bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5813: Rab GTPase 3C promotes colon cancer metastasis via regulation of IL-6 secretion and STAT3 signaling pathway
Authors: Chen Chi-Long 
Published: July 2017

Abstract
RAB GTPases is involved in membrane trafficking vesicle formation and cell motility. Recently, exocytotic RABs received growing attention in cancer research. However, the molecular mechanism of exocytotic RABs in colorectal tumorigenicity remains unclear. In this study, we found RAB GTPase 3C (RAB3C) has the most significant association with higher pathological stage, tumor recurrence, frequent distant metastasis, and poor prognosis in 215 colorectal adenocarcinoma cohort using tissue microarray (TMA) analysis. In multivariate analyses, high RAB3C expression retained its independently prognostic significance for both overall survival (p=0.001) and disease-free survival (p &lt; 0.001). Further experimental results showed increased migration and invasion ability in RAB3C overexpressing colon cancer cells compared with control group in vitro and in vivo. The cell culture medium collected from RAB3C overexpressing model could promote parental colon cancer cells further indicated that the metastasis-promoting role of RAB3C is exocytosis dependent. We then integrated the results from previously microarray and proteomics datasets and discovered that increased production of multiple cytokines in RAB3C overexpressing cell lines. Of these cytokines, IL-6 pathway is the top pathway corresponding to gene expression changes after RAB3C overexpression. Blocking of IL-6 function with IL-6 antibody or IL-6 knockdown significantly reduced the migration ability in RAB3C overexpressing colon cancer cells. Furthermore, secretion of IL-6 after RAB3C overexpression promoted the JAK2-STAT3 signaling with increased STAT3 phosphorylation levels to promote migration. In addition, Ruxolitinib, a JAK2 inhibitor, was found to significantly inhibited RAB3C induced colon cancer cell migration through blocking STAT3 phosphorylation. In conclusion, our study showed that RAB3C overexpression promoted tumor metastasis and is associated with poor prognosis of colon cancer patients through modulating the IL6 exocytosis of cancer cells to activate JAK2-STAT3 pathway. These findings suggest a new therapeutic strategy through the inhibition of STAT3 signaling pathway in RAB3C-IL-6 axis by Ruxolitinib to prevent metastasis of colon cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Chi-Long Chen. Rab GTPase 3C promotes colon cancer metastasis via regulation of IL-6 secretion and STAT3 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5813. doi:10.1158/1538-7445.AM2017-5813
Abstract 5827: Role of Ewing sarcoma EWS/FLI1 protein in midzone formation during mitosis
Authors: Azuma Mizuki 
Published: July 2017

Abstract
Ewing sarcoma remains the second most common form of bone and cartilage cancer in children. Although EWS/FLI1 fusion protein (derived by chromosomal translocation) is known to induce aberrant transcription in the patient cells, why and how this molecule leads to tumorigenesis specifically in skeletal cell lineage is not understood. We previously reported a novel role of EWS/FLI1, which interacts with EWS and leads to mitotic defects through an inhibition of EWS function. We further demonstrated that EWS interacts with Aurora B and relocates from inner centromere to the midzone (a midline structure that is consisted spindles called the central spindle) during anaphase of mitosis. Disruption of EWS-directed Aurora B-relocation leads to defects in cytokinesis, and to induction of chromosome instability (CIN).
EWS is an abundant molecule that is localized throughout the entire cytoplasm of anaphase, but how EWS specifically regulates midzone formation is not understood. A potential candidate mechanism is post-translational modification of EWS to modulate its activity in a spatial-temporal manner. Because previous studies showed that EWS/FLI1-T79 is a potential modification site of O-GlcNAcylation and phosphorylation, we hypothesized that the O-GlcNAcylation of EWS/FLI1 contributes to the impairment of Aurora B-relocation. Our study shows that high cellular O-GlcNAc increases the level of O-GlcNAcylation of EWS/FLI1 accompanied by the impairment of the Aurora B relocation and of central spindle formation. Contrary, EWS/FLI1-T79A and EWS/FLI1-T79D (phospho-mimic mutant) does not impair the mislocation of Aurora B at the midzone, suggesting that the O-GlcNAcylation of EWS/FLI1 is responsible for mislocation of Aurora B at the midzone. The O-GlcNAc-dependent impairment of midzone formation by EWS/FLI1 may lead to the identification of therapeutic targets for Ewing sarcoma patients.
Citation Format: Mizuki Azuma. Role of Ewing sarcoma EWS/FLI1 protein in midzone formation during mitosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5827. doi:10.1158/1538-7445.AM2017-5827
Abstract 5832: Rho-associated kinase is a therapeutic target in neuroblastoma
Authors: Dyberg Cecilia H. , Fransson Susanne , Andonova Teodora , Sveinbjörnsson Baldur , Lännerholm-Palm Jessika , Forsberg David , Herlenius Eric , Martinsson Tommy , Kogner Per , Johnsen John Inge , Wickström Malin 
Published: July 2017

