bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B21: Epigenetic modifiers MLL1 and JMJD3 regulate neuroblastoma tumorigenicity by maintaining a cancer stem cell-like population
Authors: Agarwal Saurabh , Tomolonis Julie , Vasudevan Sanjeev , Shohet Jason 
Published: February 2019

Abstract
High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology. Despite significant dose escalation of intense therapies, long-term survival for NB patients remains poor (&lt;45%), and the disease accounts for almost 15% of all pediatric cancer deaths. Relapse of metastatic, drug-resistant disease and treatment-related toxicities mandates the development of new therapeutic strategies. Recently, we discovered a highly tumorigenic, chemoresistant, and self-renewing subpopulation in NB with features similar to cancer stem cells (CSCs). This G-CSF receptor (CD114)-expressing subpopulation can escape initial therapy and cause aggressively invasive relapsed disease. Therefore, developing direct targeting strategies and understanding for the molecular mechanisms maintaining this NB CSC-like subpopulation is essential to delineate effective therapeutics for NB patients. By using siRNA screening approach and low-density pathway arrays, we found that the epigenetic regulators mixed-lineage leukemia-1 (MLL1; KMT2A; a H3K4me3 methyltransferase) and Jumonji D3 (JMJD3; KDM6B; a H3K27me3 demethylase) are important epigenetic regulators for NB proliferation and growth. Interestingly, we found that epigenetic regulators MLL1 and JMJD3 are aberrantly expressed in CD114+ subpopulation and regulate the expression of the G-CSF receptor gene (CSF3R) itself, by maintaining active histone modifications at the promoter locus. Inhibition of MLL1 and JMJD3 with specific small-molecule inhibitors reverses the histone patterns at CSF3R promoter and blocks gene expression, induces apoptosis selectively in CD114+ cells, and inhibits overall NB proliferation in vitro. Furthermore, inhibiting MLL1 and JMJD3 leads to dramatic tumor regression (p&lt;0.001) and reduction in incidences of metastasis (p&lt;0.001) in vivo. Most interestingly, both of these inhibitors increase the overall survival of the treated mice in vivo. As expected, reduction in tumor size was significantly correlated with the reduction in tumor CD114+ cells. Taken together, these data highlight that: a) neuroblastoma is maintained by the complex interplay of epigenetic modifiers, and b) direct targeting of these epigenetic modifiers and combining this approach with current therapy is a novel therapeutic approach to high-risk NB.
Citation Format: Saurabh Agarwal, Julie Tomolonis, Sanjeev Vasudevan, Jason Shohet. Epigenetic modifiers MLL1 and JMJD3 regulate neuroblastoma tumorigenicity by maintaining a cancer stem cell-like population [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B21.
Abstract B22: Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo
Authors: Hansen Jeanne N. , Lotta Louis T. , Eberhardt Allison , Zheng Yujun George , Ji Sen , Yang Shengyong , Schor Nina F. , Li Xingguo 
Published: February 2019

Abstract
The MYC family of transcription factors is one of the most frequently overexpressed oncogenes in human malignancies, including tumors that are derived from the nervous system. MYCN plays a causative role in neuroblastoma, a common and fatal childhood cancer of the developing sympathetic nervous system. Thus, the MYC family has been considered as a promising cancer target; however, so far, no small molecules can directly target MYC or MYCN in vivo. We have recently reported that PRMT1 functions as a key regulator of the stability and oncogenicity of MYCN. In this study, we have performed the structure-activity relationship analysis of diamidine-related PRMT1-seletive inhibitors. In correlation with their inhibition against PRMT1 in biochemical assays, these compounds showed remarkable anticancer properties both in neuroblastoma cell lines in vitro and in a preclinical mouse model of neuroblastoma in vivo. Mechanistically, these potent PRMT1 inhibitors destabilized MYCN, caused cell cycle arrest, and restored normal developmental signals of the developing sympathetic neuroblast precursors. Together, our results demonstrate that PRMT1-seletive inhibitors are promising anti-neuroblastoma agents and may represent a general strategy to target certain MYC/MYCN-driven cancers.
Citation Format: Jeanne N. Hansen, Louis T. Lotta, Allison Eberhardt, Yujun George Zheng, Sen Ji, Shengyong Yang, Nina F. Schor, Xingguo Li. Antitumor effects of selective PRMT1 inhibitors on neuroblastoma in vitro and in vivo [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B22.
Abstract B24: Characterization of somatically acquired regulatory mutations in high-risk neuroblastoma
Authors: Harenza Jo Lynne , Chen Gregory , Maris John M. 
Published: February 2019

