tbuckley/cabot-search huggingface dataset:
Abstract 924: Upregulation of the MET transcript is consistently associated with invasion and tumor budding in colorectal cancer
Authors: Conor Bradley, Philip Dunne, Stephen McQuaid, Victoria Bingham, Mark Lawler, Manuel Salto-Tellez, Patrick Johnston, Sandra Van Schaeybroeck
Journal: Cancer Research (2016)

Abstract Background: The c-MET proto-oncogene is frequently overexpressed (50-60%), amplified (1-3%), and mutated (1-3%) in colorectal cancer (CRC). Hepatocyte growth factor (HGF)-dependent and independent activation of c-MET has been associated with increased survival and resistance to targeted therapies. This study aimed to investigate the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Methods: In order to model CRC tumour cell invasion, we have generated invasive CRC subpopulations using Boyden Invasion chambers. To model the CRC microenvironment, we have used a range of co-culture techniques with CRC cells and colon fibroblasts. Migration/invasion was determined using xCELLigence System (Roche). c-MET expression in parental and invasive cell lines was measured using Western blotting and qRT-PCR. c-MET expression in CRC FFPE tissues was measured using IHC and RNAScope®. Results: We identified marked upregulated expression of c-MET at both the protein and transcript levels in our invasive CRC cell line models. Importantly, both parental and invasive subpopulations were found to be inherently dependent on c-MET for migration, as RNAi against c-MET abrogated migration/invasion in both parental and invasive models. We also demonstrated that stimulation of CRC cells with rh-HGF resulted in increased CRC cell migration/invasion. In addition, co-culture of CRC cells with colonic myofibroblasts, resulted in marked increases in migratory and invasive capacity, and this was dependent on HGF/c-MET signaling. Interestingly, stimulation with myofibroblast conditioned medium or HGF promotes rapid degradation of c-MET at the protein level, followed by recycling, while MET transcript remains unaltered, illustrating a dynamic expression of c-MET protein in response to activation. We further showed that MET is transcriptionally upregulated in tumour budding foci at the invasive front of a cohort of stage III CRC tumors. Intriguingly, c-MET protein levels do not correlate with the transcript, most likely due to a similar protein degradation process observed in our aforementioned in vitro models. Conclusions: We show for the first time a key role for transcriptional upregulation of MET as a molecular driver of tumour invasion, both in vitro and in stage III CRC tumours. Citation Format: Conor Bradley, Philip Dunne, Stephen McQuaid, Victoria Bingham, Mark Lawler, Manuel Salto-Tellez, Patrick Johnston, Sandra Van Schaeybroeck. Upregulation of the MET transcript is consistently associated with invasion and tumor budding in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 924.
Abstract 1426: Racial variation in annexin A2(AnxA2) gene expression and poor outcome in triple-negative breast cancer
Authors: Lee D. Gibbs, Jamboor K. Vishwanatha
Journal: Cancer Research (2016)

Abstract Background: Triple-negative breast cancer (TNBC) is identified by the absence of three major receptors that drive most breast cancers. The incidence of TNBC is also associated with health disparity due to its disproportionate occurrence in African American (AA) women. Our previous studies and others have shown that AnxA2 is overexpressed in TNBC, but its association with racial variation and outcomes is unknown. Methods: AnxA2 gene expression was evaluated in breast cancer subtypes from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) mRNA database that include 1,094 patients. Associations between clinical outcomes and AnxA2 gene expression were tested in a genome wide association study of combined publicly available datasets that include 4,147 patients. Results: AnxA2 gene expression was significantly increased in TNBC in comparison to other breast cancer subtypes. Furthermore, AnxA2 gene expression was significantly elevated in AA women in comparison with Caucasian (CA) women and was associated with the disproportionate occurrence of TNBC in AA women. High expression levels of AnxA2 was associated with reduced overall survival (hazard of death = 2.66; 95% confidence interval {CI] = 1.14 - 6.25, P = 0.0192), reduced relapse free survival (hazard of relapse = 1.45; 95% confidence interval {CI] = 1.12 – 1.89, P = 0.0051), and reduced distant metastasis free survival (hazard of metastasis = 1.7; 95% confidence interval {CI] = 1.00 – 2.91, P = 0.048). AnxA2 gene expression was not associated with poor outcome in other intrinsic breast cancer subtypes, such as Luminal A, Luminal B, and Her-2, indicating the specific association of AnxA2 with the aggressive behavior of TNBC. Conclusion: AnxA2 overexpression is associated with racial variation and is a potential prognostic candidate for TNBC. Impact: AnxA2 has potential prognostic value, implicating a role for AnxA2 in the aggressive biology of TNBC in AA women. Citation Format: Lee D. Gibbs, Jamboor K. Vishwanatha. Racial variation in annexin A2(AnxA2) gene expression and poor outcome in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1426.
Abstract 2284: Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR
Authors: Sakiko Otani, Jiichiro Sasaki, Kuniko Masuda, Kazuya Okamoto, Akiko Namubu, Toshihide Matsumoto, Masumi Tanaka, Mikiko Ishihara, Yoshiro Nakahara, Tomoya Fukui, Satoshi Igawa, Noriyuki Masuda
Journal: Cancer Research (2016)

