bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B86: Impact of multi targeted epigenetic therapy (MTET): a series of 100 consecutive advanced solid tumor cancers
Authors: Nezami M. A. , Hager Steven , Lanman Richard 
Published: May 2016

Abstract
Background:
Tumor heterogeneity is a key underlying factor that leads to resistance to chemo-and matched therapies. Circulating cell-free tumor DNA (ctDNA) may capture more tumor heterogeneity than a tissue biopsy-derived DNA analysis. In addition, markers of vasculogenesis have been shown to be sensitive markers of tumor growth vs. response to treatment. Here we study the impact of a novel multitargeted epigenetic therapy (MTET) on ctDNA, markers of vasculogenesis and radiographic response.
Methods:
One hundred consecutive patients with advanced solid tumor cancers were treated with multi targeted epigenetic therapy (MTET). More than 60% were stage IV, with 52% male and 48% women, 24 to 81 years of age. Pre-treatment and post-treatment imaging, circulatory tumour cells (CTC), (Biofocus Lab), ctDNA (Guardant Health, Inc.) and plasma VEGF (LabCorp) were obtained. PET scan metabolic activities were determined by a radiologist in a tertiary hospital based metabolic imaging canter. The average patient had undergone two or more lines of therapy previously. Patients underwent 10 or more cycles of a novel multitargeted epigenetic therapy (MTET), consisting the administration of polyphenols intravenously, either independently or in addition to conventional chemotherapies, consisting of standard and palliative chemotherapies.
Results:
Overall positive imaging response rate(in favor for metabolic response) was observed in 62%. The magnitude of response was independent of type of tumor. Among the patients who had circulating tumor cells (CTC) and/or ctDNA analyzed(number 20 and number 4 respectedly), a positive response (80% for CTC) was seen with improved CTCs and/or the ctDNA alterations for the gene variant at highest mutant allele. Reduction and normalization of plasma VEGF were seen in 92% of patients. Tolerability was good and none of the patients discontinued therapy due to toxicity.
Conclusions:
There were significant radiographic responses in advanced solid tumor cancer patients receiving MTET therapy. These changes were paralleled by the changes in serological assessment of vasculogenic factors and/or CTC/ctDNA. The high response rate is unusual for patients who have undergone multiple lines of therapy and a prospective randomized therapy of MTET is being planned.
Citation Format: M. A. Nezami, Steven Hager, Richard Lanman. Impact of multi targeted epigenetic therapy (MTET): a series of 100 consecutive advanced solid tumor cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B86.
Abstract B89: Mechanistic assessment of heat shock network perturbation by novel chemotypes identified using chemogenomic screening
Authors: Goode Kourtney M. , Thomas Fiona M. , Pascuzzi Pete , Davisson V. Jo , Hazbun Tony R. 
Published: May 2016

Abstract
The 90-kDa heat shock protein 90 (Hsp90) is a chaperone protein responsible for the folding and activation of numerous proteins disregulated in various cancers that drive oncogenesis. Consequently, inhibition of Hsp90 is thought to be an attractive anti-cancer therapeutic strategy, though to date, clinical success has been limited. Hsp90 inhibition leads to simultaneous degradation of multiple oncogenic client proteins, giving “polypharmacologic” effects through the targeting of a single, highly networked protein. Hence, the development of small molecule inhibitors of Hsp90 may be effective anti-cancer agents that have reduced likelihood of development of resistance when compared to other less networked single protein targets. This study demonstrates identification and validation of a novel chemotype that perturbs the heat shock protein network. A liquid culture-based phenotypic screen employing Saccharomyces cerevisiae haploid deletions strains with known sensitivities to Hsp90 inhibitors by screening of the NCI diversity II chemical library set. The screen identified 9 hit compounds; 2 previously identified heat shock modulators and 7 novel heat shock modulator hits. To validate these novel compounds as heat shock network selective, we bioinformatically show that the NSC145366 compounds sensitivity profile in NCI tumor cell lines significantly correlates with other Hsp90 inhibitors. Also, biochemical analyses demonstrate NSC145366 has direct interactions with two cytoplasmic isoforms of human Hsp90 both in recombinant protein preparations and in crude tumor cell lysates. In addition, we show that the compound preferentially interacts with the Hsp90 C-terminal dimerization domain as opposed to many of the current N-terminal domain-based inhibitors. Further characterization of the compound interaction with Hsp90 and its effects on the heat shock cellular network are ongoing. This study demonstrates the utility of phenotypic screening to identify heat shock protein network modulators and the possibility inhibiting Hsp90 in a novel and different mode from previous inhibitors.
Citation Format: Kourtney M. Goode, Fiona M. Thomas, Pete Pascuzzi, V. Jo Davisson, Tony R. Hazbun. Mechanistic assessment of heat shock network perturbation by novel chemotypes identified using chemogenomic screening. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B89.
Abstract C127: Chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC activities
Authors: Kato Yukinari , Kaneko Mika K. 
Published: May 2016

