bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2869: Zika virus is a potent oncolytic agent against aggressive human ependymoma
Authors: Kaid Carolini , Semedo-Kuriki Patrícia , Goulart Ernesto , Caires-Júnior Luiz , Astray Renato , Okamoto Oswaldo Keith , Zatz Mayana 
Published: August 2019

Abstract
Ependymoma is a metastatic CNS tumor responsible for 10% of all pediatric brain tumors. Displaying a poor survival rate of only 32.5%, the conventional ependymoma treatment is surgery and radiation therapy associated to significant morbidity. Previous studies found significantly increased expression of NESTIN, a neural progenitor cell (NPC) marker, in aggressive ependymoma. Zika virus (ZIKV) has recently emerged as an oncolytic therapy against adult and pediatric CNS tumors due to its ability to infect NPCs and neural stem-like tumor cells. We showed for the first time that Brazilian Zika virus strain efficiently destroyed pediatric CNS tumor cells in vitro and in vivo, resulting in significantly mice longer survival and fewer metastasis. Once tumor cells overexpressing NPCs markers are more susceptible to ZIKV infection, here we evaluated the oncolytic properties of Brazilian ZIKV against human ependymoma. A patient-derived ependymoma cell line (USP21-EPE) has been established and found to abnormally express the pluripotency markers CD133, SOX2 and NESTIN. USP21-EPE monolayer culture showed massive cell death three days after ZIKV infection in four tested MOIs: 0.01, 0.1, 1 and 2. At MOI 0,1 50% of cell population decreased viability while at higher MOIs was observed 100% of cell death 72 hours post ZIKV infection. Moreover, ZIKV significantly disrupted CNS ependymoma tumorspheres reinforcing its oncolytic effect against the ependymoma tumor cells. Considering the poor effectiveness and severe side effects of available treatments for ependymoma and that most ZIKV infections are associated to very mild or no symptoms, our findings open new avenues for novel therapies against this aggressive pediatric tumor.
Citation Format: Carolini Kaid, Patrícia Semedo-Kuriki, Ernesto Goulart, Luiz Caires-Júnior, Renato Astray, Oswaldo Keith Okamoto, Mayana Zatz. Zika virus is a potent oncolytic agent against aggressive human ependymoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2869.
Abstract 2871: Global reduction of H3K4me3 improves chemotherapeutic efficacy for pediatric ependymomas
Authors: Xi Guifa , Wadhwani Nitin , Hashizume Rintaro , Mania-Farnell Barbara , Soares Marcelo Bento , James Charles D. , Tomita Tadanori 
Published: August 2019

Abstract
Background Ependymomas (EPNs) are the third most common brain tumor in children. These tumors are resistant to available chemotherapeutic treatments, therefore new effective targeted therapeutics must be identified. Increasing evidence shows epigenetic alterations including histone posttranslational modifications (PTMs), are associated with malignancy, chemotherapeutic resistance and prognosis for pediatric EPNs. In this study we examined histone PTMs in EPNs and identified potential targets to improve chemotherapeutic efficacy.
Methods Global histone H3 lysine 4 trimethylation (H3K4me3) levels were detected in pediatric EPN tumor samples with immunohistochemistry and immunoblots. Candidate genes conferring therapeutic resistance were profiled in pediatric EPN tumor samples with micro-array. Promoter H3K4me3 occupancy was examined for two candidate genes, CCND1 and ERBB2, with chromatin-immunoprecipitation coupled with real-time PCR (ChIP-PCR). These methods and MTS assay were used to verify a relationship between H3K4me3 levels and CCND1 and ERBB2, and to investigate cell viability in response to chemotherapeutic drugs in primary cultured pediatric EPN cells.
Results H3K4me3 levels positively correlate with WHO grade malignancy in pediatric EPNs and are associated with progression free survival in patients with posterior fossa group A EPNs (PF-EPN-A). Reduction of H3K4me3 by silencing its methyltransferase SETD1A, in primary cultured EPN cells, increased cell response to chemotherapy.
Conclusions Our results support the development of a novel treatment that targets H3K4me3 to increase chemotherapeutic efficacy in pediatric PF-EPN-A tumors.
Key words: promoter, H3K4me3, human SETD1A, chemotherapy, pediatric ependymoma
Citation Format: Guifa Xi, Nitin Wadhwani, Rintaro Hashizume, Barbara Mania-Farnell, Marcelo Bento Soares, Charles D. James, Tadanori Tomita. Global reduction of H3K4me3 improves chemotherapeutic efficacy for pediatric ependymomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2871.
Abstract 2874: De novo acquisition of RD3 loss with intensive multi-modal therapy harmonize neuroblastoma relapse
Authors: Somasundaram Dinesh Babu , Subramanian Karthikeyan , Aravindan Sheeja , Yu Zhongxin , Natarajan Mohan , Herman Terence S. , Aravindan Natarajan 
Published: August 2019

