bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4873: Therapeutic targeting of LSD1 in Ewing sarcoma with SP-2509
Authors: Pishas Kathleen , Boone Megann , Sharma Sunil , Lessnick Stephen 
Published: August 2018

Abstract
Objective: Multimodal regimes remain the cornerstone treatment for Ewing sarcoma (ES), the second most common solid bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches specifically targeting the drivers of ES oncogenesis. As LSD1 (Lysine Specific Demethylase 1) is highly expressed in ES tumors, with elevated expression levels associated with worse overall survival, this study examined biomarkers of sensitivity/mechanisms of cytotoxicity to targeted LSD1 inhibition using SP-2509 (reversible LSD1 inhibitor).
Methods: The antiproliferative effects of SP-2509 were determined through Cell Titre Glo assays following 72hrs of treatment in a panel of 17 ES cell lines with varying STAG2/TP53 mutational status and basal LSD1 expression levels. RNA-seq analysis of six ES cell lines -/+ SP-2509 treatment (2μM) was also conducted.
Results: Innate resistance to SP-2509 was not observed in our cell line cohort (72hr IC50:81nM-1593nM). In contrast, resistance to the clinical next-generation LSD1 irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (144hr IC50&gt;300μM). Although TP53/STAG2 mutational status and basal LSD1 mRNA/protein levels did not correlate with SP-2509 response, induction of LSD2 (homologue of LSD1) following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity (R2=0.562). shRNA mediated knockdown of LSD2 significantly reduced the cytotoxic effects of SP-2509 (4.3 fold IC50 increase) only in hypersensitive cell lines. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts apoptosis through engagement of the endoplasmic reticulum stress pathway, with hypersensitive cell lines sharing similar transcriptomic profiles. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively, following SP-2509 treatment only in our hypersensitive cell lines. Finally, we demonstrate that the transcriptional profile driven by SP-2509 strongly mirrors LSD1 genetic depletion.
Conclusion: Our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict LSD1 inhibitor sensitivity in ES.
Citation Format: Kathleen Pishas, Megann Boone, Sunil Sharma, Stephen Lessnick. Therapeutic targeting of LSD1 in Ewing sarcoma with SP-2509 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4873.
Abstract 489: Up-regulation of miR-130b is involved in prostate cancer racial disparity through FHIT pathway inactivation
Authors: Hashimoto Yutaka , Shiina Masrisa , Kato Taku , Yamamura Soichiro , Tanaka Yuichiro , Majid Shahana , Saini Sharanjot , Shahryari Varahram , Kulkarni Priyanka , Dasgupta Pritha , Bhagiratha Divya , Bhat Nadeem , Deng Guoren , Tabatabai Laura , Kumar Deepak , Dahiya Rajvir 
Published: August 2018

Abstract
Purpose: Prostate cancer (PCa) is a common cancer in men. African-American (AfA) men have higher incidence and significantly higher prostate cancer mortality rates than Caucasian-American (CaA) men. In this study, we investigated the biochemical role of miR-130b in this disparity.
Methods: We used meta-analyses and data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). PCa cell lines from CaA (DU145, LNCaP, PC3), AfA (MDA-PCa-2b, E006AA-hT) and a normal epithelial cell line (PWR1E) were used for examining miR-130b expression levels and/or establishing stable miR-130b knock-down clones. Total RNA was extracted from clinical samples and cell lines. miR-130b and mRNA levels of its target genes were determined by quantitative real-time PCR (qPCR). qPCR based gene expression arrays were used to identify miR-130b target genes. Cell proliferation, apoptosis and cell cycle were monitored after stable miR-130b knock down. Western blotting was performed to detect miR-130b target protein expression levels.
Results: TCGA data showed up-regulation of miR-130b in AfA PCa tissue samples compared with CaA samples. miR-130b was significantly up-regulated in AfA prostate cancer tissues and cell lines compared to CaA cells and tissues. Utilizing SFVAMC and NDRI patient cohorts, we confirmed that miR-130b expression was linked to a racial difference between AfA/CaA PCa patients. Knock down of miR-130b showed decreased growth and cell cycle arrest, though the effect was less in CaA compared to AfA cells. We found unique changes in biological pathways associated with miR-130b knock down in AfA cells by qPCR array. Evaluation of the altered pathways showed that Fragile Histidine Triad (FHIT) was markedly changed in the AfA compared with CaA cells.
Conclusion: These results demonstrate that miR-130b may be a central regulator of key events that contribute racial differences in prostate cancer. FHIT may also be a new AfA specific tumor-suppressive pathway that may be of therapeutic importance in AfA prostate cancer patients.
Citation Format: Yutaka Hashimoto, Masrisa Shiina, Taku Kato, Soichiro Yamamura, Yuichiro Tanaka, Shahana Majid, Sharanjot Saini, Varahram Shahryari, Priyanka Kulkarni, Pritha Dasgupta, Divya Bhagiratha, Nadeem Bhat, Guoren Deng, Laura Tabatabai, Deepak Kumar, Rajvir Dahiya. Up-regulation of miR-130b is involved in prostate cancer racial disparity through FHIT pathway inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 489.
Abstract 4910: Development of an antagonist to the TWEAK-Fn14 ligand-receptor interaction with enhanced efficacy/potency in glioblastoma cells
Authors: Harder Bryan , Sereduk Chris , Dhruv Harshil , Millard Nghia , Kim Anthony , Winkles Jeffrey , Woodworth Graeme , Yin Holly , Tran Nhan L. 
Published: August 2018