Abstract
Background: Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. The non-canonical Wnt/planar cell polarity (PCP) signaling pathway regulates cytoskeletal organization, migration and maturation of neural crest cells during neuritogenesis. Here we show that neuroblastoma harbors frequent mutations of genes controlling the PCP signaling pathway and Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. The majority of these mutations were detected in GTPase activating proteins and guanine nucleotide exchange factors genes, which may result in inhibition of Rac and activation of Rho and was associated with aggressive high-stage neuroblastomas.
Methods: We performed whole-exome sequencing of neuroblastoma samples of all clinical subgroups to search for mutations and genetic aberrations. Cytotoxic activity of Rho-associated kinases (ROCK) inhibitors was studied in cell viability assays. Morphology and invasion were studied with microscopy. The molecular mechanisms were characterized using cell- and molecular biology techniques. In vivo studies (xenografts and the transgenic mouse model TH-MYCN) in mice were carried out to validate the therapeutic effects and toxicity.
Results: Exome sequencing detected frequent mutations and gene aberrations in genes controlling the activity of PCP signaling. Analysis of gene signatures and immunohistochemistry showed that high expression of ROCK1 and ROCK2 correlated with poor patient survival. Several mediators of Rac/Rho were differentially expressed in cell lines and patient samples. Pharmacological or genetic inhibition of ROCK, a key molecule in Rac/Rho signaling resulted in differentiation, inhibition of neuroblastoma cell growth and migration and degradation of MYCN protein. Finally, ROCK inhibition reduced the growth of established neuroblastoma xenografts in nude mice and repressed tumor progression in a MYCN-driven mouse model of neuroblastoma (T-MYCN)
Conclusions: These results provide evidence that inhibition of the non-canonical/PCP signaling cascade using ROCK inhibitors suppress the growth of neuroblastoma in preclinical models and suggest possibilities for improved treatment of high-risk neuroblastomas.
Citation Format: Cecilia H. Dyberg, Susanne Fransson, Teodora Andonova, Baldur Sveinbjörnsson, Jessika Lännerholm-Palm, David Forsberg, Eric Herlenius, Tommy Martinsson, Per Kogner, John Inge Johnsen, Malin Wickström. Rho-associated kinase is a therapeutic target in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5832. doi:10.1158/1538-7445.AM2017-5832
Abstract 584: From code to cure: Computational discovery of novel immune checkpoints
Authors: Benita Yair , Novik Amit , Cojocaru Gady , Borukhov Itamar , Wool Assaf , Kliger Yossef , Zekharya Tomer , Levine Zurit , Nemzer Sergey , Levy Ofer , Toporik Amir 
Published: July 2017

