tbuckley/cabot-search huggingface dataset:
Abstract 1125: Eukaryotic Elongation Factor 2 Kinase (eEF-2K) is a novel therapeutic target in BRCA1+ mutated breast cancer
Authors: Elif Asik, Nermin Kahraman, Tulin Guray, Murvet Volkan, Gabriel Lopez-Berestein, Bulent Ozpolat
Journal: Cancer Research (2017)

Abstract BReast CAncer 1 and 2 (BRCA1/2) tumor suppressor genes are frequently mutated in familial breast and ovarian cancers. Recent clinical trials in breast cancers with BRCA1/2 mutations indicate that 50-75% of patients may not have response to poly (ADP-ribose) polymerase inhibitors (PARP) inhibitors. Thus, identification of novel molecular targets and therapeutic interventions are needed to improve poor clical outcome and patient survival. Here we report that Eukaryotic Elongation Factor-2 Kinase (EF2K), an atypical kinase, is highly upregulated in BRCA1+ mutated cell lines and involved in colony formation, migration/ invasion and enhances the effect of PARP inhibitors. Furthermore, in vivo therapeutic targeting of EF2K by once a week systemic injections with magnetic nanoparticles (MNPs) incorporating EF2K siRNA significantly inhibits growth of BRCA1+ tumors in orthotopic xenograft models in mice by inhibition of tumor cell proliferation, angiogenesis and induction of robust apoptosis, which were associated with in vivo inhibition of clinically relevant molecular pathways including, proliferation, survival/drug resistance (PI3K/Akt, c-Myc), cell cycle (Cyclin D1), motility/invasion (Src/FAK/Paxillin), translation (4E-BP1), angiogenesis (VEGF) and stem-cell markers. No toxicity was detected during the study and by postmortem analysis of major organs, indicating that targeting EF2K is safe. The combination of PARP inhibitor (AZD2281, Oleparib) with MNP-EF2K siRNA enhanced significantly growth inhibition in MDA-MB-436 cells indicting EF2K siRNA sensitize BRCA1 + mutation breast cancer cells to PARP inhibitors. Collectively, our results suggest, for the first time, that EF2K is involved in tumorigenesis and progression and may serve as a potential therapeutic target in BRCA1+ mutated breast cancers. Citation Format: Elif Asik, Nermin Kahraman, Tulin Guray, Murvet Volkan, Gabriel Lopez-Berestein, Bulent Ozpolat. Eukaryotic Elongation Factor 2 Kinase (eEF-2K) is a novel therapeutic target in BRCA1+ mutated breast 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 1125. doi:10.1158/1538-7445.AM2017-1125
Abstract 3809: SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents
Authors: Zhewei Shen, Jean Davidson, Jonathan Pollack
Journal: Cancer Research (2017)

Abstract While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair. Thus, we hypothesized that pancreatic cancers with SWI/SNF aberrations might exhibit compromised DNA repair, and show increased sensitivity to DNA damaging agents. Here, we studied pancreatic cancer cell lines with deficient (or else exogenously reconstituted) SWI/SNF subunits, as well as normal pancreatic epithelial cells (HPDE) following SWI/SNF subunit knockdown. Cells were challenged with DNA damaging agents, including those used in current combination regimens, and then cell viability assayed. We found that pancreatic cells with SWI/SNF dysfunction showed markedly increased sensitivity to DNA damaging agents, and in particular DNA crosslinking agents (cisplatin and oxaliplatin). Assaying clearance of γH2AX foci confirmed that SWI/SNF dysfunction impaired DNA damage response/repair. Finally, by analyzing pancreatic cancer patient data (TCGA), we found that pancreatic cancers with SWI/SNF deficiency (subunit mutation and/or decreased expression) showed a strong trend towards extended survival with platinum containing chemo regimens. Thus, SWI/SNF dysfunction sensitizes pancreatic cancer cells to DNA crosslinking agents, and SWI/SNF mutation status may provide a useful biomarker to predict which patients are likely to benefit from platinum-containing chemotherapy regimens. Citation Format: Zhewei Shen, Jean Davidson, Jonathan Pollack. SWI/SNF aberrations sensitize pancreatic cancer cells to DNA crosslinking agents [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 3809. doi:10.1158/1538-7445.AM2017-3809
Phase III study of vinflunine plus gemcitabine versus paclitaxel plus gemcitabine in the first-line treatment of anthracycline pretreated advanced breast cancer.
