bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5741: Dexamethasone suppresses cytokine-induced dual oxidase 2 and VEGF-A expression in human pancreatic cancer cells in vitro and pancreatic cancer growth in xenografts
Authors: Wu Yongzhong , Doroshow James H. 
Published: August 2018

Abstract
Chronic pancreatic inflammation is strongly associated with pancreatic cancer. We previously demonstrated that inflammatory cytokines interact to produce a DUOX2 -dependent, reactive oxygen species (ROS)-related, pro-oxidant milieu that could increase the pathologic potential of pancreatic inflammation, enhancing malignant transformation. Furthermore, we have shown that DUOXuox2 expression is upregulated in patients with chronic pancreatitis as well as pancreatic ductal adenocarcinoma (PDAC). Dexamethasone (Dex) has been reported to inhibit PDAC invasiveness, the formation of pancreatic intraepithelial neoplasia in genetically-engineered mouse models of pancreatic cancer, as well as epithelial to mesenchymal transition in PDACs, and local tumor recurrence and metastasis in vivo. Using cultured human pancreatic cancer cell lines, we found that in a dose- and time-dependent fashion Dex inhibited cytokine (IFN-γ/LPS, IL-4, and IL-17)-mediated up-regulation of DUOXuox2 and VEGF-A expression in several human pancreatic cancer cell lines, including BxPC-3, ASPC-1, and CFPAC-1. Dex pretreatment also blocked DUOX2-related DNA double strand breaks (detected as activated γH2AX) and the expression of HIF-1α in PDAC cells treated with pro-inflammatory cytokines. The effects of Dex were abolished by pre-treatment with the Dex antagonist RU-486. As expected, we did not observe anti-proliferative effects of Dex on PDAC cells in vitro. However, Dex strongly repressed DUOXuox2 mRNA and protein expression as well as the growth of xenografts initiated from BxPC-3 cells; in contrast, for the MIA-Paca line that is unresponsive to cytokines in culture, Dex produced no effect on DUOXuox2 expression and tumor growth when these cells were grown as xenografts. Examination of the human DUOXuox2 promotor in silico revealed a putative negative glucocorticoid receptor (GR) binding element. Western analysis, using nuclear extracts from pancreatic cancer cells treated with Dex, revealed that both activated glucocorticoid receptor and certain co-repressors, such as NCOR-1/2 and histone deacetylases (HDAC1, 2, and 3) exist in human pancreatic cancer cell nuclei. Our ongoing experiments are focused on understanding the molecular mechanism of Dex-mediated DUOXuox2 repression both in vitro and in vivo. In summary, these studies suggest that cytokine-related oxidant stress, generated by Duox2, could play a role in the progression of pancreatic cancer.
Citation Format: Yongzhong Wu, James H. Doroshow. Dexamethasone suppresses cytokine-induced dual oxidase 2 and VEGF-A expression in human pancreatic cancer cells in vitro and pancreatic cancer growth in xenografts [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 5741.
Abstract 575: Prediction of genomic instability in triple-negative breast cancer patients utilizing a CTC phenotype classifier
Authors: Jendrisak Adam , Ebrahim Nadia , Rodriguez Angel , Lee Jerry , Sutton Ramsay , Wang Yipeng , Landers Mark , Dittamore Ryan 
Published: August 2018