Abstract
Background: Podoplanin (PDPN), a platelet aggregation-inducing transmembrane glycoprotein, is expressed in a variety of tumors, and binds to C-type lectin-like receptor-2 (CLEC-2). Overexpression of PDPN is involved in invasion and metastasis. Several anti-PDPN monoclonal antibodies (mAbs) such as NZ-1 showed antimetastatic activities by binding to platelet aggregation-stimulating (PLAG) domain of PDPN. Recently, we developed a novel mouse anti-PDPN mAb, LpMab-7 using the cancer-specific mAb (CasMab) method. LpMab-7 is more sensitive than anti-PLAG domain mAbs. Methods: We generated and characterized a mouse-human chimeric anti-PDPN mAb, chLpMab-7. We investigated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities in vitro. Furthermore, we evaluated the in vivo efficacy of chLpMab-7 using both xenograft models and experimental metastasis models. In xenograft models, PDPN-expressing CHO (CHO/hPDPN) or a lung cancer cell line PC-10 was engrafted into nude mice. In experimental metastasis models, CHO/hPDPN cells were inoculated into tail vein of the nude mice. Results: ChLpMab-7 antibody showed ADCC and CDC activities against CHO/hPDPN, glioblastoma, mesothelioma, or lung cancer cell lines. Treatment with chLpMab-7 abolished both tumor growth in xenograft and spontaneous pulmonary metastasis. ChLpMab-7 exhibited dramatic suppression of experimental pulmonary metastasis, even when it was injected five days after the inoculation of tumor cells. Conclusion: ChLpMab-7 suppressed tumor development and hematogenous metastasis via ADCC/CDC activities. PDPN should be useful as a novel antibody-based therapy.
Citation Format: Yukinari Kato, Mika K. Kaneko. Chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC activities. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C127.
Abstract C131: ‘KRAS addiction’ an artifact of 2D culture? Inhibitors of the mut-KRAS NSCLC 3D growth
Authors: Kirkpatrick D. Lynn , Delaney Roisin , Grandjean Geoff , Madrigal Assael , Indarte Martin , Scott Mike , Powis Garth 
Published: May 2016