Abstract
Antibody blockade of CTLA4 and PD-1 immune checkpoints emerged as an effective treatment modality for cancer. However, the majority of patients do not achieve sustained long term benefit, suggesting a need for targeting of additional immune checkpoints. To identify additional B7/CD28 immune checkpoint targets, we developed a unique compendium of computational algorithms that identified multiple novel targets including TIGIT in 2008, which was an unknown protein at the time of discovery [Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17858-63], and PVRIG which we recently disclosed. Since their initial discovery, these targets have been functionally validated and anti-tumor activity was demonstrated with antibodies that target them.
In this presentation, we will describe the computational algorithms that led to the discovery of these novel immune checkpoints. These algorithms combine two complementary aspects: (i) endogenous immune checkpoint function prediction and (ii) prediction of immuno-modulatory activity in cancer. Immune checkpoint function was predicted based on gene structure similarity to B7/CD28 family members that is reminiscent of ancient common evolutionary origins. A gene structure alignment tool was developed to identify functional homologs of B7/CD28 genes even in the absence of sequence similarity. Next, the expression profile of these candidates was modeled and compared to profiles of known immune checkpoints in normal and cancer tissues. We will review the details of TIGIT and PVRIG discovery, which were among the immune checkpoints predicted in this process.
Our approach demonstrates the powerful ability of computational biology to translate genomic knowledge into rational and reliable drug target discovery.
Citation Format: Yair Benita, Amit Novik, Gady Cojocaru, Itamar Borukhov, Assaf Wool, Yossef Kliger, Tomer Zekharya, Zurit Levine, Sergey Nemzer, Ofer Levy, Amir Toporik. From code to cure: Computational discovery of novel immune checkpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 584. doi:10.1158/1538-7445.AM2017-584
Abstract 5842: Therapeutic enhancement of aminolevulinic acid-mediate tumor fluorescence and photodynamic therapy with kinase inhibitors
Authors: Chen Bin , Palasuberniam Pratheeba 
Published: July 2017

Abstract
Photodynamic therapy (PDT) involves the combination of a photosensitizer and light of a specific wavelength. Upon light activation in the presence of oxygen, photosensitizer molecules generate reactive oxygen species that cause cytotoxicity by inducing oxidative stress. Aminolevulinic acid (ALA) is a pro-drug used for the diagnosis and PDT treatment of various solid tumors based on endogenous production of heme precursor protoporphyrin IX (PpIX). Although all human cells express heme biosynthesis enzymes and produce PpIX, tumor cells are often found to have higher PpIX production and accumulation than normal cells, allowing for the detection and treatment of solid tumors. In exploring ALA-based tumor detection and therapy in breast cancer, we have reported that high ABCG2 transporter activity in triple negative breast cancer cells (TNBC) contributes to reduced PpIX levels in tumor cells, causing cell resistance to ALA-PDT. The administration of an ABCG2 inhibitor Ko143 was able to reverse cell resistance to ALA-PDT by increasing PpIX levels. In this study, we showed that some kinase inhibitors were able to increase ALA-mediated PpIX by inhibiting ABCG2 activity. Particularly, our results demonstrate that lapatinib, a dual inhibitor of EGFR and Her2, increased the ALA-PpIX level and cell sensitivity to ALA-PDT in the MDA-MB-231 TNBC cells. Lapatinib treatment had little effect on MCF10A breast epithelial cells. These results indicate that small molecule kinase inhibitors such as lapatinib can be used for enhancing ALA-based tumor detection and PDT in tumors with high ABCG2 activity.
Citation Format: Bin Chen, Pratheeba Palasuberniam. Therapeutic enhancement of aminolevulinic acid-mediate tumor fluorescence and photodynamic therapy with kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5842. doi:10.1158/1538-7445.AM2017-5842
Abstract 5843: Role of CDK9 inhibition as a sensitizer to radiation in esophageal adenocarcinoma: In vitro and in vivo efficacy study
Authors: Veeranki Omkara Lakshmi M. , Dokey Rashmi , Mejia Alicia , Tong Zhimin , Zhang Jianhu , Qiao Yawei , Singh Pankaj Kumar , Katkhuda Riham , Minoo Barbara , Canales Jaime Rodriguez , Lin Steven , Krishnan Sunil , Maru Dipen 
Published: July 2017