Authors: Antonio Llombart, Marc Espie, Anantbhushan Ranade, Dmytro Trukhin, Roberto Hegg, Auro Del Giglio, Robert Paridaens, Elzbieta Staroslawska, Corinne Veyret, Dina Sakaeva, Henry Leonidas Gomez, Dasappa Lokanatha, Guillermo Luis Lerzo, Balaji Keshavrao Shewalkar, Denis Charles Talbot, Armando Santoro, Henri Hubert Roche
Journal: Journal of Clinical Oncology (2014)

1011 Background: Paclitaxel (PTX), plus gemcitabine (GEM) showed survival advantage over paclitaxel in advanced breast cancer (ABC) patients who relapsed after adjuvant anthracycline. This was associated with increased toxicity, especially neurotoxicity. Vinflunine (VFL) plus GEM was confronted to PTX- GEM in this clinical setting. Methods: This open-label phase 3 study enrolled 1004 Her-2 negative ABC patients who had received neo- or adjuvant anthracycline more than 12 months prior to study entry. Patients were randomised to VFL 320 mg/m² on day 1 plus GEM 1000 mg/m² on days 1 and 8 every 3 weeks (N = 503) or PTX 175 mg/m² on day 1 plus GEM 1250 mg/m² on days 1 and 8 every 3 weeks (N = 501). Randomisation was stratified by PS, (neo)adjuvant taxane, disease measurability and visceral lesions. The primary objective was to test the non-inferiority of VFL-GEM vs PTX-GEM in terms of PFS assessed by a blinded independent review committee in the intent-to-treat population assuming a median PFS of 5.2 months in the control arm and a 20% margin. Results: Patients had a median age of 54 years [range: 22-79]; visceral disease for 84.5% and 33.7% had received adjuvant taxane. The median number of cycles was 6 in both arms. Median PFS was 8 months for VFL plus GEM and 8.4 months for PTX plus GEM (HR 1.05, 95%CI: 0.91-1.20, P = 0.54). The upper limit of HR 95% CI being below 1.25, non-inferiority was demonstrated. Response rates were 11.3% for VFL plus GEM and 14.6% for PTX plus GEM (P = 0.10). Median OS were similar: 18.9 months for VFL plus GEM and 19.1 months for PTX plus GEM. Rate of toxic deaths was 1.6% for VFL plus GEM and 0.4% for PTX plus GEM. Grade 3 - 4 neutropenia was common in both arms (74.3% of patients for VFL plus GEM vs 60% for PTX plus GEM), but rarely complicated (< 5% of febrile neutropenia or neutropenic infection in both arms). Grade 3 - 4 constipation was more frequent for VFL plus GEM (7.3% vs 0.2%) and grade 3 - 4 peripheral sensory neuropathy for PTX plus GEM (6.7% vs 0.8%) as well as alopecia (63.5% vs 40.4%). Conclusions: VFL plus GEM can be seen as an alternative option to PTX plus GEM considering its similar efficacy and its reduced neurotoxicity.
Abstract 681: Methylomics profiling reveals epigenetically silenced HS3ST2 sensitize IL6 signaling and confers poor prognosis of ovarian cancer
Authors: Rui-Lan Huang, Hsiang-Ju Chan, Lin-Yu Chen, Yaw-Wen Hsu, Tai-Kuang Chao, Po-Hsuan Su, Yu-Chun Weng, Chiou-Chung Yuan, Hung-Cheng Lai
Journal: Cancer Research (2017)

Abstract The attempts of target therapy in ovarian cancer therapy mostly fail. There is a need of biomarkers for better patient stratification in clinical trials. Epigenetics is a driving force for cancer development and may serve as a molecular marker of disease. The present study was to analyze the clinical relevance of methylation phenotypes and figure out the mechanism in ovarian cancer. We integrated the analysis using public dataset of epigenomics and transcriptomics, and our hospital-based methylomic database and tissue arrays of patients diagnosed with epithelial ovarian cancers (EOC). Bioinformatics results were verified and validated in cell lines and clinical samples. From 25 genes, we identified even genes, ADRA1A, CD248, HS3ST2, NEFH, IGSF21, POU4F2, and TWIST1, of which hypermethylation was significantly related to the poor overall survival (OS). The association of NEFH and HS3ST2 hypermethylation and poor 5-year OS was validated in our independent dataset and TCGA database. The NEFH/HS3ST2 hypermethylated signature was an independent risk factor for 5-year OS (adjusted Hazard ratio = 2.93, 95% confidence interval = 1.25 to 6.85, P = 0.013). In vitro experiment re-expressing HS3ST2 repressed migration and invasion, and suppressed IL-6 signaling pathways. The combination of hypermethylation of HS3ST2 and high expression of IL-6 confers the worse outcome. Our data suggested that methylation of NEFH/HS3ST2 constituted a poor prognostic signature of ovarian cancer. The sulfation status of proteoglycan modified by HS3ST2 implicates an intrinsic sensitivity of ovarian cancer cells to IL-6, which shed a new light on the application of HS3ST2 as a biomarker for personalized medicine of targeting IL-6. Note: This abstract was not presented at the meeting. Citation Format: Rui-Lan Huang, Hsiang-Ju Chan, Lin-Yu Chen, Yaw-Wen Hsu, Tai-Kuang Chao, Po-Hsuan Su, Yu-Chun Weng, Chiou-Chung Yuan, Hung-Cheng Lai. Methylomics profiling reveals epigenetically silenced HS3ST2 sensitize IL6 signaling and confers poor prognosis of ovarian 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 681. doi:10.1158/1538-7445.AM2017-681
