bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: Novel lncRNA regulates PAX3/FOXO1 expression and is essential for RMS tumorigenesis
Authors: Chen Xiang , Herrera-Herrera Mireya , McEvoy Justina 
Published: February 2019

Abstract
Rhabdomyosarcoma (RMS) is a pediatric cancer of the developing skeletal muscle, and the mechanisms that drive this tumor are not completely understood. Despite the genetic alterations discovered in this disease, therapeutics targeting these mutations have not improved patient survival over the past 25 years. Since more than 60% of patients with metastatic disease do not survive, this creates an urgency to identify new vulnerabilities to exploit for therapeutic development. To do this we performed a comprehensive evaluation of the epigenomic landscape across 16 RMS orthotopic patient-derived xenograft tumors. We identified 41 super enhancers unique to RMS tumors. Within these, we discovered 9 novel lncRNAs of which 3 have potential cis-regulatory activity. We hypothesize that these lncRNAs are required for RMS tumorigenesis. Indeed, from preliminary knockdown analysis of one of these lncRNAs, lnc19_31, we observed rapid cell death in RMS cell lines and concomitant upregulation of apoptotic genes based on RNA-seq, such as TP53. Remarkably, we also observed more than 70 cancer consensus genes that were up- or downregulated, including genes that are frequently mutated in RMS patients such as BCOR and FGFR4. Within these we were excited to discover the loss of PAX3/FOX1 translocation, as this is a major driver of the alveolar subtype and often associated with poor prognosis. Taken together, we hypothesize that lncRNA deregulation is required for expression of key oncogenes and tumor suppressor and essential for RMS cell survival and tumorigenesis. These data will shed insight into a new underlying mechanism that drives this disease. These exciting findings present potential tumor vulnerabilities and, thus, new opportunities for future therapeutic discoveries that would otherwise be beyond our reach.
Citation Format: Xiang Chen, Mireya Herrera-Herrera, Justina McEvoy. Novel lncRNA regulates PAX3/FOXO1 expression and is essential for RMS tumorigenesis [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 B26.
Abstract B35: Reactivation of p53 signaling in hepatoblastoma with a stapled peptide dual inhibitor of MDM2 and MDM4
Authors: Woodfield Sarah E. , Patel Roma H. , Ibarra Aryana M. , Chen Zhenghu , Vasudevan Sanjeev A. 
Published: February 2019

Abstract
Introduction: Hepatoblastoma is the most common pediatric liver malignancy. Despite aggressive therapeutic regimens, long-term survival of patients with high-risk, metastatic disease is less than 50%. Most cases of hepatoblastoma do not carry mutations in the TP53 tumor suppressor gene; therefore, we hypothesized that targeting the two major regulators of p53, MDM2 and MDM4, with the stapled peptide dual inhibitor, ATSP-7041, to reactivate p53 signaling would be an effective therapeutic strategy for hepatoblastoma.
Methods: Levels of MDM2 and MDM4 gene expression were examined in HB cell lines and in a cohort of 18 primary HB patient samples from stage III (n=12) and IV (n=6) patients in comparison to expression in four adjacent uninvolved liver samples with qPCR experiments. The effects of the dual MDM2/MDM4 inhibitor ATSP-7041 (Aileron Therapeutics) on the same cell lines were analyzed with MTT assays for cytotoxicity and qPCR experiments to look at changes in mRNA expression of p53 targets Bax, Puma, CDKN1A, and MDM2.
Results: In 16 of 18 samples, MDM4 expression was higher than average in the uninvolved liver samples; in five samples expression was at least 5-fold higher and in four samples expression was at least 10-fold higher. Of note, all four samples with at least 10-fold higher expression were from stage IV patients. In comparison, MDM2 expression was only elevated in one of the 18 patient samples. All three hepatoblastoma cell lines showed expression of both MDM2 and MDM4. Treatment with ATSP-7041 showed cytotoxic (5.7-8.6 μM) effects in all cell lines tested. All cell lines also showed upregulation of p53 targets Bax (1.4- to 2.4-fold), Puma (2.4- to 3.2-fold), CDKN1A (2.4- to 7.2-fold), and MDM2 (6.1- to 8.3-fold) with treatment.
Conclusions: Dual inhibition of MDM2 and MDM4 shows efficacy in preclinical models of hepatoblastoma 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. Reactivation of p53 signaling in hepatoblastoma with a stapled peptide dual inhibitor of MDM2 and MDM4 [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 B35.
Abstract B39: Osteosarcoma cells interact with bronchial cells in lung to drive production of prometastatic cytokines
Authors: Hinckley John , Gross Amy , Roberts Ryan 
Published: February 2019