Abstract
Background: Genomic scars and HRD gene mutations are biomarkers for PARP inhibitor (PARPi) and platinum agent therapy response in breast cancer. Tests for these markers are usually performed by next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) and have limitations such as sample accessibility/availability and under-sampling due to inter/intratumor heterogeneity. Previously we predicted genomic instability (GI) using CTC phenotypic features without the use of NGS in metastatic castration-resistant prostate cancer (mCRPC) pts with high accuracy (&gt;76%) (ASCO 2016). In addition, patients with phenotypically predicted GI (pGI) CTCs had significantly better PSA responses on abiraterone + veliparib (92%) vs. abiraterone alone (23%) (ESMO 2016), and also responded better to platinum agents vs. taxane agents (ESMO 2017). Here, we sought to develop and analytically validate an algorithm for predicting CTC pGI in TNBC.
Methods: Training set: 521 CTCs from 26 mCRPC pts were detected with the Epic Sciences CTC platform and analyzed for 19 phenotypic digital pathology features, including protein expression and cell morphology. The same CTCs were single-cell sequenced for the number of large-scale transitions (LSTs) as an indicator of GI. A linear regression algorithm to predict GI by CTC phenotype was developed, cross validated, and utilized to generate a CTC pGI score. Test set: 114 CTCs from 8 TNBC blood samples, median of 8 CTCs/pt, were sequenced for GI and phenotypically predicted for pGI.
Results: Analytical cutoff for GI (8.74) was determined in the mCRPC training set by separation of a binomial distribution low vs. high GI scores. pGI cutoff (8.74) was set the same as GI. The training set performance was: sensitivity = 69%, specificity = 83%, accuracy = 77%. In the TNBC test set, pGI vs. GI demonstrated: sensitivity = 86%, specificity = 92%, accuracy = 88%.
Conclusions: Previous studies showed that pGI was an analytically validated biomarker with clinical utility to predict PARPi or platinum therapy response in mCRPC pts. Here we show the same test concept can be applied to TNBC. Further analytical validation in a larger cohort is ongoing. The ability to identify PARPi/platinum sensitivity using an IF CTC staining method for CTC phenotype without the use of NGS will help to stratify patients more rapidly, at reduced cost, and aid in the acceleration of drug development.
Citation Format: Adam Jendrisak, Nadia Ebrahim, Angel Rodriguez, Jerry Lee, Ramsay Sutton, Yipeng Wang, Mark Landers, Ryan Dittamore. Prediction of genomic instability in triple-negative breast cancer patients utilizing a CTC phenotype classifier [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 575.
Abstract 5753: Cancer stem cell markers allow for immune evasion in triple-negative breast cancer
Authors: Hoffmann Andrew D. 
Published: August 2018

Abstract
Triple-negative breast cancer tumor-initiating cells, or cancer stem cells (CSCs) are identified as a population that is CD44+ and CD24low. These cells are important drivers of distant metastasis and recurrence. An important component of both the recurrence and metastasis functions of CSCs is the capacity to evade immune detection. Our work has identified key members of the antigen presentation machinery required for proper immunosurveillance as being differentially expressed in tumor cells expressing CD44 compared to cells lacking CD44, including a differential response to important immune system cytokines. We are currently working to identify functional differences related to the altered protein levels in these cells.
Citation Format: Andrew D. Hoffmann. Cancer stem cell markers allow for immune evasion in triple-negative breast 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 5753.
Abstract 5759: Discovery of a novel claudin 6 (CLDN6) specific monoclonal antibody
Authors: Stafford Lewis J. , Screnci Brad , Sulli Chidananda , Rosenberg Erin , Molino Nicholas , Tucker David , Sullivan Jonathan , Barnes Trevor , Pfaff Jennifer , Hazarika Tanmayee , Charpentier Thomas , Gilman Samantha , Rimkunas Rebecca , Wilf Rona , Willis Sharon , Doranz Benjamin , Rucker Joseph , Chambers Ross 
Published: August 2018