Abstract
Preoperative chemoradiation in neoadjuvant setting is the standard of care for loco-regional esophageal adenocarcinoma (EAC). However, less than 30% of patients develop complete pathological response indicating need for newer therapeutic strategies. Cyclin dependent kinase 9 (CDK9) is found to be over expressed in EAC compared to Barrett’s esophagus. Our previous studies demonstrated strong antitumor effects on inhibition of CDK9 in EAC both in vitro and in vivo. Here we report augmented tumor regression in irradiated xenografts on combination with Flavopiridol, a well-established clinically used CDK inhibitor, compared to single modality treatments. In vitro studies indicate that Flavopiridol could radiosensitize FLO-1 and SKGT4 EAC cells with sustained 53BP1 foci especially in SKGT4 cells. Flavopiridol and BAY1143572, a more selective inhibitor of CDK9, could radiosensitize additional EAC radiation sensitive and resistant cell lines (SKGT4-R, OE-33 and OE-33-R) as analyzed by MTT assay, apoptosis, formation of 53BP1 foci and clonogenic assay. Flavopiridol and BAY1143572 showed a radio-synergistic action by downregulating MCL-1 and Axl. In conclusion, the radio-sensitizing capacities of CDK9 inhibitors presented here suggest that their adjuvant administration might improve EAC therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Omkara Lakshmi M. Veeranki, Rashmi Dokey, Alicia Mejia, Zhimin Tong, Jianhu Zhang, Yawei Qiao, Pankaj Kumar Singh, Riham Katkhuda, Barbara Minoo, Jaime Rodriguez Canales, Steven Lin, Sunil Krishnan, Dipen Maru. Role of CDK9 inhibition as a sensitizer to radiation in esophageal adenocarcinoma: In vitro and in vivo efficacy study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5843. doi:10.1158/1538-7445.AM2017-5843
Abstract 5858: MicroRNA-338-5p regulates radioresistance by directly targeting survivin in esophageal squamous cell carcinoma
Authors: Park Misun , Yoon Hyeon-joon , Kang Moon Chul , Lee Jun Ah , Kwon Junhye , Lee Haewon 
Published: July 2017

Abstract
Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and resent studies have reported the miRNA-mediated radiotherapy resistance. However, further research would be necessary to reveal the regulation mechanisms and the treatment strategies using miRNA have yet to be established in ESCC. We compared the miRNA expression profile in ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell line using miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of the miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering the survivin, which is known to play an inhibitor of apoptosis. Over expression of survivin using plasmid vector reversed miR-338-5p induced apoptosis. From tumor xenograft experiments, we found that therapeutic delivery of the miR-338-5p mimics via direct injection to tumor mass increased sensitivity to radiation therapy. In conclusion, these findings suggested that miR-338-5p is a potential radiosensitizer and may be one of the therapeutic biomarkers for radioresistant in ESCC.
Citation Format: Misun Park, Hyeon-joon Yoon, Moon Chul Kang, Jun Ah Lee, Junhye Kwon, Haewon Lee. MicroRNA-338-5p regulates radioresistance by directly targeting survivin in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5858. doi:10.1158/1538-7445.AM2017-5858
Abstract 5867: Reversal of drug resistance in prostate cancer using PBM nanoparticle
Authors: Singh Santosh K. , Lillard James W. , Singh Rajesh 
Published: July 2017

