bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: Histone demethylase KDM3A in rhabdomyosarcoma
Authors: Sobral Lays M. , Jedlicka Paul 
Published: August 2018

Abstract
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, adolescents, and young adults, presenting a myogenic phenotype. RMS can be divided into two major histopathologic subtypes: driver oncofusion (PAX3/7-FOXO1) positive, alveolar (ARMS), and oncofusion-negative embryonal (ERMS). Histone methylation is a key element of chromatin-based modifications that regulates a number of cellular processes, including DNA replication, DNA repair, and gene transcription. Histone demethylase gene family members (HDMs) regulate gene expression by removing methyl marks on histone tails to activate or repress transcription. KDM3A (lysine-specific demethylase 3A or JMJD1A) is a histone demethylase belonging to the Jumonji C-terminal domain (JmjC)-containing histone demethylases that selectively removes mono- and dimethyl groups from H3K9. It has been demonstrated that KDM3A is overexpressed in many kinds of cancer, such as bladder, lung, and breast cancer, and, previously shown by our laboratory, in Ewing sarcoma, contributing to carcinogenesis. We and others have identified KDM3A as overexpressed in RMS, but the functional consequences of this overexpression have not been examined. The aim of this study was to analyze the influence of KDM3A on RMS biology. Two different RMS cells lines were used, RH30 (ARMS) and RD (ERMS), to perform stable shRNA-mediated KDM3A knockdown. The protein and RNA levels were analyzed by Western blotting and RT-qPCR, respectively. The phenotypic effects of KDM3A knockdown were analyzed by proliferation assays (MTT and clonogenic assay) and cell migration (transwell migration assay). KDM3A knockdown was able to inhibit the proliferation, colony formation, and migration of RMS cell lines, demonstrating an important role in RMS biology.
Citation Format: Lays M. Sobral, Paul Jedlicka. Histone demethylase KDM3A in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A33.
Abstract B13: COP1-ETS axis regulates ERK transcriptional output and modulates sensitivity to MAPK inhibitors
Authors: Xie Yuanyuan , Cao Zhen , Wong Wai Pung , Guan Youxin , Zhang Jenny , Walczak Edward , Murphy Devan , Ran Leili , Sirota Inna , Wang Shangqian , Shukla Shipra , Gao Dong , Wongvipat John , Knott Simon , Chang Kenneth , Antonescu Cristina , Hannon Gregory , Chi Ping , Chen Yu 
Published: August 2018

Abstract
Aberrant activation of the mitogen activate kinase (MAPK) pathway is highly prevalent in cancer and therapies targeting the pathway are approved or under active investigation in multiple malignancies. MAPK signaling leads to activation of a transcriptional program that includes general growth promoting genes, negative feedback regulators of the MAPK pathway, and lineage-specific genes. While the mechanisms of upstream signal transduction that leads to MAPK activation have been studied in detail, how MAPK activation is dynamically coupled with downstream nuclear transcriptional response is not fully understood. In gastrointestinal stomal tumor (GIST) and melanoma, two malignancies with aberrant MAPK activation, we find that Pea3 family ETS transcription factors ETV1, ETV4, and ETV5 are critical nuclear effectors of MAPK signaling. We find that the primary mechanism linking MAPK and Pea3 activity is through protein stability via the COP1 E3 ligase. The loss of COP1 leads to decoupling between upstream MAPK signaling and downstream transcription with constitutively stabilized Pea3 protein levels, constitutively high MAPK transcriptome, yet decreased upstream signaling due to Pea3-mediated transcription of negative feedback regulators. This leads to decreased therapeutic sensitivity to MAPK pathway inhibition in vitro and in vivo. These observations indicate that MAPK signaling-dependent regulation of Pea3 ETS protein stability is a crucial pathway that couples downstream transcriptional response to MAPK signaling and can shape the therapeutic sensitivity to MAPK pathway inhibition in cancer.
Citation Format: Yuanyuan Xie, Zhen Cao, Wai Pung Wong, Youxin Guan, Jenny Zhang, Edward Walczak, Devan Murphy, Leili Ran, Inna Sirota, Shangqian Wang, Shipra Shukla, Dong Gao, John Wongvipat, Simon Knott, Kenneth Chang, Cristina Antonescu, Gregory Hannon, Ping Chi, Yu Chen. COP1-ETS axis regulates ERK transcriptional output and modulates sensitivity to MAPK inhibitors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B13.
Abstract B14: A restricted cell population propagates MPNST growth after treatment
Authors: Sun Daochun , Parada Luis 
Published: August 2018