Abstract Background: Standard second-line chemotherapy against advanced non-small-cell lung cancer (NSCLC) is a single agent such as docetaxel, pemetrexed, or erlotinib (Erl). We recently reported that the combination of amrubicin (AMR) and Erl was clinically safe and effective for previously treated NSCLC patients. The purpose of this research is to confirm the experimental effectiveness of the combination and to investigate mechanism of the action. Methods: We perform to evaluate the NSCLC cell lines proliferation inhibition by using XTT assay and to make two-dimension isobolograms for assessment of the combination effect. Flowcytemetry analysis (FACS) and Western blot analysis (WB) is also done in vitro. In vivo growth inhibition assay using subcutaneous model on SCID mice is performed. In addition, we measure intracellular concentration of amrubicinol(AMR-OH) which is converted as active metabolite from AMR in both cells treated with AMR alone and the combination. Results: The combination of AMR and Erl had significant synergistic effect on EGFR wild type NSCLC cell line A549, while additive effect on EGFR mutant cell line PC-9. Sub G0-G1 population on FACS was significantly increased in A549 cells treated with combination. The combination activated apoptosis related proteins in WB. The strong growth inhibition of subcutaneous tumors on SCID mice was observed in the combination cohort. Intracellular concentration of AMR-OH was significantly increased in the combination than in AMR monotherapy. Conclusion: The combination of AMR and Erl is synergistically induced apoptosis and growth inhibition on A549 cells via increasing intracellular concentration of AMR-OH. This combination may be a promising therapeutic option against advanced NSCLC with wild type EGFR. Citation Format: Sakiko Otani, Jiichiro Sasaki, Kuniko Masuda, Kazuya Okamoto, Akiko Namubu, Toshihide Matsumoto, Masumi Tanaka, Mikiko Ishihara, Yoshiro Nakahara, Tomoya Fukui, Satoshi Igawa, Noriyuki Masuda. Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2284.
Regulation Of Normal and Malignant Hoxa Gene Expression Through Higher H3K79 Methylated States
Authors: Aniruddha J Deshpande, Liying Chen, Amit U. Sinha, Nan Zhu, David Chen, Jenny Chang, Andrei V. Krivtsov, Kathrin Bernt, James E Bradner, Scott A. Armstrong
Journal: Blood (2013)
Multi-institutional Analysis Shows that Low PCAT-14 Expression Associates with Poor Outcomes in Prostate Cancer
Authors: Nicole M. White, Shuang G. Zhao, Jin Zhang, Emily B. Rozycki, Ha X. Dang, Sandra D. McFadden, Abdallah M. Eteleeb, Mohammed Alshalalfa, Ismael A. Vergara, Nicholas Erho, Jeffrey M. Arbeit, Robert Jeffrey Karnes, Robert B. Den, Elai Davicioni, Christopher A. Maher
Journal: European Urology (2016)

Long noncoding RNAs (lncRNAs) are an emerging class of relatively underexplored oncogenic molecules with biological and clinical significance. Current inadequacies for stratifying patients with aggressive disease presents a strong rationale to systematically identify lncRNAs as clinical predictors in localized prostate cancer.To identify RNA biomarkers associated with aggressive prostate cancer.Radical prostatectomy microarray and clinical data was obtained from 910 patients in three published institutional cohorts: Mayo Clinic I (N=545, median follow-up 13.8 yr), Mayo Clinic II (N=235, median follow-up 6.7 yr), and Thomas Jefferson University (N=130, median follow-up 9.6 yr).The primary clinical endpoint was distant metastasis-free survival. Secondary endpoints include prostate cancer-specific survival and overall survival. Univariate and multivariate Cox regression were used to evaluate the association of lncRNA expression and these endpoints.An integrative analysis revealed Prostate Cancer Associated Transcript-14 (PCAT-14) as the most prevalent lncRNA that is aberrantly expressed in prostate cancer patients. Down-regulation of PCAT-14 expression significantly associated with Gleason score and a greater probability of metastatic progression, overall survival, and prostate cancer-specific mortality across multiple independent datasets and ethnicities. Low PCAT-14 expression was implicated with genes involved in biological processes promoting aggressive disease. In-vitro analysis confirmed that low PCAT-14 expression increased migration while overexpressing PCAT-14 reduced cellular growth, migration, and invasion.We discovered that androgen-regulated PCAT-14 is overexpressed in prostate cancer, suppresses invasive phenotypes, and lower expression is significantly prognostic for multiple clinical endpoints supporting its significance for predicting metastatic disease that could be used to improve patient management.We discovered that aberrant prostate cancer associated transcript-14 expression during prostate cancer progression is prevalent across cancer patients. Prostate cancer associated transcript-14 is also prognostic for metastatic disease and survival highlighting its importance for stratifying patients that could benefit from treatment intensification.
Abstract CT306: Radiolabeled anti-PSMA antibody J591 immunotherapy is associated with favorable circulating tumor cell (CTC) count control in men with castration-resistant prostate cancer
Authors: Pravin Date, Beerinder S. Karir, Jaspreet S. Batra, Yuliya Jhanwar, Himisha Beltran, David M. Nanus, Neil H. Bander, Scott T. Tagawa
Journal: Cancer Research (2015)

