrance. We now investigated the role of p53 restoration therapy in prevention and treatment of pineoblastoma using this mouse model.
Results: We found that restoration of p53 in mouse pre-malignant proliferating pineal tumors results in tumor prevention, shown by effective cell cycle exit and induction of cellular senescence, a tumor suppressor mechanism. Conversely, p53 reactivation in established malignant pineal tumors had no effect cell proliferation, unless paired with DNA damaging therapy. The response to p53 restoration did not correlate with levels of p19Arf expression. Interestingly, in premalignant lesions, p53 restoration was associated with secondary amplification of MAPK signaling and induction of p19Arf expression. Subsequent inactivation of p53 after senescence resulted in diffuse re-entry into the cell cycle and rapid tumor progression. Evaluation of a panel of human supratentorial primitive neuroectodermal tumors showed low activity of the p53 pathway, while only one of 6 tumors had p53 deletion or mutation.
Conclusion: Our data shows that, in a mouse model of Cyclin D1-driven pineoblastoma, restoration of p53 has different effects in premalignant versus invasive pineal tumors, where it may need to be paired with DNA damaging agents for effective tumor suppression. Furthermore, p53 activation may need to be continually sustained in such lesions undergoing senescence. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene seems to be intact but the pathway inactive in the majority of examined tumors.
Citation Format: Mohammad Harajly, Hassan Zalzali, Zafar Nawaz, Raya Saab. Investigation of p53 restoration therapy in a mouse model of pineoblastoma. [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 A52.
Abstract B01: MicroRNAs as novel therapeutic adjuvants to treat high-risk medulloblastoma.
Authors: Abdelfattah Nourhan , Subbarayalu Panneerdoss , Onyeagucha Benjamin , Rajamanickam Subapriya , Chen Hung-I Harry , Rao Manjeet 
Published: May 2016

Abstract
Medulloblastoma is the most common malignant brain tumor in children, accounting for 18% of newly diagnosed brain tumors and 10% of all children cancer-related deaths. Despite improvement in the 5-year survival rate of medulloblastoma in recent years, only a small percentage of patients survive high-risk metastatic disease. The quality of life for those who do survive is often substantially reduced due to the toxicity associated with radiation and chemotherapy. Vincristine is a microtubule-destabilizing antimitotic drug, which is routinely administered in higher dosages to both high and average risk medulloblastoma patients. As a result, these patients suffer from devastating neurotoxic effects that include but not limited to: sensorimotor and autonomic neuropathy, hearing loss, mononeuropathy, and seizures. Using high-throughput microRNA mimic library screens, we identified a group of microRNAs that may improve the efficacy of vincristine against c-MYC amplified medulloblastoma as well as re-sensitize vincristine-resistant medulloblastoma. Our findings revealed that these microRNAs may act as tumor suppressors since their overexpression inhibited colony formation, migration and invasion ability of medulloblastoma cells. Furthermore, these microRNAs suppressed stem cell renewal/proliferation of c-MYC amplified medulloblastoma cells. Expression analysis, gene enrichment analysis and target prediction algorithms revealed that these microRNAs exert their vincristine sensitizing and tumor suppressor effect by targeting genes involved in microtubule organization, cell cycle regulation, DNA damage repair and mRNA translation. One of our most interesting targets is EIF4E3, which is a translation initiation factor. Our preliminary findings indicate that EIF4E3 may regulate medulloblastoma cell growth, progression and vincristine sensitivity by modulating c-MYC translation. Further experiments are underway to test the potential of candidate miRNA and EIF4E3 as vincristine sensitizer in vivo. In conclusion, this study may identify novel factors that have potential not only to decrease the current therapeutic dose of vincristine and therefore eliminate its side effects, but also have potential to multiply the efficacy of lower doses in order to overcome hard to treat high-risk tumors.
Citation Format: Nourhan Abdelfattah, Panneerdoss Subbarayalu, Benjamin Onyeagucha, Subapriya Rajamanickam, Hung-I Harry Chen, Manjeet Rao. MicroRNAs as novel therapeutic adjuvants to treat high-risk 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 B01.
Abstract B26: Therapeutic targeting of sarcomas driven by EWSR1 fusion oncogenes by modulation of the fusion oncogene pre-mRNA
Authors: Slotkin Emily , Stanchina Elisa de , Cartegni Luca , Ladanyi Marc , Spraggon Lee 
Published: May 2016