Abstract
Claudin 6 (CLDN6) is a tight junction molecule that is involved in cell to cell adhesion of epithelial and endothelial cell sheets. CLDN6 is considered an oncofetal protein which is not expressed in normal human tissue but is expressed in some cancers such as endometrial, ovarian and testis cancer. Expression of CLDN6 in endometrial and urothelial cancer leads to a poor prognosis. The problem of developing antibodies against CLDN6 is that the family member claudin 9 (CLDN9) is highly homologous, only varying by 2 amino acids in the extracellular domain. To address this need, Integral Molecular has developed the MPS Discovery Engine® to enable the isolation, characterization, and engineering of monoclonal antibodies for tight junction proteins, GPCRs, ion channels, and transporters. MPS utilizes a collection of technologies to address each of the barriers to monoclonal antibody development against the native extracellular epitopes of multispan membrane proteins. These include, antigen engineering to attain high levels of surface expression, DNA and Lipoparticle immunization to present native epitopes to the immune system, diverse immunization host species to deal with highly conserved proteins, Lipoparticles (high concentration native membrane proteins) to enable phage display, microfludic B-cell isolation to isolate rare MAbs, and shotgun mutagenesis (comprehensive alanine scanning) for epitope mapping. Using the MPS Discovery Engine® we were able to successfully screen a large panel of clones for claudin 6 specificity. From these clones there were 72 potential antibodies that reacted with either claudin 6 or 6/9. A subset of these antibodies reacted only to claudin 6 and not to claudin 9 which has led to our lead drug candidate. With our MPS Discovery Engine® platform, we have the ability to target intact, conformationally specific, and functional antibodies to multipass membrane proteins.
Citation Format: Lewis J. Stafford, Brad Screnci, Chidananda Sulli, Erin Rosenberg, Nicholas Molino, David Tucker, Jonathan Sullivan, Trevor Barnes, Jennifer Pfaff, Tanmayee Hazarika, Thomas Charpentier, Samantha Gilman, Rebecca Rimkunas, Rona Wilf, Sharon Willis, Benjamin Doranz, Joseph Rucker, Ross Chambers. Discovery of a novel claudin 6 (CLDN6) specific monoclonal antibody [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 5759.
Abstract 576: A cancer drug atlas enables prediction of parallel drug vulnerabilities
Authors: Narayan Ravi , Molenaar Piet , Teng Jian , Tannous Bakhos , Wurdinger Tom , Koster Jan , Westerman Bart 
Published: August 2018

Abstract
Personalized cancer treatments using synergistic combinations of drugs is attractive but proves to be highly challenging. The combinatorial nature of such problems results in an enormous parameter space that cannot be resolved by empirical research, i.e. testing all combinations for all molecularly defined tumors. In addition, effective drug synergy is hard to predict. Here we present an approach to map data of drug-response encyclopedias and represent these as a drug atlas. This atlas consists of a framework of chemotherapeutic responses that represents a drug vulnerability landscape of cancer. Based on data from the literature we found that many synergistic drug combinations show distinct inter therapy responses and drug sensitivities. We confirmed this by performing a drug combination screen against glioblastoma where we used 270 combination experiments. From the identified dual therapies we were able to predict and validate a triple drug synergy which was validated in vivo. This new and generalizable strategy opens the door to unforeseen personalized multidrug combination approaches.
Citation Format: Ravi Narayan, Piet Molenaar, Jian Teng, Bakhos Tannous, Tom Wurdinger, Jan Koster, Bart Westerman. A cancer drug atlas enables prediction of parallel drug vulnerabilities [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 576.
Abstract 5818: Globally optimizing therapeutic combinations against bortezomib-resistant multiple myeloma using a quantitative parabolic optimization platform
Authors: Rashid Masturah , Toh Tan Boon , Hooi Lissa , Silva Aleidy , Zhang Yanzhou , Karnani Neerja , Jha Sudhakar , Ho Chih-Ming , Chng Wee Joo , Ho Dean , Chow Edward Kai-Hua 
Published: August 2018