Abstract
Neuroblastoma is a childhood cancer of the developing peripheral nervous system and is uniquely characterized by a broad spectrum of phenotypes ranging from spontaneous tumor regression to relentless progression. The 5-year survival rate for children in the low- and intermediate-risk groups is over 95%; however, children with high-risk disease have a 40-50% likelihood of survival despite aggressive multimodal therapy. High-risk neuroblastomas harbor relatively few protein coding mutations at diagnosis, with the oncogenic mechanisms underlying MYCN amplification and ALK activation remaining obscure. We therefore hypothesized that characterizing high-risk neuroblastoma noncoding genetic variation will define gene regulatory mechanisms driving tumor progression, and that somatically acquired noncoding mutations alter critical neurodevelopmental gene regulatory regions. Here, we have integrated neuroblastoma cell line histone ChIP-Seq (N = 10), ATAC-Seq (N = 12), and RNA-Seq (N = 39) with high-risk patient (N = 105) whole-genome mutation data to define the landscape of noncoding somatic events dysregulating enhancers and promoters in high-risk neuroblastoma. We found a significantly higher number of mutations per patient in high-risk and stage 4 patients, compared to other risk groups (Wilcox Whigh-low = 129.5, p = 1.47e-07; Whigh-int = 70, p = 3.66e-08) and stages (WStage4-Stage3 = 86, p = 2.68e-3; WStage4-Stage4s= 65.5, p = 1.21e-12). We found a median of 1,809 somatic noncoding single nucleotide mutations per patient, and a subset of these recurrently mutate sequences underlying super-enhancer peaks of 102 genes. An additional subset lie within CCCTC-binding factor (CTCF) motifs (a median of 5 mutations per patient), suggesting potential dysregulation of chromosome looping in neuroblastoma. Understanding noncoding drivers of oncogenic gene expression and translating these basic science discoveries to the clinic is a critical step towards changing the devastating course of this disease.
Citation Format: Jo Lynne Harenza, Gregory Chen, John M. Maris. Characterization of somatically acquired regulatory mutations in high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B24.
Abstract B36: Targeting MDM4 in neuroblastoma to reactivate p53 signaling
Authors: Woodfield Sarah E. , Patel Roma H. , Ibarra Aryana M. , Chen Zhenghu , Vasudevan Sanjeev A. 
Published: February 2019