Abstract
Many predominantly pediatric sarcomas are driven by chromosomal translocations that generate oncogenic fusion transcription factors. The Ewing sarcoma breakpoint region 1 (EWSR1) is one of the most commonly involved genes in sarcoma translocations. This gene has a large number of fusion partners, primarily associated with the pathogenesis of Ewing sarcoma, but also with other soft tissue sarcomas. Targeting the resulting aberrant oncogenic chimeric transcription factors would provide an ideal therapy, but this has approach has proved elusive with conventional small molecule approaches. We have developed an approach to employ splice-switching oligonucleotides to redirect the pre-mRNA splicing of EWSR1 fusion transcription factors. Through targeted exon skipping, and/or activation of intronic polyadenylation, these new compounds provide a targeted therapeutic approach for EWSR1 translocation positive sarcomas and other malignancies.
Citation Format: Emily Slotkin, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi, Lee Spraggon. Therapeutic targeting of sarcomas driven by EWSR1 fusion oncogenes by modulation of the fusion oncogene pre-mRNA. [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 B26.
Abstract B38: Developing a functional genomics platform to interrogate rare pediatric cancers
Authors: Hong Andrew L. , Cowley Glenn S. , Tseng Yuen-Yi , Cheah Jaime H. , Jonas Oliver , Doshi Mihir B. , Kynnap Bryan D. , Oh Coyin , Meyer Stephanie , Clemons Paul , Burger Michael , Vazquez Francisca , Weir Barbara , Kryukov Gregory V. , Church Alanna , Imamovic Alma , Tsherniak Aviad , Bielski Craig , Crompton Brian , Mullen Elizabeth , Roberts Charles , Rodriguez-Galindo Carlos , Janeway Katherine A. , Stegmaier Kimberly , Hummelen Paul van , Langer Robert , Garraway Levi A. , Schreiber Stuart L. , Root David E. , Boehm Jesse S. , Hahn William C. 
Published: May 2016

Abstract
Of pediatric solid tumors, as many as 10% of tumors are categorized as rare. Many of these rare tumors lack standard effective known therapy. The ability to identify vulnerabilities for many rare tumors has been significantly limited by the lack of in vitro and in vivo models. Furthermore, current approaches to study such vulnerabilities are usually limited to a specific compound or target. Our objectives were 1) to develop a platform to collect tumor samples and generate in vitro models and 2) to develop systematic and orthogonal approaches focused on currently known druggable cancer targets to identify vulnerabilities in these difficult to treat cancers. We have developed a proof of concept cell line from a patient who succumbed to progressive undifferentiated sarcoma treated on an aggressive multi-therapy regimen. This cell line, in its early passages, has novel gene fusions that match that of the primary tumor. Furthermore, even at early passages, this cell line was amenable to high throughput functional screens. Using a targeted pooled shRNA screen (employing matched seed controls) and an analogous CRISPR screen we identified dependencies to XPO1 and CDK4. In parallel, compounds against these targets were identified in a small molecule compound screen. These targetable dependencies were further validated in vivo with a micro-dosing device. These observations identify new targets in this rare malignancy. Furthermore, this suggests that the interrogation of patient derived cell lines facilitates the identification of testable therapeutic approaches.
Citation Format: Andrew L. Hong, Glenn S. Cowley, Yuen-Yi Tseng, Jaime H. Cheah, Oliver Jonas, Mihir B. Doshi, Bryan D. Kynnap, Coyin Oh, Stephanie Meyer, Paul Clemons, Michael Burger, Francisca Vazquez, Barbara Weir, Gregory V. Kryukov, Alanna Church, Alma Imamovic, Aviad Tsherniak, Craig Bielski, Brian Crompton, Elizabeth Mullen, Charles Roberts, Carlos Rodriguez-Galindo, Katherine A. Janeway, Kimberly Stegmaier, Paul van Hummelen, Robert Langer, Levi A. Garraway, Stuart L. Schreiber, David E. Root, Jesse S. Boehm, William C. Hahn. Developing a functional genomics platform to interrogate rare pediatric cancers. [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 B38.
Abstract B46: MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma
Authors: Ribeiro Diogo , Westermark Ulrica , Klarqvist Marcus , Lovén Jakob , Henriksson Marie Arsenian 
Published: May 2016