Abstract
Multiple myeloma is an incurable hematological malignancy that relies on drug combinations as first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these drug combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure. Thus, there remains a need to identify improved drug combinations that may serve as later lines of treatment for improved treatment against bortezomib-resistant multiple myeloma. We have developed the quantitative parabolic optimization platform (QPOP) to optimize drug combinations against bortezomib-resistant multiple myeloma. By mapping phenotypic output data to parabolic response surfaces, QPOP is able to deterministically optimize drug combinations as well as drug dosages. By continuously optimizing in multiple systems of interest, from in vitro to in vivo, drug combinations can be globally optimized for greater efficacy in increasingly complex biological systems. While QPOP does not rely on molecular mechanism modeling or prediction, identified optimal drug combinations can reverse DNA hypermethylation and silencing of tumor suppressors that occurs following acquired bortezomib-resistance in multiple myeloma. Furthermore, this drug combination is broadly effective across a range of primary multiple myeloma patient samples. Beyond bortezomib-resistant multiple myeloma, global optimization of drug combinations by QPOP can serve to improve drug combination design across a range of other cancers and diseases through a continuous optimization process across the entire drug development pipeline.
Citation Format: Masturah Rashid, Tan Boon Toh, Lissa Hooi, Aleidy Silva, Yanzhou Zhang, Neerja Karnani, Sudhakar Jha, Chih-Ming Ho, Wee Joo Chng, Dean Ho, Edward Kai-Hua Chow. Globally optimizing therapeutic combinations against bortezomib-resistant multiple myeloma using a quantitative parabolic optimization platform [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 5818.
Abstract 5836: Activation Induced Cytosine Deamination, AICDA, is induced after EGFR TKI exposure leading to secondary resistant mutations in lung adenocarcinoma
Authors: Kadi Najwa El , Davis April , Cooke Alexander , Wang Luo , Korkaya Hasan , Kalemkerian Gregory , Hassan Khaled 
Published: August 2018

Abstract
Background: Epidermal growth factor receptor (EGFR) activation mutations occur in 10-50% of lung adenocarcinomas. This leads to constitutive activation of EGFR, which triggers multiple downstream survival and proliferation pathways. EGFR tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. Acquired EGFR mutations are the main mechanism of on-target resistance to TKIs. T790M mutation that occurs after first line TKI treatment, is a cytosine to thymine (C&gt;T) single nucleotide transition leading to a threonine to methionine amino acid change at position 790 (i.e. T790M). Interestingly, treatment with Osimertinib, that overcomes the T790M mutation, leads to other acquired resistant mutations, C797S, G796S/R and L792F/H. Our data suggest that resistant mutations are acquired events secondary to cytosine deamination through Activation Induced Cytosine Deamination enzyme (AICDA).
Results: Sub clones of the lung adenocarcinoma cell line PC9 with no evidence of T790M mutation by droplet digital PCR (ddPCR) at baseline, were treated with EGFR TKI. After serially increasing the treatment dose, T790M mutation was detected by ddPCR associated with a significant increase in AICDA expression. Knocking down AICDA by shRNA, decreases the development of T790M in PC9 cell lines after TKI exposure. Similarly, when the resistant T790M PC9 clones were treated with Osimertinib, the expression of AICDA was also induced. Using mass spectrometry, we established that cytosine at codon 790 is methylated; thus, deamination of 5-methylcytosine leads to thymine directly, explaining the T790M C&gt;T mutation. In addition, using ChIP assay and pharmacological inhibition we confirm that upon TKI exposure, NFĸB binds AICDA promoter and induces its expression. In a mouse xenograft model, the induction of NFĸB and AICDA after EGFR TKI exposure is abrogated by concurrent use of an NFĸB inhibitor. Finally, patients treated with EFR TKI had an increased expression of AICDA upon progression.
Conclusion: In EGFR driven lung adenocarcinoma, NFĸB pathway is activated upon exposure to EGFR TKIs which induces AICDA expression. AICDA deaminates cytosine into other nucleotides leading to treatment resistance.
Citation Format: Najwa El Kadi, April Davis, Alexander Cooke, Luo Wang, Hasan Korkaya, Gregory Kalemkerian, Khaled Hassan. Activation Induced Cytosine Deamination, AICDA, is induced after EGFR TKI exposure leading to secondary resistant mutations in lung adenocarcinoma [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 5836.
Abstract 585: Exosomal EphA2 transmits chemoresistance and predicts pancreatic cancer patient responses to therapy
Authors: Fan Jia , Wei Qian , Koay Eugene J. , Liu Yang , Zhao Zhen , Hu Ye 
Published: August 2018