Abstract
Glioblastoma multiforme (GBM) remains the most common and deadly primary brain tumor with minimal advances in therapeutic development for pharmacological treatment. Tumor resection followed by temozolomide (TMZ) and radiotherapy adds months to survival; however, tumor recurrence usually occurs. The fibroblast growth factor-inducible 14 (Fn14) receptor has been shown to be up-regulated in the GBM cells left behind after surgery and contributes to an invasive and pro-survival phenotype, providing a desirable molecule to target after removal of the primary tumor. Previously, L524-0366 was reported by our lab to be the first antagonist of Fn14 signaling; however, minimal efficacy/potency has limited this drug from progressing from a useful research tool to preclinical studies. Structure activity relationship (SAR) studies using the parent L524-0366 compound gave rise to K78, which was found to bind to Fn14 with enhanced affinity, while showing no binding to the structurally-related TNFα receptor. Furthermore, K78 was able to abate the downstream signaling effects initiated by the Fn14 ligand, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), as well as sensitize GBM cells to the cytotoxic effects of TMZ. TWEAK-induced cellular migration was also mitigated with co-treatment of K78 in GBM cells, compared to a vehicle control. It is anticipated that further development of Fn14 antagonists will be of great importance for the advancement of GBM patient treatment and warrant further investigation as primary and combination therapy, especially for the prevention of recurrent disease.
Citation Format: Bryan Harder, Chris Sereduk, Harshil Dhruv, Nghia Millard, Anthony Kim, Jeffrey Winkles, Graeme Woodworth, Holly Yin, Nhan L. Tran. Development of an antagonist to the TWEAK-Fn14 ligand-receptor interaction with enhanced efficacy/potency in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4910.
Abstract 4926: Preclinical intratumoral pharmacokinetics (PK) of capecitabine (Cap) given +/- eribulin (Eri)
Authors: Casulleras Maria Jove , Spencer Jade , Loadman Paul , Clench Malcolm , Shnyder Steve , Cooper Patricia , Russo Cristina , Race Amanda , Salazar Ramon , Twelves Chris 
Published: August 2018