Abstract
Introduction: KRAS, the predominant form of mutated RAS (mut-KRAS), is found in ∼25% of patient tumors across many cancer types and plays a critical role in driving tumor growth and resistance to therapy. We identified CNKSR1 (connector enhancer of kinase suppressor of Ras 1) to be critical for mut-KRAS but not wild type (wt)-KRAS signaling and cell proliferation. Its product CNK1 is a multi-domain organizer protein found as part of the Ras membrane signaling nanocluster where it binds to mut-KRas although not to wt-KRas, and is necessary for mut-KRas cell growth and signaling. We have exploited the pleckstrin homology (PH)-domain of CNK1 as a target for drug discovery to inhibit mut-KRas. To understand the role of CNK1 as a regulator of KRas cell growth, evaluation of siKRAS and siCNK1 on 2D and 3D growth were evaluated. We also studied the effects of KRAS cell growth conditions on response to selective inhibitors the PH-domain of CNK1 identified using a computational modeling approach.
Results: Using a panel of twelve NSCLC lines and siRNA knockdown of KRAS we found that the reported growth addiction of some cancer cell lines for mut-KRAS, and the resistance of others, is most likely an artifact of 2D culture. Mut-KRAS NSCLC cell lines showing addiction in 2D growth did not show addiction in 3D anchorage independent growth in agarose, where all cell lines were more sensitive. Wt-KRAS cell lines were largely unaffected by siKRAS knockdown. Additionally, the CNK1 inhibitor PHT-7390 IC50s for 2D growth inhibition of a panel of 8 mut-KRAS NSCLC lines ranged from 0.60 to 100 μM (ave 18.7 μM) yet was found to be considerably more potent in 3D culture with IC50s from 0.03 to 2.99 μM (ave 0.69 μM). The most pronounced difference was seen in H2009 and Calu1 mut-KRAS cells where PHT-7390 IC50s in 2D were &gt;100 μM, while 0.093 and 0.35 μM in 3D. Wt-KRas NSCLC growth inhibition (3 lines) was largely unaffected by PHT-7390 under either condition with average IC50s of 68 and 69 μM in 2D and 3D conditions, respectively. Target engagement in 2D has shown these CNK1 inhibitors block mut-KRAS signaling but not that of wt-KRAS.
Conclusion: Variable enhanced growth dependence on mut-KRAS (“addiction”) is seen in 2D but not 3D. Potent and specific inhibition of mut-KRAS cell line growth by CNK1 PH-domain inhibitors is considerably more robust in 3D culture suggesting a novel approach to inhibit mut-KRAS effect on cancer growth.
Citation Format: D. Lynn Kirkpatrick, Roisin Delaney, Geoff Grandjean, Assael Madrigal, Martin Indarte, Mike Scott, Garth Powis. ‘KRAS addiction’ an artifact of 2D culture? Inhibitors of the mut-KRAS NSCLC 3D growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C131.
Abstract C142: Functional characterization of P58IPK-PERK pathway in prostate cancer cells
Authors: Sheng Xia , Storm Margrethe , Jin Yang , Saatcioglu Fahri 
Published: May 2016

Abstract
Androgen signaling is important for the normal development and function of the prostate as well as for prostate cancer (PCa). We recently found that androgens activated the IRE1α-XBP1 arm of the canonical unfolded protein response (UPR) pathways and simultaneously inhibited PERK-eIF2α signaling. Activation of the IRE1α-XBP1 arm was mediated by direct binding of the androgen receptor (AR) in the vicinity of IRE1, as well as XBP1s target genes, and increase in their expression. Consistently, AR and IRE1α pathway gene expression are correlated in human PCa samples and XBP1s protein expression is significantly increased in cancer compared to normal prostate. However, the mechanisms behind androgen mediated inhibition of PERK-eIF2α signaling are not clear at present. One possible mediator in this regard is P58IPK, an XBP1s target gene that can interact with and inhibit PERK and eIF2α phosphorylation. Here, we show that P58IPK expression is increased by androgens in a time-dependent manner and that it plays a pro-survival role in PCa cells. P58IPK knockdown activated PERK expression as well as subsequent eIF2α phosphorylation when induced with the UPR activator thapsigargin. These findings suggest that P58IPK mediates, at least in part, the differential androgen effects between the IRE1α and PERK signaling in PCa and may be a potential therapeutic target.
Citation Format: Xia Sheng, Margrethe Storm, Yang Jin, Fahri Saatcioglu. Functional characterization of P58IPK-PERK pathway in prostate cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C142.
Abstract C155: Cyclin-dependent kinase 1 (Cdk1) is a promising therapeutic target to overcome ovarian cancer
Authors: Cho Hanbyoul , Yang Wookyeom , Shin Ha-Yeon , Lee Eun-ju , Chay Doo-Byung , Kim Jae-Hoon 
Published: May 2016