Abstract 1083: Synergistic drug combination prediction through drug differential dependency network analysis
Authors: Seungchan Kim, Gil Speyer, Harshil Dhruv, Jeff Kiefer, Michael Berens
Journal: Cancer Research (2017)

Abstract In an effort to discover strategies which identify effective drug combinations, we analyzed 39 of the 480 compounds screened in the Cancer Therapeutics Response Portal (CTRP) where combinations of two compounds were tested against 860 cancer cell lines; this enabled a comparison of the drug sensitivity of the combinations versus that of the individual compounds. More than half of the drug combinations (n=21) did not significantly improve the drug sensitivity, compared to individual compounds alone. In fact, some of the combinations showed reduced drug sensitivity. In EDDY-CTRP* analysis, the Cancer Cell Line Encyclopedia (CCLE) RNAseq data and CTRP compound response measurements were analyzed to discover both 1) pathways enriched with differential dependencies between sensitive and non-sensitive cell lines for each compound and 2) the mediators of cell line response to a drug. A mediator is a gene in a pathway that plays a significantly different role between sensitive and non-sensitive conditions. The significance is assessed for either essentiality, measured as a node’s centrality change, or specificity, measured as the difference in condition specific edges. These drug-pathway-mediator connections are predicted to reveal crucial molecular determinants of drug sensitivity that otherwise are hidden in the complexities of the molecular networks of the cell (Speyer et al., PSB 22:497-508, 2017). We further investigated whether mediators identified for single compounds could predict sensitivity to drug combinations. This analysis revealed that if two single compounds share the same specificity mediators, i.e. the genes with the most significant re-wiring of gene dependencies between sensitive and non-sensitive cell lines, combination of these two compounds correlate with improved sensitivity. The converse was also found: compounds that do not share mediators rarely show synergy. Further analysis and empirical testing of predicted combinations promises to prioritize synergistic drug combinations. We believe that this methodology may predict synergistic drug combinations from cancer cell line drug screening data. Supported by NIH U01CA168397. *available at http://biocomputing.tgen.org/software/EDDY/CTRP Citation Format: Seungchan Kim, Gil Speyer, Harshil Dhruv, Jeff Kiefer, Michael Berens. Synergistic drug combination prediction through drug differential dependency network analysis [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 1083. doi:10.1158/1538-7445.AM2017-1083
Abstract 1812: <i>In vitro</i> and <i>in vivo</i> antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways
Authors: Minfeng Chen, Xueping Lei, Qiulin Nie, Jianyang Hu, Zhenjian Zhuo, Anita Yiu, Heru Chen, Nanhui Xu, Maohua Huang, Kaihe Ye, Liangliang Bai, Wencai Ye, Dong-Mei Zhang
Journal: Cancer Research (2017)

Abstract Background and Objective: Tumor angiogenesis process is regulated by multiple proangiogenic pathways, such as VEGFR2 and Axl. Inhibition of VEGF/VEGFR2 signaling alone fails to block tumor neovascularization, and anti-VEGF resistance is often associated with Axl. Hence, discovery of novel agents that target multiple angiogenesis pathways is in demand. Here, we describe desacetylvinblastine monohydrazide (DAVLBH), a derivative of vinblastine (VLB) that exerts a more potent antiangiogenic effect than VLB in vitro and in vivo by inhibiting VEGFR2 and Axl pathways. Methods: The antiangiogenic effects of DAVLBH were studied in vitro (proliferation, migration, and tube formation assays) and ex vivo (aortic ring assay). In vitro pericyte migration to endothelial tubes was assessed using a three-dimensional co-culture assay. In vivo assay was performed in HeLa xenograft model. Western blotting, immunohistochemical and immunofluorescence assays