Abstract
Neuroblastoma is the most common extra-cranial solid tumor in children and arises from neural crest cells involved in the development of sympathetic nervous tissue. This childhood tumor is characterized by heterogeneity and amplification of the MYCN oncogene is highly associated with aggressive tumors and poor outcome. The aim of this study was to investigate the role of the MYCN-driven miR-17-92 cluster in neuroblastoma pathogenesis. In order to identify putative targets of miR-17-92 we performed in silico prediction analysis and found that miR-17-92 target sites are significantly enriched in the nuclear hormone receptor (NHR) super family, indicating a role for hormonal regulation in neuroblastoma tumorigenesis. Importantly, high expression of several of the NHRs correlated with increased event-free survival of neuroblastoma patients. By using non-MYCN amplified neuroblastoma cells with a tet-regulatable miR-17~92 we could verify a differentially expressed NHR profile in induced compared to uninduced cells. Interestingly, one of the most significantly dowregulated NHRs was the glucocorticoid receptor (GR). Moreover, luciferase reporter assays containing the wildtype or mutated 3'UTR from the gene encoding GR demonstrate that it is a direct target of miR-17~92. Importantly, both MYCN and miR17~92 are able to downregulate GR. We further show that activation of GR signaling by dexamethasone induces differentiation markers and contributes to neural differentiation. Inhibition of MYCN activity and activation of GR signaling induced a significant reduction in tumor growth in a xenograft model of neuroblastoma. Taken together, our findings indicate an important role for miR-17-92 cluster in regulation of NHRs in neuroblastoma biology, with important implications for future therapeutic approaches in patients with MYCN-amplification.
Citation Format: Diogo Ribeiro, Ulrica Westermark, Marcus Klarqvist, Jakob Lovén, Marie Arsenian Henriksson. MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma. [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 B46.
Abstract IA02: Human ES cells for modeling brain cancer
Authors: Tabar Viviane 
Published: May 2016

Abstract
Diffuse Intrinsic Pontine Gliomas (DIPG) are a highly aggressive tumor of the brainstem occurring primarily in children. The outlook of patients with this disease is particularly dire due to the tumor's inaccessible location and its lethal course over one or two years. Recent sequencing data identified, for the first time in human cancer, heterozygous mutations in the histone H3 that create a lysine to methionine amino acid substitution. Using a human ES-based platform, we demonstrate the exquisitely cell-context specific oncogenic role of the H3K27M mutation. The model recapitulated the histological features and in vivo progression of the human tumor, as well as its transcriptomal and epigenetic profile. Genome wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive state, with evidence of major modifications of histone marks at master regulatory genes.
Drug screens in the ES model identified a compound that targets menin, a protein with multiple partners the mixed leukemia lineage protein MLL. The compounds have been validated in patient derived DIPG cell lines and are undergoing intense preclinical assessments. The ES model, coupled with more recent gene editing technology, provides a very powerful platform for the dissection of the requirements of neoplastic transformation in specific tumors, the specification of cells of origin, as well insight into the downstream effectors of individual and combined mutations.
Human pluripotent stem cells have an excellent potential as platform for modeling cancer. Work to extend these findings to additional mutations and tumor types is ongoing.
Ref. Funato et al. Science. 2014 Dec 19;346 (6216)
Citation Format: Viviane Tabar. Human ES cells for modeling brain cancer. [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 IA02.