Abstract
Malignant peripheral nerve sheath tumor is a type of soft-tissue sarcoma that arises from the neural crest lineage and is commonly associated with nerve trunks. Surgical removal is the major treatment conjugated with chemo/radiation therapy when applicable. However, the complete tumor clearance is limited by the resectability, especially when tumor is associated with large peripheral nerve such as sciatic nerve, brachial plexus, and sacral plexus. The local recurrence of MPNST is 40-45% and distal recurrence is 40-48%. By harnessing our Nes-hsvTK-GFP transgene that successfully labeled the cancer stem cells in glioblastoma, we identified a small quiescent cell population in MPNSTs from both cisNf1+/-;Trp53+/- (cisNP) spontaneous model and skin progenitor (SKP)-based allograft model. Inhibition of these cells by feeding mice ganciclovir chow significantly decreased the tumor growth in both cisNP model and allograft model. We also found that the transgene-labeled GFP+ cells enrich in the sciatic nerve region compared to the distal tumor mass in MPNST allograft model. Tumor primary culture from the sciatic nerve vicinity forms significantly larger and more spheres in vitro than the distal tumor mass. The BrdU-EdU sequential labeling assay after chemotherapy in MPNST allograft model shows that the GFP+ cells can continuously repopulate tumor. These results indicate that the transgene-labeled GFP+ cells may serve as a source of tumor growth and, at the same time, a novel target to reduce MPNST relapse after treatment.
Citation Format: Daochun Sun, Luis Parada. A restricted cell population propagates MPNST growth after treatment [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B14.
Abstract B17: Utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST)
Authors: Sebro Ronnie , Niziolek Paul 
Published: August 2018

Abstract
Aim: To assess the utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST).
Methods: We retrospectively identified 68 patients with histologically confirmed nerve sheath tumors. All of these patients had pretreatment magnetic resonance imaging (MRI) studies and 17 patients had pretreatment 18-fluorodeoxyglucose positron emission tomography (PET/CT). Age, history of neurofibromatosis, maximum size of the tumor, MR features, and maximum standardized uptake values (SUV) from PET/CT were obtained. We used Wilcoxon-Rank sum or Fisher's exact tests to compare benign versus malignant nerve sheath tumors.
Results: There was no significant difference in the mean age of the patients with benign versus MPNST (P=0.85). Patients with NF1 had higher odds of MPNSTs (OR=26.7, P=2.6 x10-7). There was no difference in the mean size of the benign versus MPNSTs (P=0.44). Homogeneous enhancement of a lesion after intravenous contrast (OR=0.08, P=0.008) and the target sign (OR=0.0, P=0.041), were both associated with decreased odds of MPNST. Bone destruction seen on MRI (P=5.7x10-4) and an enlarged nerve (OR = 3.89, P=0.048) were associated with increased odds of MPNST. MPNSTs had significantly higher mean maximum SUV than benign nerve sheath tumors (P=0.0272). The previously published threshold maximum SUV of 3.5 had 100% sensitivity and 50% specificity to exclude MPNST as 50% (4/8) of the benign nerve sheath tumors had a maximum SUV &gt;3.5.
Conclusion: MRI and PET/CT are useful for differentiating benign from MPNST, but neither is specific. A maximum SUV of 3.5 is highly sensitive for identifying MPNST; however, tissue sampling is often necessary to confirm the diagnosis since using this threshold results in a large proportion of false positives.
Citation Format: Ronnie Sebro, Paul Niziolek. Utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST) [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B17.
Abstract B24: Molecular and functional dissection of the CIC-DUX4 fusion in undifferentiated round cell sarcoma
Authors: Okimoto Ross A. , Wu Wei , Bivona Trever G. 
Published: August 2018