Abstract
Background: Eri & Cap are active as single agents in metastatic breast cancer, but the combination appears particularly active & well tolerated clinically. We explored the hypothesis that normalisation of tumor vasculature by Eri seen in preclinical models may enhance delivery of Cap to the tumor when given in combination.
Methods: Mice bearing MDA-MD-231 xenografts were treated with Cap 540mg/kg p.o. day 1 alone or following Eri 1mg/kg i.v. on day -8 then sacrificed on day 1 at 15min, 30min, 1h, 2h, 4h, 6h or 24h after Cap (n=3/ time point). Concentrations of Cap & its metabolites (5'-deoxy-5-fluorocytidine, 5DFCR; 5-Fluoro-5'-deoxyuridine, 5DFUR; 5-Fluorouracil, 5FU; 5-Fluorouridine, 5FUrd; & 5-Fluoro-2'-deoxyuridine, 5FdUrd) in plasma, tumor, skin & muscle were analysed by LC-MS/MS. Half the tumor was reserved to study Cap distribution using matrix-assisted laser desorption/ionization mass spectrometry imaging with haem imaged as a surrogate marker for tumour vasculature.
Results: We found no differences in the plasma, skin, muscle or tumor PK profiles of Cape & its metabolites with the addition of Eri (Table 1). In both treatment arms intratumoral concentrations of 5DFUR, 5FU, 5FUrd & 5FdUrd appeared higher in tumors while those of Cape & 5DFCR appeared higher in normal healthy tissues. To mitigate the variability in tumor Cape concentrations between animals, we also expressed the results as the ratio of drug concentration in tumour:healthy tissue but again found no apparent effect of Eri on intratumoral drug concentrations. Analyses of drug distribution are on-going & will be presented.
Conclusion: No clear effect of Eri on intratumoral concentrations of Cape or its metabolites was seen. We are exploring potential differences in tumour drug distribution.
Citation Format: Maria Jove Casulleras, Jade Spencer, Paul Loadman, Malcolm Clench, Steve Shnyder, Patricia Cooper, Cristina Russo, Amanda Race, Ramon Salazar, Chris Twelves. Preclinical intratumoral pharmacokinetics (PK) of capecitabine (Cap) given +/- eribulin (Eri) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4926.
Abstract 4935: High-throughput immune-oncology screen identifies EGFR inhibitors as potent enhancers of CTL antigen-specific tumor cell killing
Authors: Lizotte Patrick H. , Luster Troy , Cavanaugh Megan E. , Taus Luke J. , Dhaneshwar Abha , Mayman Naomi , Yang Aaron , Bittinger Mark , Kirschmeier Paul , Gray Nathanael S. , Barbie David A. , Janne Pasi A. 
Published: August 2018

Abstract
As immune checkpoint blocking antibodies increasing become foundational therapies for the treatment of cancer, there is a pressing need to identify compounds that synergize with checkpoint blockade as the basis of combinatorial treatment regimens. We have developed a screening assay in which a luciferized tumor cell line expressing a model antigen is co-cultured with a transgenic CD8+ T cell specifically recognizing the model antigen in a H-2b-restricted manner. The target tumor cell/T cell assay was screened with a small molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells in an antigen-dependent manner. The EGFR inhibitor Erlotinib was the top hit that enhanced T cell killing of tumor cells. Subsequent experiments with Erlotinib and additional EGFR inhibitors validated the screen result. EGFR inhibitors increase both basal and IFN-γ-induced antigen processing and presentation of MHC class-I, which enhanced recognition and lysis by CD8+ cytotoxic T lymphocytes. The tumor cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen utilizing the same target tumor cell/T cell assay identified sgRNAs targeting EGFR as sensitizing tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in the MC38 syngeneic colon cancer model that was superior to PD-1 blockade or EGFR inhibition alone, further validating EGFR inhibitors as immunomodulatory agents that enhance PD-1 checkpoint blockade. This novel target tumor cell/T cell assay can be screened in high-throughput with small molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds AND target genes, respectively, that enhance or inhibit T cell recognition and killing of tumor cells.
Citation Format: Patrick H. Lizotte, Troy Luster, Megan E. Cavanaugh, Luke J. Taus, Abha Dhaneshwar, Naomi Mayman, Aaron Yang, Mark Bittinger, Paul Kirschmeier, Nathanael S. Gray, David A. Barbie, Pasi A. Janne. High-throughput immune-oncology screen identifies EGFR inhibitors as potent enhancers of CTL antigen-specific tumor cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4935.
Abstract 4982: Oncogenic role of THOR, a conserved cancer/testis long noncoding RNA
Authors: Niknafs Yashar , Hosono Yasuyuki , K Matthew , Prensner John , Mehra Rohit , Pitchiaya Sethuramasundaram , Tien Jean , Malik Rohit , Zhao Weibin , Chinnaiyan Arul 
Published: August 2018