Abstract
Purpose: Ovarian cancer shows heterogeneous characteristics which cause chemoresistance and recurrence. The goal of this study was to elucidate characteristics common to various ovarian cancers in order to evaluate their potential for targeted therapy.
Methods: Microarray results for cell lines of serous, mucinous, and brenner types of ovarian cancers were reanalyzed and validated via ovarian cancer cell lines, GEO datasets and TMA blocks. RO-3306 which is an inhibitor of Cdk1 and si-cdk1 was used to measure the growth rate of ovarian cancer cell lines via FACS analysis. In addition, combination treatment with RO-3306 and cisplatin was administered in vitro and in in vivo xenograft mouse model.
Results: Microarray reanalysis revealed that expression of Cdk1 and cyclinB1 was higher in 5 types of ovarian cancer cell lines, 4 GEO datasets and ovarian cancer TMA blocks than in HOSE cells. Ovarian cancer TMA particularly showed increased level of cytoplasmic Cdk1 protein, but not in nucleus. When Cdk1 was inhibited by siRNA and a potent Cdk1 inhibitor (RO-3306), growth of ovarian cancer cells decreased, while G2/M arrest or apoptosis increased. In addition, tumor growth was significantly lesser in a xenograft mouse model treated with a combination of RO-3306 and cisplatin than in mice treated with each drug alone.
Conclusions: Cdk1 is a promising gene for targeted anticancer therapy. It is expected that combined treatment with Cdk1 inhibitor and chemotherapeutic agents would maximize the effects of ovarian cancer treatment.
Citation Format: Hanbyoul Cho, Wookyeom Yang, Ha-Yeon Shin, Eun-ju Lee, Doo-Byung Chay, Jae-Hoon Kim. Cyclin-dependent kinase 1 (Cdk1) is a promising therapeutic target to overcome ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C155.
Abstract C31: Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells in vitro
Authors: Robb Ryan N. , Yang Linlin , Chatterjee Moumita , Saji Moto , Ringel Matt , Chakravarti Arnab , Williams Terence 
Published: May 2016

Abstract
Background: BRAF mutations are oncogenic drivers which occur in about 60% of papillary thyroid cancer (PTC) as well as a significant proportion of anaplastic thyroid cancer (ATC). BRAF mutations drive MAPK signaling and treatment resistance in thyroid cancer. BRAFV600E is the most common of these mutations in PTC, and can be selectively inhibited by vemurafenib.
Methods: We used a panel of PTC and ATC cell lines to assess how the presence/absence of BRAFV600E impacts radiation sensitivity. We used radiation clonogenics, comet assays, nuclear foci formation, and western blots to determine the effect of vemurafenib on PTC and ATC cell lines.
Results: Analysis of radiation clonogenics revealed relative radioresistance in cell lines containing the BRAFV600E mutation versus wild-type. Vemurafenib inhibited MAPK signaling in V600E mutants, but showed no effect on BRAF wild-type cell lines. Vemurafenib pretreatment selectively radiosensitized BRAFV600E mutants, as assessed by radiation clonogenic assays. Neutral comet assays also showed that vemurafenib impairs DNA repair in BRAFV600E lines. Furthermore, γ-H2A.x westerns and nuclear foci staining indicated that vemurafenib pretreatment decreases the ability of cells to repair double-strand DNA breaks in cell lines containing the BRAFV600E mutation. Vemurafenib also appeared to alter the kinetics of nuclear foci formation and resolution of 53BP1 as well as Rad51 in these cell lines.
Conclusions: From our initial results, BRAF mutations appear to be associated with radioresistance in PTC and ATC cell lines. Vemurafenib selectively radiosensitizes both PTC and ATC cells through inhibition of DNA repair mechanisms. Together, these data suggest that combining vemurafenib and radiation may improve therapeutic control for BRAFV600E mutant thyroid cancers.
Citation Format: Ryan N. Robb, Linlin Yang, Moumita Chatterjee, Moto Saji, Matt Ringel, Arnab Chakravarti, Terence Williams. Vemurafenib selectively radiosensitizes BRAF V600E mutant papillary and anaplastic thyroid carcinoma cells in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C31.
Abstract C40: Inhibition of Mcl-1 through covalent modification of a non-catalytic lysine side chain
Authors: Su Qibin , Akçay Gizem , Grimster Neil , Belmonte Matthew , Rawlins Philip , Lamb Michelle , Hird Alexander , Aquila Brian 
Published: May 2016

