tbuckley/cabot-search huggingface dataset:
Abstract 3365: Epigenetic inactivation of PTPRT and sensitivity to STAT3 inhibition in lung cancer
Authors: Malabika Sen, Audrey Kindsfather, James G. Herman
Journal: Cancer Research (2017)

Abstract Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor is persistently activated in several malignancies including lung cancer. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 transcriptional activity, and is methylated in many types of human cancer. Loss-of-function of PTPRT by promoter methylation contributes to STAT3 mediated growth and survival and represent one of the plausible mechanism of STAT3 hyperactivation. We report identification of hypermethylation in CpG islands of the PTPRT promoter which correlates with its transcriptional silencing as well as expression of pSTAT3 protein and STAT3 target genes in both lung cancer cell lines and primary human tumors. Analyses of the TCGA (The Cancer Genome Atlas) data revealed that PTPRT promoter is frequently hypermethylated in a subset of lung squamous cell carcinoma and approximately 25% of adenocarcinoma tumors in association with downregulation of PTPRT mRNA expression. This observation was verified in vitro using lung cancer cell lines. Out of the 7 lung cancer cell lines examined, one lung cancer cell line showed lack of methylation (only unmethylated sequences) of the PTPRT promoter region and revealed mRNA expression (H520). All 6 cell lines which showed PTPRT promoter methylation had nearly absent PTPRT mRNA and had high levels of pSTAT3Tyr705, while H520 had little or no pSTAT3Tyr705 protein expression. Silencing of PTPRT using siRNA in H520, where PTPRT was not endogenously silenced by promoter hypermethylation, resulted in the upregulation of the STAT3 target genes such as cyclin D1 and Bcl-XL mRNA and protein expression as well as increased pSTAT3Tyr705 level. Analyses of the methylation status in the PTPRT promoter region in primary lung tumor samples revealed methylation in one of the 3 tumor samples. This correlated with increased STAT3 target genes (cyclin D1 and Bcl-XL) mRNA expression. In lung cancer cell lines, PTPRT promoter methylation is associated with sensitivity to STAT3 inhibition. Our data suggests that silencing of PTPRT by promoter hypermethylation is a frequent mechanism of STAT3 hyperactivation, and targeting STAT3 may be an effective molecular targeted approach in the treatment of this subset of lung cancer. Citation Format: Malabika Sen, Audrey Kindsfather, James G. Herman. Epigenetic inactivation of PTPRT and sensitivity to STAT3 inhibition in lung 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 3365. doi:10.1158/1538-7445.AM2017-3365
Abstract 1660: Humanization of patient derived xenograft (PDX) cancer model mice with peripheral blood mononuclear cells (PBMCs)
Authors: Jens Henrik Norum, Dag Josefsen, Gunnar Kvalheim, Olav Engebråten, Therese Sørlie, Gunhild M. Mælandsmo
Journal: Cancer Research (2017)

Abstract Immunocompetent transgenic mouse models have for decades served as valuable tools to address the effect of oncogenes and tumor suppressors. Immunodeficient mice have been used to establish patient derived xenograft (PDX) models harboring human tumors. These types of models have been used to study cancer initiation and progression as well as preclinical evaluation of anticancer drugs. One major limiting factor for both these model systems is the immune system; the PDX models lack an immune system and the immune system in immunocompetent mouse models display differences compared to the human immune system. Thus, in cancer research there is a need for preclinical models to study the influence of human immune cells on tumor progression and response to cancer therapies. We have established and optimized protocols for intravenous (IV) or intraperitoneal (IP) injections of isolated human PBMCs, to generate humanized mice harboring human immune cells. Our protocols do not require irradiation or busulfan pretreatment of the animals. Flow cytometry analyses showed that mainly T helper cells, CD4+, and cytotoxic T cells, CD8+, were present in the humanized mice. Immunohistochemistry (IHC) analyses of humanized PDX cancer model mice showed that human lymphocytes were present in the tumor periphery and some very few cells within the tumor, in addition to the human leukocytes in the liver and spleen. The growth rates of the PDX tumors were not affected by the humanization. Our protocols require minimal preparations of the animals and generate humanized PDX mice harboring human lymphocytes locating in close proximity of, as well as inside the PDX tumors. The model systems are suitable for preclinical studies of human, adaptive immune responses in tumor progression and cancer therapies. Citation Format: Jens Henrik Norum, Dag Josefsen, Gunnar Kvalheim, Olav Engebråten, Therese Sørlie, Gunhild M. Mælandsmo. Humanization of patient derived xenograft (PDX) cancer model mice with peripheral blood mononuclear cells (PBMCs) [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 1660. doi:10.1158/1538-7445.AM2017-1660
Abstract 1104: Novel specific RTK targeting of EGFR/FAK axis in glioblastoma invasion
Authors: Raghupathy Vengoji, Satyanarayana Rachagani, Suprit Gupta, Kavita Mallya, Maneesh Jain, Moorthy Ponnusamy, Surinder Batra, Nicole Shonka
Journal: Cancer Research (2017)