Abstract
CIC-DUX4 soft-tissue tumors are an aggressive subset of undifferentiated round cell sarcomas that arise in children and young adults. The cytogenetic hallmark, (t(4;19) or t(10;19)), of this tumor is a chromosomal translocation that fuses the transcription factor, Capicua (CIC), with the double homeobox 4 protein, DUX4. Despite morphologic similarities to Ewing sarcoma, CIC-DUX4 sarcomas are clinically distinct with rapid development of lethal metastatic disease and chemoinsensitivity. The unique cytogenetic and clinical features that distinguish CIC-DUX4 sarcomas from other small round cell tumors provide a unique opportunity to identify and rationally target this population to improve clinical outcomes.
To meet this need, we are taking a systematic functional approach to identify critical CIC-DUX4 targets that promote tumor progression and metastasis. Leveraging a comparative transcriptional analysis between cytogenetically distinct small round cell sarcomas, we reveal that the CIC-DUX4 fusion activates highly conserved molecular networks to control tumor growth and metastatic capacity. Using an orthotopic soft-tissue sarcoma model, we show that CIC-DUX4 induces ETV4 expression to drive invasion and metastasis. Genetic silencing of ETV4 in CIC-DUX4 expressing tumors limits tumor dissemination without a profound impact on tumor cell growth. These findings suggest that CIC-DUX4 enhances metastasis and tumor growth through distinct transcriptional repertoires. Consistent with this, we identify multiple components of the cell cycle machinery that are transcriptionally regulated by CIC-DUX4 expression. Specifically, the CIC-DUX4 fusion co-opts native CIC-binding specificity to transcriptionally activate these cell cycle target genes. Altogether, our molecular and functional dissection of the CIC-DUX4 fusion reveals highly conserved CIC-regulated transcriptional targets that promote tumor growth and metastasis. We aim to pharmacologically exploit these key CIC-DUX4-dependent transcriptional nodes to improve outcomes for this population with few therapeutic options.
Citation Format: Ross A. Okimoto, Wei Wu, Trever G. Bivona. Molecular and functional dissection of the CIC-DUX4 fusion in undifferentiated round cell sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B24.
Abstract B27: Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy
Authors: Keung Emily Z. , Tsai Jen-Wei , Ali Ali M. , Cormier Janice N. , Bishop Andrew J. , Guadagnolo B. Ashleigh , Hunt Kelly K. , Torres Keila E. , Somaiah Neeta , Wargo Jennifer A. , Lazar Alexander , Wang Wei-Lien , Roland Cristina L. 
Published: August 2018

Abstract
Introduction: Undifferentiated pleomorphic sarcoma of the extremity and trunk (ET UPS) presents a unique diagnostic and therapeutic challenge. Recently, immunotherapy has been employed in the treatment of patients with advanced UPS with preliminary evidence of benefit in 40% of a small initial cohort (SARC028). However, there is currently a paucity of data characterizing the immune infiltrate population in ET UPS. Radiotherapy (RT) is associated with improved locoregional control in combination with surgery. Localized RT has been shown in other tumor types to promote tumor antigen release and enhance tumor-specific targeting by the adaptive immune system. The aim of this study was two-fold: 1) to characterize the immune infiltrate in ET UPS and 2) to evaluate the effect of preoperative RT on immune cell infiltrates in ET UPS.
Methods: We identified 17 matched ET UPS tumor samples before and after RT. Immunohistochemistry for CD8, CD4, PD-L1, PD1, CD3, CD163, and FOXP3 was performed on the matched pairs. Changes in immune infiltrate over time between the pairs were compared with a paired t-test.
Results: CD8, CD4, PD-L1, PD1, CD3, CD163, and FoxP3 positive cells were identified in all samples. The effects were variable, but there was an overall trend towards an increase in the density of tumor-infiltrating immune cells of all assayed types in ET UPS following completion of RT, with increases in the median number of CD8 (55 vs. 111 cells/mm2, p=0.17), CD4 (3 vs. 13 cells/mm2, p=0.01), CD3 (158 vs. 219 cells/mm2, p=0.06), CD163 (1363 vs. 2001 cells/mm2, p=0.76), and FOXP3 (14 vs. 25 cells/mm2, p=0.23) positive cells in RT-treated tumor sections. Interestingly, although PD-L1 was not expressed in any pre-RT ET UPS tumors, positive PD-L1 expression was observed in 21% (3/14) of tumors after RT treatment (p=0.07).
Conclusion: An immune infiltrate is present in ET UPS at the time of diagnosis, with a trend towards increased density of immune infiltrate and PD-L1 expression after completion of RT. These data support evaluating immune checkpoint inhibitors with standard of care RT in the treatment of ET UPS.
Citation Format: Emily Z. Keung, Jen-Wei Tsai, Ali M. Ali, Janice N. Cormier, Andrew J. Bishop, B. Ashleigh Guadagnolo, Kelly K. Hunt, Keila E. Torres, Neeta Somaiah, Jennifer A. Wargo, Alexander Lazar, Wei-Lien Wang, Cristina L. Roland. Analysis of the immune infiltrate in undifferentiated pleomorphic sarcoma of the extremity and trunk in response to radiotherapy [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B27.
Abstract B36: A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric sarcomas
Authors: Shelat Anang A. , Tinkle Christopher L. , Stewart Elizabeth , Federico Sara Michele , Bianski Brandon , Mellado-Lagarde Marcia 
Published: August 2018