Abstract
Exosomes are small extracellular vesicles secreted by most cells that are found in blood and other bodily fluids, and which contain cytoplasmic material and membrane factors corresponding to their cell type of origin. Exosome membrane factors and contents have been reported to alter adjacent and distant cell behavior in multiple studies, but the impact of cancer-derived exosomes on chemoresistance is less clear. We therefore analyzed exosomes from the human pancreatic cancer (PC) cell lines PANC-1, MIA PaCa-2 and BxPC-3 for their ability to transmit chemoresistance, finding that PANC-1 exosomes increased the gembicitabine (GEM) resistance of MIA PaCa-2 and BxPC-3 cell cultures. Comparative proteomics determined that PANC-1 exosomes overexpressed Ephrin type-A receptor 2 (EphA2) versus exosomes of less chemoresistant PC cell lines MIA PaCa-2 and BxPC-3. EphA2-knockdown in PANC-1 cells inhibited their ability to transmit exosome-mediated chemoresistance to MIA PaCa-2 and BxPC-3, while treatment of MIA PaCa-2 and BxPC-3 cells with soluble EphA2 did not promote chemoresistance, indicating that membrane carried EphA2 was important for the EphA2 chemoresistance effect. EphA2 levels on circulating exosomes were markedly increased in mice bearing PANC-1 tumors and PC patients who subsequently revealed poor responses to treatment. We thus concluded that exosomal EphA2 expression could transmit chemoresistance and may serve as a minimally-invasive predictive biomarker for PC treatment response. Further work should address whether additional exosomal factors regulate resistance to other cancer therapeutic agents for PC or other cancer types.
Citation Format: Jia Fan, Qian Wei, Eugene J. Koay, Yang Liu, Zhen Zhao, Ye Hu. Exosomal EphA2 transmits chemoresistance and predicts pancreatic cancer patient responses to therapy [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 585.
Abstract 5853: Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma
Authors: Pang Ying , Lu Yanxin , Caisova Veronika , Liu Yang , Bullova Petra , Huynh Thanh-Truc , Frysak Zdenek , Hartmann Igor , Taïeb David , Pacak Karel , Yang Chunzhang 
Published: August 2018

Abstract
Background: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.
Experimental design: We investigated molecular signatures in clinical specimens from cluster I and II PCPGs, with a focus on the therapeutic resistance mechanisms. Further, we tested the applicability of a combination therapy including an FDA approved PARP inhibitor olaparib (Ola) and temozolomide (TMZ) in both in vitro cellular model and an in vivo allograft animal model.
Results: Our findings showed that cluster I PCPGs develop a distinctive dependency on mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Mechanistically, alteration in mitochondrial function resulted in strengthened NAD+ metabolism, which provides essential cofactor for PARP catalytic activity, prompting base excision repair and chemo resistance. Combining PARP inhibitor Ola with TMZ not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival in a mouse model with PCPG allograft.
Conclusions: Our results suggest that the NAD+/PARP pathway is a crucial targetable therapeutic resistance mechanism in SDHB-mutated PCPG. Combination therapy using TMZ and Ola could become an effective strategy against these and other advanced cluster I tumors.
Disclosure Statement: The authors have nothing to disclose.
Citation Format: Ying Pang, Yanxin Lu, Veronika Caisova, Yang Liu, Petra Bullova, Thanh-Truc Huynh, Zdenek Frysak, Igor Hartmann, David Taïeb, Karel Pacak, Chunzhang Yang. Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma [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 5853.