were conducted to evaluate the key proteins of the VEGF/VEGFR2 and Gas6/Axl pathways. Results: DAVLBH (1 nM) inhibited VEGF- and Gas6-induced angiogenesis in vitro. At 0.75 μmol/kg, DAVLBH significantly delayed tumor growth and reduced vascular density in vivo, which was associated with the inactivation of VEGF/VEGFR2 and Gas6/Axl signalling pathways. DAVLBH blocked the compensatory upregulation of Axl in response to bevacizumab treatment in HUVECs. DAVLBH also suppressed the recruitment of pericytes to well-established endothelial tubes and reduced pericyte coverage in vivo, which was accompanied by inhibition of Axl. Conclusions: DAVLBH potently inhibited angiogenesis-mediated tumor growth by blocking the activation of VEGF/VEGFR2 and Gas6/Axl pathways. DAVLBH might serve as a promising antiangiogenic agent for cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Minfeng Chen, Xueping Lei, Qiulin Nie, Jianyang Hu, Zhenjian Zhuo, Anita Yiu, Heru Chen, Nanhui Xu, Maohua Huang, Kaihe Ye, Liangliang Bai, Wencai Ye, Dong-Mei Zhang. In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways [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 1812. doi:10.1158/1538-7445.AM2017-1812
Abstract 3697: The impact of HER3 signaling mediated PD-L1 regulation in triple negative breast cancer
Authors: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Masakazu Toi
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) is still difficult to treat partly because of lacking specific target. Although 50-70% of TNBC expresses EGFR, it is less sensitive to the treatment of EGFR inhibition for TNBC as compared to the efficacy of HER2 inhibition for HER2-positive breast cancer. Several phase II study on EGFR blockade treatment has been reported, however it has not applied in a clinical setting yet. It was reported that residual tumors after treatment with EGFR-targeted antibodies showed increased HER3 abundance leading to EGFR/HER3 receptor dimerization. The signals of HER3/EGFR dimerization to PI3K/AKT/mTOR pathways are thought to be involved in cancer survival, proliferation and also up-regulation of PD-L1 expression. Thus, we hypothesized that up-regulation of HER3 signal caused by anti-cancer treatment might induce PD-L1 expression and inhibit host anti-tumor immunity. In this study, we tested the relationships between HER3 signal and PD-L1 expression by using three basal-like breast cancer cell line; MDA-MB-231, HCC70, and MDA-MB-468. MDA-MB-231 is HER3-negative, and HCC70 and MDA-MB-468 are HER3-positive cell lines. We added neureglin 1 (NRG1: HER3 ligand) to those three cell lines and analyzed PD-L1 expression of protein by flowcytometry and mRNA by qRT-PCR. Both protein and mRNA level of PD-L1 on HCC70 and MDA-MB-468 treated with NRG1 are increased as compared with those without NRG1 while there was no change of PD-L1 expression of MDA-MB-231 either with or without NRG1. In order to confirm the significance of potential treatment target of HER3, we evaluated HER3 expression in biopsy samples by immunohistochemistry before neoadjuvant chemotherapy (NAC) including all phenotypes. Thirteen pathological complete response (pCR) cases after NAC and 6 non pCR cases were included. We scored the HER3 stainability from 0 to 3 and found that non pCR cases showed significantly higher HER3 score than pCR cases (84.6% and 33% respectively, p=0.0149). Although further study is needed, these results suggest that HER3 signal possibly regulates PD-L1 expression in HER3-positive basal-like breast cancer and treatment with anti-HER3 targeting therapy combination with an immune checkpoint inhibition therapy for HER3 positive NAC resistant patients might be warranted. Note: This abstract was not presented at the meeting. Citation Format: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Takeshi Kotake, Masakazu Toi. The impact of HER3 signaling mediated PD-L1 regulation in triple negative breast 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 3697. doi:10.1158/1538-7445.AM2017-3697
Abstract 2163: Combined targeting of MEK and MCL-1 induces apoptosis and tumor regression of KRAS mutant NSCLC
Authors: Aaron N. Hata, Faria M. Siddiqui, Maria Gomez-Caraballo, Samantha J. Bilton, Daria Timonina, Varuna Nangia, Angela Coxon, Sean Caenepeel, Paul Hughes
Journal: Cancer Research (2017)