Abstract
Multidrug-resistance (MDR) is the major reason behind the failure of prostate cancer (PCa) therapy. ATP-binding cassette (ABC) transporters contribute to drug resistance via ATP-dependent drug efflux. P-glycoprotein (Pgp), which is encoded by MDR1 gene, confers resistance to certain anticancer agents. The development of agents able to modulate MDR mediated by Pgp and other ABC transporters remained a major goal for PCa therapy. The proposed study evaluated a novel method for targeted delivery of resveratrol alone or in combination with docetaxel at desired rates for reversal of drug resistance. We described a proprietary planetary ball milling approach (PBM) that uses a natural polysaccharide (starch; FDA approved) to create a drug-polysaccharide nanoparticle as a core that is subsequently coated with novel folate-conjugated poly (ϵ-caprolactone) / poly (ethylene glycol) co-polymer, which allows binding to high-affinity folate receptors presents on PCa cells. The resulting PBM nanoparticles were shown to be rapidly internalized and induce significant cancer cell apoptosis at lower doses compared to unformulated resveratrol and/or docetaxel. Our data showed that resveratrol potently synergizes with docetaxel to inhibit proliferation and induce cell death in resistance PCa cells. The up-regulation of pro-apoptotic (BAX, BID, BAK), p53 and down regulation of anti-apoptotic (BCL-2, MCL-1), Pgp and NF-κB protein confirmed that a synergistic combination of resveratrol-docetaxel with targeted delivery to tumor cells could provide a more potent therapeutic effect at lower drug concentrations and improve the therapeutic index. These results suggested that the co-delivery of resveratrol, and a cytotoxic agent in a PBM nanoparticle might potentially improve the treatment of drug-resistant tumors. [This work is supported from Grant # 5SC1CA193758-03]
Citation Format: Santosh K. Singh, James W. Lillard, Rajesh Singh. Reversal of drug resistance in prostate cancer using PBM nanoparticle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5867. doi:10.1158/1538-7445.AM2017-5867
Abstract 5874: Cdk4/6 kinase inhibitor resistance in prostate cancer
Authors: Leeuw Renee de , Schiewer Matthew J. , McNair Christopher , Augello Michael A. , Yoshida Akihiro , Hazard Edward S. , Courtney Sean , Hardiman Gerard T. , Drake Justin , Feng Felix Y. , Tomlins Scott , Hussain Maha H. , Diehl J Alan , Kelly William K. , Knudsen Karen E. 
Published: July 2017

Abstract
Non-organ confined prostate cancer (PCa) is often effectively, but only transiently treated by targeting the androgen receptor (AR) signaling axis through androgen depletion strategies, often coupled with AR antagonists. Unfortunately, disease recurs within a median of 3-4 years, presenting as castration resistant PCa (CRPC), for which there are limited therapeutic options. This emphasizes the need for more efficacious drugs and a patient-tailored approach towards cancer therapy to improve disease outcome. One class of drugs currently tested clinically, Cdk4/6 kinase inhibitors, blocks phosphorylation of the retinoblastoma (RB) tumor suppressor, thereby boosting its function, and likely preventing castration resistance. As Cdk4/6 inhibitor resistance has already been reported in other cancers, some PCa patients are anticipated to develop drug resistance. Here, we created palbociclib-resistant PCa cell models by continuously culturing them in presence of the drug to unravel mechanisms of acquired resistance, and assessed them for cross-resistance to ribociclib and response to other therapeutics. While the parental PCa cell models, Cdk4/6 inhibitors efficiently induce a G1 cell cycle arrest, the resistant cell lines bypass this cell cycle checkpoint. Although loss of RB is a known mechanism for Cdk4/6i resistance, none of the models lost RB expression. Strikingly, these originally hormone-sensitive cell lines, upon developing Cdk4/6 inhibitor resistance display altered response to selected therapeutic regimens. Mechanisms of resistance, as informed by Whole Exome Sequencing and RNASeq, will be discussed.
Citation Format: Renee de Leeuw, Matthew J. Schiewer, Christopher McNair, Michael A. Augello, Akihiro Yoshida, Edward S. Hazard, Sean Courtney, Gerard T. Hardiman, Justin Drake, Felix Y. Feng, Scott Tomlins, Maha H. Hussain, J Alan Diehl, William K. Kelly, Karen E. Knudsen. Cdk4/6 kinase inhibitor resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5874. doi:10.1158/1538-7445.AM2017-5874