Abstract
Large scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Through a recent large-scale transcriptomic analysis over 6,500 tumor RNA-seq samples, we discovered over 50,000 lncRNAs in the human genome, many of which exhibited highly evolutionarily conserved sequence patterns. Building upon the discovery of these highly conserved lncRNAs, we functionally characterized a novel ultraconserved lncRNA, THOR, which exhibits expression exclusively in testis and a broad range of human cancers. We establish THOR as the first discovered cancer/testis lncRNA, and further investigated its functional significance. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. Namely, we generated CRISPR knockout cell line models, showing a definitive role for THOR in cancer progression. Additionally, given the sequence conservation of THOR through the mouse and zebrafish, we generated a zebrafish knockout model, and also a zebrafish overexpression model for THOR. Through RNA-pulldown followed by mass spectrometry, we discovered a conserved interaction of THOR with the RNA binding protein, IGF2BP1, in both human and zebrafish cells. We further show that THOR contributes to the mRNA stabilization activities of IGF2BP1. These findings are corroborated by iCLIP data for IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset in an NRAS K61-induced zebrafish melanoma model. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.
Citation Format: Yashar Niknafs, Yasuyuki Hosono, Matthew K, John Prensner, Rohit Mehra, Sethuramasundaram Pitchiaya, Jean Tien, Rohit Malik, Weibin Zhao, Arul Chinnaiyan. Oncogenic role of THOR, a conserved cancer/testis long noncoding RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4982.
Abstract 499: MicroRNA-411 downregulation promotes tumorigenesis and inhibits chemotherapy sensitivity by upregulating MLLT11 expression in human bladder cancer
Authors: Jin Honglei , Huang Haishan , Huang Chuanshu , Hua Xiaohui , Zhu Junlan 
Published: August 2018

Abstract
Although several previous studies have reported the implication of various microRNAs (miRNAs) in regulation of human bladder cancer (BC) development, alterations and function of many miRNAs in BC carcinogenesis and anti-cancer therapy are not explored yet at present. Here, we screened 1900 known miRNAs and first discovered that miR-411 was one of major miRNAs that was downregulated in a n-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BC mouse model. This miR-411 downregulation was also observed in human BC tissues and cell lines. The results from evaluating the relationship between miR-411 and patient survival in BC using the TCGA database also indicated that miR-411 was positively correlated with survival (&gt;3 years). Our studies also showed that miR-411 inhibited tumorigenesis and increased chemotherapy sensitivity in human BC. Mechanistic studies revealed that overexpression of miR-411 repressed expression of ALL1-fused gene from the chromosome 1q (MLLT11) by binding to the 3′-untranslated region of MLLT11 mRNA, induced p21 expression, and caused cell cycle arrest at the G2/M phase, in turn inhibiting BC tumorigenic growth. Ectopic expression of miR-411 also increased the sensitivity of BC cells to the chemotherapeutic agents, whereas MLLT11 restoration in miR-411-overexpressing cells increased resistance to the chemotherapeutic agents.
Citation Format: Honglei Jin, Haishan Huang, Chuanshu Huang, Xiaohui Hua, Junlan Zhu. MicroRNA-411 downregulation promotes tumorigenesis and inhibits chemotherapy sensitivity by upregulating MLLT11 expression in human bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 499.
Abstract 5005: Aging promotes changes to peritoneal and omental collagen structure that contribute to increased ovarian cancer metastatic success
Authors: Harper Elizabeth , Loughran Elizabeth , Leonard Annemarie , Hilliard Tyvette , Asem Marwa , Liu Yueying , Yang Jing , Klymenko Yuliya , Johnson Jeff , Sheedy Emma , Shi Zonggao , Leevy Matthew , Ravosa Matthew , Stack M. Sharon 
Published: August 2018