Abstract There are currently no effective targeted therapeutic strategies for KRAS mutant non-small cell lung cancer (NSCLC). Single agent MEK inhibitors have demonstrated showed disappointing clinical activity, partly due to inability to induce a robust apoptotic response. Combining MEK inhibitors with BCL-XL/BCL-2 inhibitors may be effective for a subset of KRAS mutant cancers that are dependent on BCL-XL for survival, however this combination is unlikely to be an effective strategy for cancers dependent on MCL-1. We investigated the effect of combining the MEK inhibitor trametinib with a novel MCL-1 inhibitor (compound A), which possesses potent and selective anti-MCL-1 activity in vitro and in vivo, on KRAS mutant cancers. In contrast to colorectal cancer models, which are largely sensitive to combined MEK + BCL-XL inhibition, a subset of cell line and patient-derived mouse xenograft (PDX) KRAS mutant NSCLC models were significantly more sensitive to MEK + MCL-1 inhibition compared to MEK + BCL-XL. To model potential clinical strategies, we tested intermittent dosing regimens and unexpectedly discovered a method strategy for dramatically sensitizing KRAS mutant NSCLC cells to the MEK + MCL-1 combination. These studies provide rationale for the clinical evaluation of combined MEK + MCL-1 inhibitors for KRAS mutant NSCLC. Citation Format: Aaron N. Hata, Faria M. Siddiqui, Maria Gomez-Caraballo, Samantha J. Bilton, Daria Timonina, Varuna Nangia, Angela Coxon, Sean Caenepeel, Paul Hughes. Combined targeting of MEK and MCL-1 induces apoptosis and tumor regression of KRAS mutant NSCLC [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 2163. doi:10.1158/1538-7445.AM2017-2163
Abstract 1435: Immune/inflammatory polymorphisms predict lung cancer survival
Authors: Donovan Watza, Chrissy Lusk, Angie Wenzlaff, Christine Neslund-Dudas, Gregory Dyson, Ayman Soubani, Shirish Gadgeel, Ann G. Schwartz
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer related mortality in the United States, with a median five year survival of ~16%. Recent advancements in the treatment of lung cancer focus on modulating the immune system to improve patient outcomes with markedly reduced toxicity profiles. This study aims to investigate single nucleotide polymorphisms (SNPs) within functional units of the immune system genome to identify genetic markers indicative of overall survival in a cohort of metropolitan Detroit lung cancer patients. This cohort presents a unique population of lung cancer patients for analysis, consisting of 40% African Americans, whom are known to have worse outcomes than their Caucasian counterparts. To assess SNPs within functional units of the immune genome, a hierarchical immune system gene and pathway list was constructed, incorporating genes and pathway identifiers from the Reactome database as well as previous genetic and inflammatory specific cancer studies to generate a well curated gene and pathway dataset. Genomic locations for the genes, together with proximal regulatory regions, were obtained from the UCSC genome browser for cross-referencing with the Illumina MEGA SNP array to generate SNPs for inclusion. Preliminary analysis of 848 NSCLC patients in association with 29,126 immune specific SNPs identified six SNPs as significantly associated with survival (p-value &amp;lt;10-4) in this lung cancer cohort, implicating the following six genes, PXN, GFRA3, HLA-DQA1, KSR2, BTBD1, and ATF2; although further gene/pathway analysis is necessary to elucidate how these associations interact in the context of genes and pathways of the immune system. PXN over expression has been previously implicated in both high risk lung epithelial dysplasia as well as in the development of lung adenocarcinoma in prior clinical studies. Additionally, GFRA3 has been identified as an activator of the RET kinase and increased GFRA3 activity in context of the Artemin pathway is a known promoter of NSCLC progression. As well, select polymorphisms in the HLA-DQA1 gene are known clinical modifiers of lung squamous cell carcinoma risk. Finally, ATF2 is a broadly active transcription factor and ATF2 upregulation has been associated with tumorigenesis and metastasis in both cell models and patient tumor samples in multiple cancer studies. The previous association of these genes in lung cancer is promising and further immune system gene/pathway analysis is warranted. Citation Format: Donovan Watza, Chrissy Lusk, Angie Wenzlaff, Christine Neslund-Dudas, Gregory Dyson, Ayman Soubani, Shirish Gadgeel, Ann G. Schwartz. Immune/inflammatory polymorphisms predict lung cancer survival [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 1435. doi:10.1158/1538-7445.AM2017-1435