Abstract
Myeloid cell leukemia 1 (Mcl-1), a potent anti-apoptotic protein of the BCL2 family, has been studied as a key resistance factor in human cancers. Restoring apoptotic signals by inactivating Mcl-1 protein interactions with small molecule inhibitors has been intensively pursued as targets for cancer therapeutics. We herein describe our effort towards the structure-based design, synthesis and evaluation of first potent, covalent binders of Mcl-1. The resulting inhibitors specifically modified a non-catalytic lysine residue with high level of Mcl-1 potency in biochemical and cell based assays. Our covalent inhibitors could provide potent probes to interrogate Mcl-1 dependent cancer biology.
Citation Format: Qibin Su, Gizem Akçay, Neil Grimster, Matthew Belmonte, Philip Rawlins, Michelle Lamb, Alexander Hird, Brian Aquila. Inhibition of Mcl-1 through covalent modification of a non-catalytic lysine side chain. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C40.
Abstract C66: SPHK1 expression associated with acquired resistance to oxaliplatin in colon cancer cell lines
Authors: Lee Hee Yeon , Lee Myung Ah , Park Jin Hee 
Published: May 2016

Abstract
Background Oxaliplatin is a main chemotherapeutic agent in the treatment of advanced colorectal cancer. The response rate has been reported to be over 50%, especially when combined with a target agent. However, most patients develop resistance to oxaliplatin even in responding patients, leading to cancer related death due to organ dysfunction. Unfortunately the mechanism of resistance of oxaliplatin is unclear. In the present study, we tried to identify the role of Sphingosine Kinase 1 (SPHK1) involved in the acquired resistance to oxaliplatin using colon cancer cell line.
Method We treated HCT-116 colon cancer cell lines with gradient concentrations of oxaliplatin starting at the dose of IC50. After treated with initial dose of oxaliplatin for 48hrs, we collected the viable cell and then treated again with elevated dose of oxaliplatin. After prolonged period of exposure to low dose of oxaliplatin, we compared cell viable test and protein expression between HCT-116 wild cell and oxaliplatin treated HCT-116 cell line. We also investigated the change of response to oxaliplatin after tranfection of SPHK1 into wild type of HCT-116 cell line. The viability was determined by Neutral Red uptake assay.
Result After prolonged repeated exposure of low dose oxaliplatin, HCT-116 cell line showed resistance to oxaliplatin and expressed new protein. We identified this new protein as SPHK1 using protemics. Comparing the wild type and the resistance cell line, phosphorylated Akt, phosphorylated ERK, and PTEN expression were upregulated in the resistant cell line. After transfection of SPHK1 into the wild type HCT-116 cell line, response to oxaliplatin decreased comparing to the control group.
Conclusion Based on our data, SPH1K can be a potential factor for the acquired resistance to oxaliplatin in colon cancer. It is not known yet the association between SPHK1 and PTEN in the mechanism of resistance. Currently, we are conducting experiment to identify these associations and mechanism of acquired resistance using other cell lines and human tissue.
Citation Format: Hee Yeon Lee, Myung Ah Lee, Jin Hee Park. SPHK1 expression associated with acquired resistance to oxaliplatin in colon cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C66.