Abstract
Ovarian cancer (OvCa) is the deadliest cancer of the female reproductive system, ranking fifth in overall cancer deaths among women. Unlike the majority of cancers, OvCa metastasizes via diffusion through the peritoneal cavity, resulting in multiple metastatic sites, including the omentum and peritoneum. These metastasizing OvCa cells induce rapid mesothelial cell retraction and readily adhere to the sub-mesothelial collagen of the extracellular matrix. Epidemiologic data identifies age as a significant risk factor in OvCa, as about half of diagnoses are in women over the age of 63. Despite this, age is understudied in the OvCa field. Using a C57Bl/6 mouse model of aging, young (Y) mice ranging from 3-6 months of age, and aged (A) mice ranging from 20-23 months of age, corresponding to women aged 20-30 years (Y) and 60-67 years (A) were used to study the role aging has on metastasis. Fluorescently tagged C57Bl/6 syngeneic ID8 p53-/- mouse OvCa surface epithelial cells were injected intraperitoneally in young and aged mice and disease progression was evaluated for 5.5 weeks. Organ-specific tumor burden was quantified with ImageJ, revealing increased tumor burden in aged mice compared to their young counterparts. These results were reproduced in the FVB mouse model using syngeneic PTENshRNA/KRASG12V modified FVB OvCa oviductal epithelial cells. Second Harmonic Generation Microscopy (SHG) was used to visualize collagen of the peritoneal and omental tissues from young and aged C57Bl/6 mice. Distinct structural differences were shown in omental collagen in the Y vs A cohorts and validated with Scanning Electron Microscopy (SEM). Additionally, Nanoindentation illustrated mechanical differences between young and aged peritoneal samples. In conclusion, aging induces changes in the structure and mechanical strength of peritoneal and omental collagen, which contribute to OvCa metastasis.
Citation Format: Elizabeth Harper, Elizabeth Loughran, Annemarie Leonard, Tyvette Hilliard, Marwa Asem, Yueying Liu, Jing Yang, Yuliya Klymenko, Jeff Johnson, Emma Sheedy, Zonggao Shi, Matthew Leevy, Matthew Ravosa, M. Sharon Stack. Aging promotes changes to peritoneal and omental collagen structure that contribute to increased ovarian cancer metastatic success [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5005.
Abstract 5024: Drug screening of biopsy-derived multicellular spheroids using microfluidic technology
Authors: Mulholland Theresa E. , McAllister Milly , Patek Samantha , Flint David , Underwood Mark , Sim Alexander , Edwards Joanne , Zagnoni Michele 
Published: August 2018

Abstract
Performing drug screening, of physiologically relevant three-dimensional (3D) tumor models, for personalized treatment remains challenging, due to the small amount of tissue available from most biopsies. New microfluidic technologies, enabling greater control over cell positioning and fluid behavior at the micro-scale, allow extensive testing of anticancer agents on human tumor tissue preparations in 3D and offer new solutions for the development of anticancer compounds and personalized medicine. We have developed a microfluidic platform for extensive drug screening of tumor biopsies in a cost-effective manner and validated the system with tumor prostate patient samples. As a typical drug screening assay, up to 22 drug concentration-response curves could be generated from a single biopsy, within a time frame of up to 4 weeks. Biopsy tissue, grown as a heterogeneous co-culture from the primary sample, was prepared as cancer-cell enriched multicellular spheroids, cultured for 3 to 5 days prior to the application of a panel of standard-of-care drugs for prostate cancer. Readouts were obtained via bright-field and epifluorescence microscopy. The microfluidic platform was designed to be operated entirely without the need of external fluid actuation, with the microfluidic network capable of generating long-lasting, stable and repeatable drug concentration gradients across arrays of 240 spheroids. Outcomes were generated as 8-point drug concentration response curves per device, with each drug concentration tested on at least 24 spheroids. In-house developed software was used to analyze bright-field and fluorescent images to provide readouts of spheroid growth and viability, as well as information on drug penetration and drug efficacy over time. Following platform and assay validation using cancer cell lines, proof-of-concept screening was performed on prostate biopsies from 2 different patients. Results showed that biopsy-derived spheroids were more resistant to treatment than LNCaP spheroids, a prostate cancer cell line. For one biopsy, spheroids were sensitive to docetaxel, but resistant to enzalutamide, despite the presence of intact androgen receptors. This preliminary data outlines how this technology could become a useful tool to investigate patient-specific drug resistance and to test novel anticancer agents in a cost-effective manner, based on maximized screening of human tumor tissue in a 3D format.
Citation Format: Theresa E. Mulholland, Milly McAllister, Samantha Patek, David Flint, Mark Underwood, Alexander Sim, Joanne Edwards, Michele Zagnoni. Drug screening of biopsy-derived multicellular spheroids using microfluidic technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5024.