Abstract
Introduction: Neuroblastoma is the most common pediatric extracranial solid tumor. Despite aggressive therapeutic regimens, long-term survival of patients with high-risk disease is less than 50%. The TP53 tumor suppressor gene is wild-type and functional in 99% of neuroblastoma cases at diagnosis. Thus, we hypothesized that targeting the p53 regulator MDM4 to reactivate p53 signaling would be effective in neuroblastoma.
Methods: Levels of gene expression of MDM4 and its association with event-free and overall survival in neuroblastoma patients were analyzed using the publically available patient datasets in the R2 Genomics Analysis and Visualization Platform. MDM4 gene and protein expression were also examined in five neuroblastoma cell lines (IMR-32, SH-SY5Y, NB-19, SK-N-AS, and LAN-1) with qPCR and immunoblotting assays. The effects of MDM4 inhibitor NSC207895 on TP53 wild-type IMR-32 and SH-SY5Y, TP53 mutant SK-N-AS, and TP53 null LAN-1 cells were analyzed with MTT assays for cytotoxicity and qPCR experiments to look at p53 targets.
Results: MDM4 expression is significantly correlated with both event-free and overall survival of neuroblastoma patients in the Kocak (n=476) and Oberthuer (n=251) datasets in the R2 Genomics Analysis and Visualization Platform, with lower expression correlated with increased survival (p&lt;0.01). All five neuroblastoma cell lines showed gene and protein expression of MDM4. NSC207895 had strong cytotoxic effects at very low concentrations (0.08-0.09 μM) after only 24 hours of treatment with TP53 wild-type IMR-32 and SH-SY5Y cells. NSC207895 exposure also led to upregulation of p53 targets Bax (3.7- to 4.3-fold), Puma (5.7- to 21.6-fold), and CDKN1A (14.5- to 53.1-fold) in these cells but not in TP53 mutant SK-N-AS or TP53 null LAN-1 cells.
Conclusions: Inhibition of MDM4 shows efficacy in preclinical models of neuroblastoma by upregulating p53 tumor suppressor signaling in TP53 wild-type cells and is a promising therapeutic strategy for high-risk patients with wild-type TP53.
Citation Format: Sarah E. Woodfield, Roma H. Patel, Aryana M. Ibarra, Zhenghu Chen, Sanjeev A. Vasudevan. Targeting MDM4 in neuroblastoma to reactivate p53 signaling [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B36.
Abstract B41: Modeling bone development and cancer predisposition in Diamond Blackfan anemia (DBA)
Authors: Hom Jimmy , Dulmovits Brian , Peters Luanne , Vlachos Adrianna , Lipton Jeffrey M. , Blanc Lionel 
Published: February 2019

Abstract
DBA is an inherited bone marrow failure syndrome characterized by pure red cell aplasia, congenital physical anomalies, and cancer predisposition, in particular an increased incidence of osteogenic sarcoma (O:E 42.44). In order to investigate the mechanism of defective bone development and ultimately oncogenesis, we used an in vitro model consisting of mouse embryonic stem cells gene trapped for the Ribosomal Protein 19 gene (Rps19) and developed an in vivo transgenic conditional mouse model with floxed Rps19 alleles and a bone-specific expressing Col1a1-CreER. Using a 23-day stepwise osteoblast differentiation model, haploinsufficient Rps19+/- mouse ES cells did not show differences in the ability to develop into mesodermal progenitors based on qPCR analysis of mesodermal transcription factors, but displayed a decreased ability to produce mature osteoblasts based upon decreased alizarin red staining. In addition, higher levels of the Trp53 protein were found in Rps19+/- mouse ES cells at both the pluripotent and mesodermal stages of differentiation. Further, Rps19+/- mouse ES cells presented with aberrant WNT signaling, as represented by decreased levels of β-catenin early in osteoblast differentiation and rising to higher levels towards late osteoblast differentiation. We assessed the hypothesis of WNT signaling involvement in lineage specification and found that Rps19+/- mouse ES cell-derived osteoblasts show decreased levels of Runx2 and increased levels of Sox9. In the transgenic mouse model, tamoxifen-induced recombination of Rps19 at E15-17 did not show gross morphologic skeletal defects at E20.5 for Rps19fl/+ embryos, although Rps19fl/fl embryos displayed severe skeletal defects through alizarin red and alcian blue staining. In conclusion, haploinsufficient levels of Rps19 found in mice contribute to improper skeletal development and probably reflect the clinical scenario. We plan to utilize these in vitro and in vivo models to provide clues into the mechanism of ribosomal protein haploinsufficiency in tumor development, which may suggest surveillance and treatment strategies.
Citation Format: Jimmy Hom, Brian Dulmovits, Luanne Peters, Adrianna Vlachos, Jeffrey M. Lipton, Lionel Blanc. Modeling bone development and cancer predisposition in Diamond Blackfan anemia (DBA) [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B41.
Abstract IA04: Identification of new vulnerabilities in fusion-driven pediatric cancers with functional and chemical genomic approaches
Authors: Stegmaier Kimberly 
Published: February 2019