Abstract Background: J591 is a monoclonal antibody that selectively binds to prostate-specific membrane antigen (PSMA). Prospective phase I and II trials with therapeutic radiolabeled 177Lu-J591 have shown favorable PSA decline rates. Additionally, our group has previously reported that non-invasive evaluation of PSMA expression by imaging with planar gamma camera imaging is associated with response and survival. Initial anecdotal experience showed declines in CTC counts which led to prospective study. Methods: Three clinical trials of 177Lu-J591 in men with metastatic CRPC have included prospective evaluation of CTC counts (CellSearch methodology) prior to and following therapy (single-dose 177Lu-J591, fractionated-dose 177Lu-J591, and fractionated-dose 177Lu-J591 + docetaxel). Based upon prior experience of J591-based therapy without an effector molecule as immunotherapy, and an anecdotal report of CTC count decline following a low (imaging) dose of J591 without an effector molecule, a cohort of patients who received J591 without 177Lu labeling was also retrospectively analyzed. Results: 44 pts unselected for PSMA expression received 177Lu-J591 therapy had prospectively measured CTC counts. 39 of 44 pts (88.6%) had imaging evidence of PSMA expression. 57% of pts had baseline unfavorable (≥ 5 cells/7.5 mL) CTC counts. Of overall evaluable pts, 72.4% had decline in CTC counts (7.5 to 100% decline), with 50% of those with unfavorable baseline counts converting to favorable counts at 4-6 weeks. 17.1% with undetectable CTC counts remained undetectable at follow up. 7 pts with mCRPC and elevated CTC counts who received low-dose (naked J591) prior to imaging were also identified, and 4 (57%) of these pts demonstrated CTC count decline. Conclusion: In addition to previously reported PSA declines, treatment with 177Lu-J591 is associated with favorable CTC count decline in men with metastatic CRPC. Infusion with unlabeled J591 may also lead to CTC count clearance. Based on this finding, we are planning a prospective clinical trial with unlabeled (naked) J591 in men with metastatic CRPC and unfavorable CTC counts. Citation Format: Pravin Date, Beerinder S. Karir, Jaspreet S. Batra, Yuliya Jhanwar, Himisha Beltran, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Radiolabeled anti-PSMA antibody J591 immunotherapy is associated with favorable circulating tumor cell (CTC) count control in men with castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT306. doi:10.1158/1538-7445.AM2015-CT306
Abstract 4470: ST3GAL1-associated transcriptomic program portends poor prognosis in glioblastoma
Authors: Yuk Kien Chong, Edwin Sandanaraj, Lynnette Koh, Moogaambikai Thangaveloo, Melanie SY Tan, Geraldene Koh, Tan Boon Toh, Grace GY Lim, Joanna Holbrook, Oi Lian Kon, Mahendran Nadarajah, Ivan Ng, Wai Hoe Ng, Nguan Soon Tan, Kah Leong Lim, Carol S. Tang, Beng Ti Ang
Journal: Cancer Research (2016)