Abstract
The majority of high-risk neuroblastoma that initially responds to therapy will ultimately relapse. Acquired genetic/molecular rearrangement contributes to tumor relapse and currently, no salvage treatment regimens are known to be curative. Our studies identified the loss of retinal-degeneration-protein-3 (RD3) in progressive disease (PD) and its association with poor clinical outcomes. Herein we investigated the acquisition of RD3-loss after current standard of care (SOC, intensive multimodal therapy) in neuroblastoma. Acquired transcriptional (RNA in situ hybridization, QPCR) and translational (IHC on a custom archived cell micro array, immunoblotting) loss of RD3 with SOC was investigated with bed-to-bench approach utilizing a panel of 15 stage-4 patient derived cell-lines with known therapy status, diagnosis [DX] vs. PD after SOC). Further, RD3-loss in progressive disease, its direct role in the pathogenesis disease progression (cell migration, invasion, tumorosphere formation and metastatic potential) was investigated using mouse model of progressive neuroblastoma and in experimental in vitro and ex vivo settings coupled with gene manipulation strategies. In addition, RD3 status in response to therapy were also affirmed by in silico analysis of independent studies on bed-to-bench and experimental models. Results demonstrated RD3-loss (transcriptional/translational) acquisition with SOC in human PD. Experimental in vitro, in vivo, ex vivo studies affirmed RD3 loss in PD and, further forced RD3-rearrangements in these models defined its functional role in PD pathogenesis. Data-mining experimental studies with salvage therapeutic agents affirmed the acquisition of RD3-loss in resistant cells and in residual tumors. For the first time, these results demonstrate the de novo acquisition of RD3 loss in PD after intensive multi-modal therapy. Defining the criticality of RD3-loss in PD and the defined role of RD3 loss in PD pathogenesis, benefit of targeted reinforcement could lead to improved salvage therapy for high-risk neuroblastoma.
Citation Format: Dinesh Babu Somasundaram, Karthikeyan Subramanian, Sheeja Aravindan, Zhongxin Yu, Mohan Natarajan, Terence S. Herman, Natarajan Aravindan. De novo acquisition of RD3 loss with intensive multi-modal therapy harmonize neuroblastoma relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2874.
Abstract 2876: p21-activated kinase 1 is a novel therapeutic target for metastatic osteosarcoma harboring p27 mislocalization
Authors: Chen Xiang , Cates Justin , Du Yuchen , Sung Yun Jung , Lo Xiao-nan , Hicks John , Man Tsz-Kwong 
Published: August 2019