Abstract
Fusion-driven pediatric cancers remain a therapeutic challenge. On one hand, the genomic simplicity of these malignancies and the tumor selectivity of their expressed fusion oncoproteins represent a therapeutic opportunity. These fusion oncoproteins, however, are typically transcription factors, and make for particularly challenging drug targets. Novel approaches to targeting these malignancies are needed. The EWS/ETS-driven pediatric solid tumor Ewing sarcoma is one exemplary childhood cancer. Our laboratory is integrating next-generation sequencing, functional genomic screening (shRNA and CRISPR/Cas9), and chemical genomic screening to identify, validate, and mechanistically dissect new targets in Ewing sarcoma. Emerging data from these efforts will be presented.
Citation Format: Kimberly Stegmaier. Identification of new vulnerabilities in fusion-driven pediatric cancers with functional and chemical genomic approaches [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA04.
Abstract PR11: Synthetic lethality between ATRX mutations and MYCN amplification in neuroblastoma
Authors: Zeineldin Maged , Federico Sara M. , Griffith Lyra , Jeon Jongyre , Chen Xiang , Easton John , Wu Jianrong , Mao Shenghua , Liu Yanling , Naranjo Arlene , Pappo Alberto S. , Hogarty Michael D. , Dyer Michael A. 
Published: February 2019

Abstract
Neuroblastoma is a clinically heterogeneous tumor responsible for 15% of cancer-related deaths in children. Older age at diagnosis and MYCN amplification are associated with poor prognosis in neuroblastoma. Previously, sequencing stage 4 neuroblastoma tumors revealed recurrent mutations in the chromatin remodeler ATRX that are significantly associated with older age and mutually exclusive with MYCN amplification. Here, we expanded our genetic analysis of neuroblastoma across all ages and stages. We sequenced 475 neuroblastoma tumors and found that the incidence of ATRX mutations is correlated with older age at diagnosis and advanced stages of the disease. We also directly studied the mutual exclusivity between ATRX mutations and MYCN amplification using both cultured cells and orthotopic mouse models. We found that targeting ATRX using shRNA or CRISPR-Cas-9 reduces cell viability in MYCN-amplified cells. Additionally, induction of MYCN overexpression results in cell death in ATRX-mutant neuroblastoma cells. To characterize the molecular basis of the ATRX-mutations/MYCN-amplification incompatibility, we studied epigenetic, metabolic, and replicative changes associated with MYCN amplification in these cells. We discovered that induction of MYCN overexpression provokes mitochondrial abnormalities, metabolic reprograming, and replicative stress in ATRX mutant cells. Collectively, these data show synthetic lethality between ATRX mutations and MYCN amplification and suggest that the chromatin remodeler ATRX is important in reducing replicative stress associated with MYCN amplification in neuroblastoma. These data will also help in identifying therapeutic targets, which will reduce the morbidity and mortality associated with high-risk neuroblastoma.
Citation Format: Maged Zeineldin, Sara M. Federico, Lyra Griffith, Jongyre Jeon, Xiang Chen, John Easton, Jianrong Wu, Shenghua Mao, Yanling Liu, Arlene Naranjo, Alberto S. Pappo, Michael D. Hogarty, Michael A. Dyer. Synthetic lethality between ATRX mutations and MYCN amplification in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR11.
Abstract PR12: Hedgehog pathway drives fusion-negative rhabdomyosarcoma initiated from nonmyogenic endothelial progenitors
Authors: Drummond Catherine J. , Hanna Jason A. , Garcia Matthew R. , Devine Daniel J. , Heyrana Alana J. , Finkelstein David , Rehg Jerold E. , Hatley Mark E. 
Published: February 2019