Abstract Cell surface sialylation has been associated with tumor cell invasiveness in several cancers. Patients with grade IV glioblastoma multiforme (GBM) often show a median survival period of fifteen months, even with the current standard-of-care treatment. Among the reasons for this poor prognosis lies in the cellular and molecular heterogeneity of tumor cells. The Cancer Genome Atlas efforts have shown that histologically identical GBM tumors can be divided into four molecular subtypes based on gene expression, with each subtype corresponding to unique genomic aberrations and clinical outcome. These findings highlight the limitation of relying solely on morphological approaches to diagnose and subsequently treat patients. We conducted a lectin screen with the goal of identifying candidates that stained normal and tumor cells differentially. We identified a sialyltransferase, ST3Gal1 as a mediator of the binding pattern of one such lectin, Peanut Agglutinin. We demonstrate that ST3Gal1 promotes tumor cell invasiveness and enriches for self-renewal potential in the mesenchymal tumor subclass of patients, typified by highly aggressive and recurrent profiles. Depletion of ST3Gal1 extends tumor latency and prolongs survival in mice. Importantly, an enrichment of the ST3GAL1 transcriptomic program portends poor prognosis in glioma patients. Moving forward, since there are no mutations or changes in copy number of ST3GAL1, we explored epigenetic regulation as a possible mechanism. By tapping into data from the NIH Roadmap Epigenome, and transcriptomic analysis of our patient tumor-derived cells, we identified a histone clustering signature that correlates with survival outcome and disease progression. We are currently investigating one such histone modifier, lysine (K)-specific demethylase 1A (LSD1) and its role at modifying ST3GAL1 transcription and activity. Citation Format: Yuk Kien Chong, Edwin Sandanaraj, Lynnette Koh, Moogaambikai Thangaveloo, Melanie SY Tan, Geraldene Koh, Tan Boon Toh, Grace GY Lim, Joanna Holbrook, Oi Lian Kon, Mahendran Nadarajah, Ivan Ng, Wai Hoe Ng, Nguan Soon Tan, Kah Leong Lim, Carol S. Tang, Beng Ti Ang. ST3GAL1-associated transcriptomic program portends poor prognosis in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4470.
Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease
Authors: Debby Ngo, Sumita Sinha, Dongxiao Shen, Eric W. Kuhn, Michelle J. Keyes, Xu Shi, Mark D. Benson, John F. O’Sullivan, Hasmik Keshishian, Laurie A. Farrell, Michael A. Fifer, Ramachandran S. Vasan, Marc S. Sabatine, Martin G. Larson, Steven A. Carr, Thomas J. Wang, Robert E. Gerszten
Journal: Circulation (2016)

Single-stranded DNA aptamers are oligonucleotides of ≈50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts.To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait.We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P<2.30E-4); >85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P<0.05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (β=0.3386, P=2.54E-22) and trigger factor 2 (β=0.2846, P=5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity.Our results highlight an emerging proteomics tool capable of profiling >1000 low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well.
Abstract 1160: FRY Inhibits progression and metastasis of breast cancer through activating Hippo signaling pathway
Authors: Hao Zhang, Fan Fei, Xushen Chen, Zi Ceng, Xiaojiang Tang, Helmut Zarbl, Xuefeng Ren
Journal: Cancer Research (2016)

Abstract Background: Recently, we reported that using quantitative trait locus (QTL) mapping in differentially susceptible rat strains, we identified Fry, the mammalian ortholog of the furry gene in Drosophila melanoganster, as a candidate mammary carcinoma susceptibility gene (Mcs30). Preliminary studies of rat Fry gene suggest that Fry may play a key role in epithelial-mesenchymal transition (EMT), tumor progression and metastasis. Methods: In the present study, we modified and established multiple breast cancer cell lines with enhanced expression of either wildtype or mutated human FRY gene. We examined the anti-tumorigenic and anti-metastatic effects of enhanced FRY expression on these cell lines in vitro and in vivo. We also utilized RNA-seq and proteomic approach to dissect FRY-regulated signaling molecules and pathways. Results: Ectopic expression of wild-type FRY significantly diminished tumorigenicity and metastasis of breast cancer cells both in vitro and in animal studies, particularly in the triple negative breast cancer cell line, MDA-MB-231 cells. Relative to the rapidly tumors growth of MDA-MB-231 cells in vitro and in nude mice assay, the growth of MDA-MB-231 cells ectopically expressing the FRY significantly reduced. In comparison, the anti-tumorigenic effects of mutated FRY were compromised but remained significant. Further, we showed that FRY's effects in suppressing proliferation, invasion, and metastasis of breast cancer cells were partially through the activation of Hippo signaling pathway. Conclusions: These results provide direct evidence in supporting the important role of FRY in breast cancer progression and metastasis, and first time reveal a connection between FRY and the Hippo signaling pathway. Citation Format: Hao Zhang, Fan Fei, Xushen Chen, Zi Ceng, Xiaojiang Tang, Helmut Zarbl, Xuefeng Ren. FRY Inhibits progression and metastasis of breast cancer through activating Hippo signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1160.