Abstract
Lung metastasis is the leading cause of death in osteosarcoma (OS), the most common bone cancer in children and young adults. Due to a lack of biomarkers and therapeutic targets, significant progress has not been made in the treatment of metastatic OS over the past three decades. The survival of metastatic patients remains dismal. We have previously reported that the tumor suppressor protein p27 (KIP1, CDKN1B) is frequently mislocalized in the cytoplasm of OS, which promotes the motility and invasiveness of the tumor cells and the development of pulmonary metastases in mice. In this study, we showed that a higher proportion score of cytoplasmic p27 significantly correlated with metastases developed within 3- or 5-year of follow-up, and poor disease-specific and event-free survival in a large OS cohort (n=136). Using immunoprecipitation followed by mass spectrometry, we demonstrated that cytoplasmic p27 interacted with p21-activated kinase 1 (PAK1), where the two proteins co-localized in the cytoplasm of OS cells. PAK1 is a serine/threonine kinase that has been implicated in various cancers; however, its role in OS is still elusive. We showed that the phosphorylations at serine-144 and threonine-423 residues of PAK1 were higher in the p27-mislocalized cells relative to the control cells. The PAK1 phosphorylations increased actin stress fiber formation in the tumor cells. Gene silencing or therapeutic inhibition of PAK1 reduced the motility of p27-mislocalized cells in vitro. Similar results were observed in other cancer cell lines known to have the p27 mislocalization, suggesting PAK1 is a common and potential downstream effector of p27-mediated metastasis. An experimental metastasis mouse model further showed that a PAK1-silenced mutant had a significant impairment in the development of pulmonary metastasis. In summary, our study indicates that cytoplasmic p27 is a novel prognostic biomarker in OS. In the tumor cell, the mislocalization activates PAK1-mediated cell motility and metastasis. Targeting PAK1 in metastatic OS harboring the p27 mislocalization may be exploited as a potential therapeutic intervention to improve the poor outcome of the affected children.
Citation Format: Xiang Chen, Justin Cates, Yuchen Du, Yun Jung Sung, Xiao-nan Lo, John Hicks, Tsz-Kwong Man. p21-activated kinase 1 is a novel therapeutic target for metastatic osteosarcoma harboring p27 mislocalization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2876.
Abstract 2878: CRISPR-Cas9 screens identify the nuclear export factor NXT1 as a novel therapeutic target in MYCN-amplified neuroblastoma
Authors: Malone Clare F. , Dharia Neekesh V. , Kugener Guillaume , Paolella Brenton , Rothberg Michael , Abdusamad Mai , Gonzalez Alfredo , Dumont Nancy , Younger Scott , Root David , Vazquez Francisca , Stegmaier Kimberly 
Published: August 2019

Abstract
Pediatric cancers, such as neuroblastoma, have a relative lack of oncogenic mutations and the known drivers of these cancers are largely transcription factors, a target class notoriously difficult to “drug.” In order to identify novel therapeutic targets for high-risk, MYCN-amplified neuroblastoma, we employed functional genomic screening using a CRISPR-Cas9 approach. We generated genome-scale CRISPR dependency data to identify a candidate gene list of 197 putative genetic dependencies in neuroblastoma. We next created a focused sgRNA library targeting these genes and performed time-course dropout screens using CRISPR and CRISPRi and Annexin-V-based positive-selection cell death screens in four MYCN-amplified neuroblastoma cell lines. We also screened this library in vivo in two xenograft models of MYCN-amplified neuroblastoma. At the intersection of these screens, we identified the nuclear export factor NXT1 as a top candidate for therapeutic development in neuroblastoma. NXT1 scores as a strong dependency using both CRISPR and CRISPRi, is strongly enriched in our Annexin-V based positive selection cell death screen and scores in our in vivo screen. We have validated that NXT1 is indeed a genetic dependency in neuroblastoma in low-throughput and that NXT1 loss induces apoptosis in these cell lines. We were next interested in identifying biomarkers of dependency on NXT1, and by integrating RNAseq data with CRISPR dependency data, we identified low expression of NXT2, a paralog of NXT1, as the top predictive feature of NXT1 dependency. Importantly, while NXT1 itself is not currently druggable, inhibitors against another nuclear export protein, CRM1, are currently in Phase II clinical trials, demonstrating this class of proteins has the potential to be effectively drugged. Together, we show that CRISPR-Cas9 functional screens can be used to identify new therapeutic targets, particularly in diseases that lack “druggable” oncogenic drivers, such as many pediatric cancers.
Citation Format: Clare F. Malone, Neekesh V. Dharia, Guillaume Kugener, Brenton Paolella, Michael Rothberg, Mai Abdusamad, Alfredo Gonzalez, Nancy Dumont, Scott Younger, David Root, Francisca Vazquez, Kimberly Stegmaier. CRISPR-Cas9 screens identify the nuclear export factor NXT1 as a novel therapeutic target in MYCN-amplified neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2878.
Abstract 2979: Boosting replication and penetration of telomerase-specific replicative virus by paclitaxel induces synthetic lethality in peritoneal metastasis of gastric cancer
Authors: Ogawa Toshihiro , Kikuchi Satoru , Ishikawa Wataru , Tazawa Hiroshi , Tabuchi Motoyasu , Kuroda Shinji , Noma Kazuhiro , Nishizaki Masahiko , Kagawa Shunsuke , Urata Yasuo , Fujiwara Toshiyoshi 
Published: August 2019