Abstract
The survival rate for patients diagnosed with osteosarcoma (OS) drops from 70% to an abysmal 20% when diagnosed with lung metastasis. We have shown that metastatic colonization of lungs by OS cells depends on the production of IL6 and CXCL8 by tumor cells, which seems to increase within the metastatic niche of the lung. Identification of key tumor-host interactions that drive this phenomenon will facilitate the development of novel therapies aimed at prevention of metastases in patients diagnosed with OS. We hypothesized that OS cells interact with lung tissues in ways that establish paracrine signal amplification loops, where IL6 and CXCL8 stimulate lung-resident cells to produce secondary signaling molecules that, in turn, stimulate tumor cell production of IL6 and CXCL8 in a feed-forward mechanism. Coculture experiments identified strong interactions between OS cells and primary cultures of bronchial epithelial cells and lung smooth muscle cells. Exposure of OS cells to conditioned supernatants from the primary cell cultures and vice versa showed that these interactions result from exchange of soluble mediators secreted by each cell type. Proteomic profiling of the resultant supernatants identifies a number of interesting candidate mediators, which might also affect the growth and survival of OS cells within the microenviroment of the lung. These results suggest a mechanism for the establishment of a metastatic niche favorable to OS cells within lung tissues.
Citation Format: John Hinckley, Amy Gross, Ryan Roberts. Osteosarcoma cells interact with bronchial cells in lung to drive production of prometastatic cytokines [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 B39.
Abstract IA07: Engineering T cells for the immunotherapy for pediatric solid tumors
Authors: Gottschalk Stephen , DeRenzo Chris , Hegde Meena , Mata Melinda , Nguyen Phoung , Krenciute Giedre , Ahmed Nabil 
Published: February 2019

Abstract
Engineering T cells for the immunotherapy for pediatric solid tumorsImmunotherapy with genetically modified T cells holds the promise to improve outcome for pediatric cancer patients who currently cannot be cured. In addition, T-cell therapy has the potential to reduce treatment-related complication for all patients. Cell therapy with T cells, genetically modified to express chimeric antigen receptors (CARs), had dramatic success for pediatric patients with recurrent/refractory CD19-positive acute lymphoblastic leukemia (ALL), resulting in the recent FDA approval of CD19-CAR T cells for recurrent/refractory ALL. In contrast, CAR T-cell therapies thus far have been less successful for pediatric solid tumors. In my talk, I will review current challenges of CAR T-cell therapies for solid tumors, highlighting our clinical studies targeting HER2 (Ahmed et al., JCO 2015 and JAMA Oncol 2017). In addition, I will review genetic engineering approaches that are being developed to improve the efficacy of CAR T cells for pediatric solid tumors.
Citation Format: Stephen Gottschalk, Chris DeRenzo, Meena Hegde, Melinda Mata, Phoung Nguyen, Giedre Krenciute, Nabil Ahmed. Engineering T cells for the immunotherapy for pediatric solid tumors [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 IA07.
Abstract IA19: MYC activation through enhancer hijacking or focal enhancer amplification drives a subset of high-risk pediatric neuroblastoma
Authors: Zimmerman Mark W. , Liu Yu , He Shuning , Durbin Adam D. , Abraham Brian J. , Easton John , Shao Ying , Xu Beisi , Zhu Shizhen , Zhang Xiaoling , Weichert-Leahey Nina , Young Richard A. , Zhang Jinghui , Look A. Thomas 
Published: February 2019

Abstract
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.
Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Beisi Xu, Shizhen Zhu, Xiaoling Zhang, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. MYC activation through enhancer hijacking or focal enhancer amplification drives a subset of high-risk pediatric 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 IA19.
Abstract IA25: Functional proteomics and site-specific genomic rearrangements of pediatric cancers
Authors: Kentsis Alex 
Published: February 2019

Abstract
Despite intense efforts, the cure rates of childhood leukemias and solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. In this presentation, I will describe my laboratory’s recent efforts to apply functional proteomic and genomic technologies to identify causal mechanisms of childhood cancer pathogenesis and therapy resistance. I will present functional proteomic studies of pediatric acute myeloid leukemias, identifying kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML. I will also present studies of site-specific genomic rearrangements in childhood solid tumors, identifying the PGBD5 DNA transposase as their oncogenic mutator. Lastly, I will present synthetic lethal approaches to leverage functional dependencies of transcription factor control and PGBD5-dependent DNA damage signaling to induce specific antitumor effects while sparing normal cells, including therapeutic strategies suitable for immediate translation to clinical trials.
Citation Format: Alex Kentsis. Functional proteomics and site-specific genomic rearrangements of pediatric cancers [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 IA25.
Abstract A011: Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents in prostate cancer
Authors: Casillas Andrea , Toth Rachel , Sainz Alva , Kraft Andrew S. , Warfel Noel A. 
Published: February 2019