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite aggressive chemotherapy, radiotherapy, and surgery, clinical outcomes for RMS have not improved for three decades, emphasizing the need to uncover the molecular underpinnings of the disease. RMS has been presumed to originate from derailed muscle progenitors based on the histologic appearance and gene expression pattern of the tumors. However, an origin restricted to skeletal muscle does not explain RMS occurring in tissues devoid of skeletal muscle, such as the prostate, bladder, salivary gland, biliary tree, and the omentum. Previously, we described that activation of Sonic Hedgehog signaling through expression of a conditional, constitutively active Smoothened allele, SmoM2, under control of an adipocyte-restricted adipose protein 2 (aP2)-Cre recombinase transgene in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human embryonal RMS (ERMS). With the short latency and anatomic restricted tumor location in the neck, we sought to leverage this model to explore the cell of origin of ERMS.
Lineage tracing experiments identified aP2-Cre labeled cells are distinctly nonmyogenic and were identified as endothelial cells found in the interstitium between muscle fibers. We illustrate that aP2-Cre is not expressed in the quiescent or activated muscle stem cells or satellite cells. Expression of oncogenic SmoM2 with aP2-Cre results in proliferation and expansion of the aP2-Cre labeled muscle interstitial cells and myogenic transdifferentiation resulting in ERMS. Activation of the Hedgehog pathway in aP2-Cre labeled endothelial progenitors results in Tbx1 expression, which is a skeletal muscle specification factor in the head and neck. We illustrate that endothelium and skeletal muscle within the head and neck arise from Kdr (Vegfr2) expressing progenitors. Hedgehog pathway activation in committed KDR+ endothelial progenitors results in Tbx1 expression and subsequent Myod1 expression driving a partially myogenic program characteristic of ERMS. Our work identifies reprogramming cell fate as a mechanism of transformation in pediatric sarcoma.
Citation Format: Catherine J. Drummond, Jason A. Hanna, Matthew R. Garcia, Daniel J. Devine, Alana J. Heyrana, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Hedgehog pathway drives fusion-negative rhabdomyosarcoma initiated from nonmyogenic endothelial progenitors [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR12.
Abstract A007: Methyl jasmonate and finasteride synergistically reduce testosterone-induced benign prostatic hyperplasia through regulation of inflammatory and apoptotic processes in rats
Authors: Adaramoye Oluwatosin A. , Owumi Solomon E. , Akanni Olubukola , Olapade-Olaopa Oluwabunmi E. , Abiola Olusoji J. , Akinloye Oluyemi 
Published: February 2019

Abstract
Background: Phytotherapy is becoming a treatment option in management of diseases, including benign prostatic hyperplasia (BPH). We have shown previously that methyl jasmonate (MeJA) ameliorated BPH; however, the underlying mechanism of action remains unknown. This study was designed to investigate in mechanistic terms the protective role of MeJA in BPH.
Methods: BPH was induced by daily injections of testosterone propionate (TP) (3 mg/kg) for 28 days.
Results: The weight and organo-somatic weight of prostate in BPH rats were 6.8 and 5.1 times higher than castrated-control group, respectively. Inflammatory markers, prostatic myeloperoxidase,and total nitric oxide were significantly increased in BPH group. The activity of aniline hydroxylase (Phase I drug metabolizing enzyme) was significantly increased in BPH rats by 22%. In BPH group, immunohistochemistry revealed strong expression of prostatic inducible nitric oxide synthase, cyclooxygenase-2 and Bcl2, while mild expression of p53 and Bax WAS seen. Serum triglyceride and total cholesterol were significantly increased, while HDL-c was decreased in BPH. Interestingly, MeJA and finasteride (singly or combination) attenuated inflammatory and apoptotic indices in BPH rats.
Conclusion: MeJA and finasteride synergistically protect against TP-induced BPH via mechanisms that involve antiinflammation, induction of apoptosis, and inhibition of phase I drug metabolizing enzyme.
Citation Format: Oluwatosin A. Adaramoye, Solomon E. Owumi, Olubukola Akanni, Oluwabunmi E. Olapade-Olaopa, Olusoji J. Abiola, Oluyemi Akinloye. Methyl jasmonate and finasteride synergistically reduce testosterone-induced benign prostatic hyperplasia through regulation of inflammatory and apoptotic processes in rats [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A007.