Abstract
Background: Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer and its prognosis is extremely poor. A promising result in phase III trial using intraperitoneal (i.p.) paclitaxel (PTX) for the peritoneal metastasis of gastric cancer has been reported in recent year; however, it is not sufficiently effective to eradicate disseminated gastric cancer. In this study, we investigated whether novel i.p. oncolytic virotherapy could be synthetically lethal with PTX for the peritoneal metastasis of gastric cancer.
Methods: OBP-401 (TelomeScan) is a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency that is driven by telomerase promoter. We assessed its synergistic effect with PTX using human gastric cancer cell lines (GCIY and KATO III) and xenograft peritoneal metastasis model. The mechanism underlying the synergistic antitumor effect was evaluated by in vitro viral replication, induction of mitotic catastrophe, and in vivo viral penetration into disseminated nodules.
Results: OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX was synthetically lethal with OBP-401 by enhancing viral replication ability in cancer cells and the combination therapy increased mitotic catastrophe induction, resulted in accelerating autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by the i.p. administration of OBP-401 in the orthotopic human gastric cancer peritoneal dissemination model. And, PTX enhanced the penetration of OBP-401 deeply into the disseminated nodules. Moreover, non-invasive in vivo imaging system (IVIS) demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited tumor growth of peritoneal metastasis and the amount of malignant ascites.
Conclusions: Intraperitoneal virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer. Clinical trials to obtain the proof of concept are warranted in peritoneally disseminated gastric cancer patients.
Citation Format: Toshihiro Ogawa, Satoru Kikuchi, Wataru Ishikawa, Hiroshi Tazawa, Motoyasu Tabuchi, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara. Boosting replication and penetration of telomerase-specific replicative virus by paclitaxel induces synthetic lethality in peritoneal metastasis of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2979.
Abstract 3: Discovery and optimization of small molecule Bax activators for cancer therapy
Authors: Liu Gang , Kim Hyejin , Ding Chunyong , Yu Zhuo , Wang Hong , Chen Haiying , Shen Qiang , Zhou Jia 
Published: August 2019

Abstract
Bax, an indispensable executioner protein of B-cell lymphoma 2 (Bcl-2) family, plays a pivotal role in controlling the mitochondrial dysfunction and apoptosis in normal and cancer cells. High throughput screening to combat the nicotine-induced Bax phosphorylation at serine 184 (S184) to activate the proapoptotic function of Bax has revealed compound SMBA1 as a promising Bax direct activator as we previously reported. Initial medicinal chemistry campaign by choosing SMBA1 as a lead compound for breast cancer treatment resulted in the identification of compound CYD-2-11 with low micromolar IC50 values against MDA-MB-231 and MCF-7 as well as in vivo inhibitory effects against MDA-MB-231 xenograft tumor growth. Herein, we report the comprehensive structural optimization based on CYD-2-11 as the lead by introducing various alkylamino side chains to have a deeper access to S184 pocket and replacing carbon atoms with nitrogen as well as reducing the nitro group of 9H-fluorene scaffold to construct diverse derivatives for enhanced drug properties. CYD-4-61 and GL0385 have been discovered as the most potent anti-breast cancer agents with submicromolar IC50 values of 0.34 and 0.33 µM against MDA-MB-231 as well as 0.65 and 0.26 µM against MCF-7, respectively. More importantly, these drug candidates exhibited significant in vivo efficacy suppressing xenograft tumor growth by activating Bax to induce cancer cell apoptosis with the potential to overcome resistance against Adriamycin (ADR) in breast cancer. This work was supported by Breast Cancer Research Program (BCRP) Breakthrough Award BC160038 (to J.Z.) and BC160038P1 (to Q.S.) from the Department of Defense (DoD).
Citation Format: Gang Liu, Hyejin Kim, Chunyong Ding, Zhuo Yu, Hong Wang, Haiying Chen, Qiang Shen, Jia Zhou. Discovery and optimization of small molecule Bax activators for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3.
Abstract 300: A new combination therapy to treat metastatic breast cancer
Authors: Sharif-Askari Bahram , Aloyz Raquel , Panasci Lawrence 
Published: August 2019