Abstract
Angiogenesis is known to play an important role in prostate cancer pathogenesis. Although the addition of VEGF-targeting agents (i.e., bevacizumab) to docetaxel improved response rates in mCRPC patients, it failed to improve overall survival. Patients can develop resistance to antiangiogenic drugs due to changes in the tumor microenvironment, including hypoxia. PIM kinases are prosurvival kinases whose expression is increased in hypoxia and advanced prostate cancer. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that antiangiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors.
We establish PIM kinase expression as a novel mechanism of resistance to antiangiogenic agents. Xenograft and orthotopic models of prostate cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. We show that PIM is upregulated following treatment with anti-VEGF therapies, and PIM expression reduces the ability of these drugs to effectively disrupt tumor vasculature. Combinatorial inhibition of PIM and VEGF produces a synergistic antitumor response that is characterized by enhanced cell death, growth arrest, decreased angiogenesis, and reduced metastasis. Mechanistically, small-molecule PIM inhibitors reduce HIF-1 activity, opposing a shift to the proangiogenic gene signature associated with hypoxia. Our data provide justification for combining PIM and VEGF inhibitors to treat advanced prostate cancer.
Citation Format: Andrea Casillas, Rachel Toth, Alva Sainz, Andrew S. Kraft, Noel A. Warfel. Hypoxia-inducible PIM kinase expression promotes resistance to antiangiogenic agents in prostate cancer [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 A011.
Abstract A036: Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer
Authors: Wang Qian (Kevin) , Geldermalsen Michelle van , Pang Angel , Zhang Blake , Holst Jeff 
Published: February 2019

Abstract
Cancer cells greatly increase their uptake of nutrients (glucose, amino acids, and lipids), and metabolize them to provide the necessary building blocks for new cancer cells. It was recently shown that extracellular amino acids make up by far the majority of the carbon sources used by cancer cells for cell division, highlighting amino acid uptake as a viable therapeutic target. In addition, amino acids such as glutamine are critical in providing nitrogen for purine and pyrimidine metabolism. We have previously shown that glutamine uptake is mediated predominantly by ASCT2 in prostate cancer, with ASCT2 knockdown blocking cell growth in vitro and in vivo. Using the TCGA dataset, we have discovered increased expression of downstream glutamine metabolism enzymes in approximately 25% of prostate cancer patients. One of these enzymes, guanine monophosphate synthase (GMPS), is a glutamine amidotransferase involved in de novo purine biosynthesis and is responsible for the last step in the synthesis of the guanine nucleotide. Expression of GMPS correlates with increasing Gleason score in prostate cancer patient samples. Furthermore, patients with high GMPS expression had significantly reduced disease-free survival in the TCGA dataset. Immunofluorescent staining shows that GMPS is localized in both the cytoplasm and nucleus of LNCaP and PC-3 cells—consistent with a secondary role for GMPS in p53 stabilization. Inhibition of GMPS using decoyinine significantly decreased cell growth of both LNCaP and PC-3 cells. Knockdown of GMPS by shRNA significantly decreased cell growth, which could be rescued by addition of extracellular guanosine to the media, suggesting a direct effect on nucleotide synthesis. These results show the importance of downstream glutamine metabolism in prostate cancer, and suggest that GMPS is a potential therapeutic target in “glutamine-addicted” prostate cancers.
Citation Format: Qian (Kevin) Wang, Michelle van Geldermalsen, Angel Pang, Blake Zhang, Jeff Holst. Blocking DNA and RNA synthesis by targeting glutamine metabolism in prostate cancer [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 A036.
Abstract A048: Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
Authors: Ylitalo Erik Bovinder , Nordstrand Annika , Thysell Elin , Jernberg Emma , Crnalic Sead , Widmark Anders , Bergh Anders , Lerner Ulf H. , Wikström Pernilla 
Published: February 2019

Abstract
Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histologic evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2), and osteocytes (SOST), we found high osteoblast activity to be coupled to high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2-positive osteoblasts and TRAP (ACP5)-positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment-naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity in metastasis tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and to patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histologic evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserves further exploration.
Citation Format: Erik Bovinder Ylitalo, Annika Nordstrand, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner, Pernilla Wikström. Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases [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 A048.
Abstract A054: Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer
Authors: Ko Hyun-Kyung , Berk Michael , Chung Yoon-Mi , Willard Belinda , Bareja Rohan , Rubin Mark , Sboner Andrea , Sharifi Nima 
Published: February 2019

Abstract
The development of castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained concentrations of testosterone and/or dihydrotestosterone, which stimulate tumor progression despite castration. 17βHSD4, encoded by HSD17B4, is an enzyme that is thought to inactive testosterone and dihydrotestosterone by way of conversion to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression is known to increase in CRPC and predict for poor prognosis. Here, we show that of 5 alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast to other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients. Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulates PSA expression, and spurs the development of CRPC in xenograft models. Together, our studies specifically implicate HSD17B4 isoform 2 loss in the development of lethal prostate cancer.
Citation Format: Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi. Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer [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 A054.