Abstract Background: Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival rate of 14.6 months. Currently, the first-line treatment includes surgical resection, chemoradiation, and adjuvant chemotherapy with temozolomide. However, GBM recurs most often within 6.9 months. Receptor tyrosine kinases are dysregulated in GBM, with epidermal growth factor receptor (EGFR) representing 57.4% of the deleted/mutated GBM. In addition, 30 - 40% of GBM patients with EGFR amplification carry an oncogenic gene rearrangement EGFR variant III (EGFRvIII) which is constitutively active. Yet most EGFR inhibitors have shown very little clinical efficacy in GBM. Methods: Afatinib, blood-brain barrier penetrant pan-EGFR inhibitor, covalently binds and irreversibly inhibits signaling from EGFR. Afatinib also persistently inhibits ErbB homo and hetero-dimers. Using GBM cell lines U87MG and U87MG transfected with wild type EGFR, EGFRvIII and EGFRvIII with dead kinase domain, we evaluated the efficacy of afatinib alone and in combination with temozolomide. Results: Afatinib treatment resulted in a dose dependent decrease in the proliferation of U87MG cells transfected with EGFRvIII. The IC50 value for this cell line is 2µM (afatinib). 50µM temozolomide inhibited cell proliferation by 50%. We evaluated the combinational efficacy of IC25 of both. Afatinib effectively blocked EGFR signaling even 72 hours after treatment in the U87MG cell line transfected with either wild type EGFR or EGFRvIII. This was evidenced by decreased phosphorylation of EGFR (Tyr 1068) and its downstream signaling. Focal adhesion kinase (FAK) signaling in EGFRvIII expressing cells, largely responsible for the invasiveness of GBM, was abolished by afatinib. Furthermore, treatment with afatinib and temozolomide significantly decreased the in vitro tumorigenicity (anchorage dependent growth - colony formation assay as well as anchorage independent growth - soft agar assay) of EGFRvIII expressing GBM cells. Conclusion: Altogether, these results support synergistic efficacy of afatinib and temozolomide in EGFRvIII expressing GBM. Citation Format: Raghupathy Vengoji, Satyanarayana Rachagani, Suprit Gupta, Kavita Mallya, Maneesh Jain, Moorthy Ponnusamy, Surinder Batra, Nicole Shonka. Novel specific RTK targeting of EGFR/FAK axis in glioblastoma invasion [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 1104. doi:10.1158/1538-7445.AM2017-1104
Abstract 478: Regulation of cross talk between AR and wnt/beta-catenin pathways in prostate cancer
Authors: Alexis Plaga, Girish C. Shukla
Journal: Cancer Research (2017)