Abstract
Poly (ADP-ribose) polymerase (PARP) resulting poly (ADP-ribosyl)ation is an early player in modification of proteins detected at single strand breaks and double strand breaks contributing to DNA repair. PARP1, 2 and 3 are involved in this process. However, PARP3 is unique in that, it is also required for efficient mitotic progression, specifically in stabilization of the mitotic spindle. The vinca alkaloids such as vinorelbine, arrest cells in metaphase due to inhibition of the assembly and dynamics of microtubules. Nontoxic concentrations of 2 PARP3 inhibitors, ME-0328 and olaparib, sensitized various her-2 negative and triple negative breast cancer cell lines greater than or equal to 10 fold to vinorelbine associated with potentiation of vinorelbine’s interaction with tubulin and also vinorelbine-induced PARP3 inhibition, mitotic arrest, and apoptosis without evidence of a DNA repair mechanism involved in this sensitization (Sharif-Askari B et al. Breast Cancer Res Treat. 2018 Nov;172(1):23-32).
Eribulin is a Halichondrin B analogue, an antitubulin drug, with a unique mechanism of action; it inhibits microtubule dynamics via a novel mechanism of action which seems to involve binding to a unique site on tubulin resulting in the suppression of microtubule polymerization without affecting depolymerization along with sequestration of tubulin into nonfunctional aggregate. After impressive results in phase III trials (including one of the rare trials to show prolongation of survival in comparison to standard of care in heavily pretreated metastatic breast cancer patients) the U.S. Food and Drug Administration approved eribulin for treatment of patients with metastatic breast cancer. PARP3 inhibitors again sensitized at least 5 fold her-2 negative and triple negative breast cancer cell lines to eribulin. We will do similar studies with eribulin as we have done with vinorelbine including in-vivo studies. These studies could define a new therapy in the treatment of metastatic triple negative and ER+/her-2 negative breast cancer. The inhibition of PARP3 may increase the sensitivity of tumor cells to mitotic spindle poison chemotherapies. Our results should stimulate development of specific PARP3 inhibitors for clinical use.
Citation Format: Bahram Sharif-Askari, Raquel Aloyz, Lawrence Panasci. A new combination therapy to treat metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 300.
Abstract 3006: A novel strategy of targeting opioidergic receptors to potentially reduce human breast cancer cell proliferation, colony formation, invasion, and migration
Authors: Murugan Sengottuvelan , Patel Vanisha , Sarkar Dipak K. 
Published: August 2019

Abstract
Breast cancer is the second most prevalent cancer after lung cancer among American women. The efficacy of current antitumor therapies is still quite limited. Endogenous opioid peptides, such as endorphin, which is involved in body stress controlling mechanisms, have been shown to enhance immune function and prevent cancer growth and progression in various animal models of cancers. Therefore, targeting the endogenous opioid peptides receptors in the regulation of cancer chemoprevention may offer new promise for the design of therapeutic strategies. Our previous studies have shown differential actions of mu-opioid receptor (MOR) and delta opioid receptor (DOR) on various cell types. In this study we tested the effects of a MOR antagonist naltrexone (NTX) and a DOR agonist (D-Ala2-,N-Me-Phe4,Gly-ol Enkephalin; DPDPE) on proliferation and invasion of human breast cancer cells of different molecular subtype such as T47D (Luminal A), MDA-MB-231 (triple negative, Claudin-Low) and MDA-MB- 468 (triple negative, basal A) in cultures. We used cytotoxicity, clonogenic, cell migration and cell invasion assays to identify effects of these drugs on cancer cells. We found that both NTX and DPDPE have significant cytotoxic effects on these breast cancer cells. Our work from clonogenic, cell migration and cell invasion assays showed that both NTX and DPDPE inhibit the formation of colony, migration and invasion of cancer cells in a concentration-dependent manner. These data suggest that naltrexone and DPDPE have anticancer efficacy in subtypes of human breast cancer cells. The anticancer effects varied depending on the concentration of the drugs and the subtype of breast cancer cells. (Supported by NIH grant R01 CA20863201).
Citation Format: Sengottuvelan Murugan, Vanisha Patel, Dipak K. Sarkar. A novel strategy of targeting opioidergic receptors to potentially reduce human breast cancer cell proliferation, colony formation, invasion, and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3006.