Abstract
Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric sarcomas and a potent inducer of DNA damage.
Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay.
Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric sarcomas, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2 Gy IR and 1-10 nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations &lt;10 nM in tumor cells expressing detectable levels of SLFN11.
Conclusion: SLFN11 is present in select pediatric sarcomas and may induce a DNA repair defect that is best exploited by combining low doses of TAL and irinotecan with IR.
Citation Format: Anang A. Shelat, Christopher L. Tinkle, Elizabeth Stewart, Sara Michele Federico, Brandon Bianski, Marcia Mellado-Lagarde. A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B36.
Abstract IA01: SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities
Authors: Roberts Charles W. M. 
Published: August 2018

Abstract
Data emerging over the last several years implicate SWI/SNF (BAF) chromatin remodeling complexes as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in 20% of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; and of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.
My laboratory began studying the SWI/SNF complex when SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT, we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines, and primary human tumor samples. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented, including our recent efforts that identify a central role for SWI/SNF complexes in enhancer regulation.
Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA01.
Abstract IA02: Modeling sarcoma susceptibility: The Li-Fraumeni syndrome paradigm
Authors: Malkin David 
Published: August 2018

Abstract
The original description of Li-Fraumeni syndrome (LFS) 1969 was generated from the ascertainment of medical and death records of over 600 children with rhabdomyosarcoma. Although the clinical definition of LFS has evolved over the decades, the occurrence of sarcoma in at least one affected TP53 gene mutation carrier is common to many families. However, the genotype:cancer phenotype association of sarcomas in mutation carriers remains poorly understood. This lecture will review some of the phenotypic characterizations of sarcomas in LFS and explore recent exciting advances that suggest a role for various genetic/genomic and epigenetic modifiers of the underlying germline TP53 mutation in defining these clinical phenotypes. The challenges and opportunities to enhance early tumor detection and modify disease risk will also be discussed.
Citation Format: David Malkin. Modeling sarcoma susceptibility: The Li-Fraumeni syndrome paradigm [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA02.
Abstract IA04: Targeting the expression of EWS-FLI1
Authors: Sen Nirmalya , Ludwig Katelyn , Rangel-Rivera Guillermo O. , Kim Suntae , Huppi Konrad , Jenkins Lisa , Dwyer Jennifer E. , Hoover Shelley , Helman Lee , Simpson Mark , Mendoza Arnulfo , Hummon Amanda B. , Caplen Natasha J. 
Published: August 2018

Abstract
Post-translational modifications (PTMs) of transcription factors represent potential therapeutic targets for a variety of diseases, including cancer. In the majority of cases of the bone and soft tissue tumor Ewing sarcoma (ES), a chromosomal translocation, t(11:22), results in expression of the fusion transcription factor EWS-FLI1. Few PTMs of EWS-FLI1 have been identified. Using functional genetic methods and mass spectrometry analysis, we have identified a phosphorylated serine residue in the FLI1 domain of EWS-FLI1 that regulates the stability of the EWS-FLI1 oncoprotein. Loss of phosphorylation of this serine residue triggers ubiquitination and proteasomal degradation of EWS-FLI1, and apoptotic cell death. Xenograft studies suggest this post-translational modification of EWS-FLI1 can be targeted in vivo and that this inhibits ES tumor growth.
Citation Format: Nirmalya Sen, Katelyn Ludwig, Guillermo O. Rangel-Rivera, Suntae Kim, Konrad Huppi, Lisa Jenkins, Jennifer E. Dwyer, Shelley Hoover, Lee Helman, Mark Simpson, Arnulfo Mendoza, Amanda B. Hummon, Natasha J. Caplen. Targeting the expression of EWS-FLI1 [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA04.