Abstract Prostate Cancer (PCa) is the second most commonly diagnosed cancer in the United States with 180,890 males diagnosed and is predicted to cause approximately 26,000 deaths in 2016. The current treatment of androgen deprivation therapy (ADT) initially depletes circulating androgens; however, intratumoral androgens rescue androgen receptor (AR) signaling and promotes the development of castration resistant prostate cancer (CRPC). The dysregulation of the Wnt/β-catenin signaling pathway has been implicated in the development of many cancers including PCa. The disruption of this signaling leads to the stabilization of β-catenin which upregulates many genes involved in tumorigenesis. Additionally, β-catenin acts as AR cofactor. Our previous studies show that AR is a direct target of miR-644a. We hypothesized that targeting the expression of both the β-catenin pathway and AR by conventional drugs and/or tumor suppressor miR-644a would have synergistic therapeutic benefits. In this study, we are investigating miR-644a mediated posttranscriptional downregulation of GSK3-β and β-catenin in the wnt/β-catenin signaling pathway. The effect of miR-644a in combination with inhibitors (β-catenin or GSK3-β) was also assessed using proliferation assays and a significant downregulation was observed. We will further study the posttranscriptional effects of tumor suppressor miR-644a on the wnt/β-catenin pathway and also the processing and regulation of miR-644a in PCa. Citation Format: Alexis Plaga, Girish C. Shukla. Regulation of cross talk between AR and wnt/beta-catenin pathways 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 478. doi:10.1158/1538-7445.AM2017-478
Abstract LB-032: Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma
Authors: Qing Wang, Jiang Zhu, Hsin-Sheng Yang
Journal: Cancer Research (2017)

Abstract Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently down-regulated in many types of cancer including colorectal cancer. In this study, we found that knockdown/knockout of Pdcd4 increased the activity of mammalian target of rapamycin complex 2 (mTORC2). Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which was resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the sin1 5’ untranslated region (5’UTR) was fused with luciferase reporter and named as 5’Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation of 5’Sin1-Luc but not the control luciferase without the sin1 5’UTR, suggesting that sin1 5’UTR mediated Pdcd4’s inhibition on Sin1 translation. Ectopic expression of wild type Pdcd4 and Pdcd4(157-469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited the Sin1 translation, and thus inhibited mTORC2 kinase activity and invasion in colon tumor cells. By contrast, Pdcd4(157-469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and as a result failed to inhibit mTORC2 activity and invasion. In addition, treating cells with an eIF4A inhibitor also efficiently inhibits Sin1 expression and invasion. These results suggest that Pdcd4-inhibited Sin1 translation is through eIF4A, and is functionally important for suppression of mTORC2 activity and invasion. In colorectal cancer tissues, Sin1 protein but not mRNA was significantly up-regulated while Pdcd4 protein was down-regulated, suggesting that loss of Pdcd4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which Pdcd4 inhibits Sin1 translation to attenuate mTORC2 activity and thereby suppress invasion. Citation Format: Qing Wang, Jiang Zhu, Hsin-Sheng Yang. Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon 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 LB-032. doi:10.1158/1538-7445.AM2017-LB-032
Abstract 3502: RNAi screen identified novel long non-coding RNAs involved in cell growth control, migration, and invasion
Authors: Tse-Chun Kuo, Sheng-Chieh Hsu, Hui-Ju Chou, Pei-Shan Li, Szu-Huei Wu, Yen-Ling Yu, Jen-Shin Song, Hsing-Jien Kung
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer often associated with poor prognosis. Owing to the lack of therapeutic targets, patients with TNBC tend to rely on standard chemotherapy; however, chemo-resistance often develops in TNBC as a result of deregulated cell death control like in many other tumors. Long non-coding RNAs (lncRNAs) are transcripts longer than 200bp and have little or no protein-coding capacity. Although once considered as transcriptional noise, significant numbers of lncRNAs are now known as modulators of protein expression and functions and are implicated in a range of developmental processes and diseases. As many of them influence oncogenes and tumor suppressors in cancer, they represent excellent biomarkers as well as potential targets for therapy. In order to gain more insight on cell death regulation and to seek potential targets for TNBC, we employed an RNAi screen targeting 2231 lncRNAs in MDA-MB-231 TNBC cells. By using changes in cell metabolic activity (MTT assay) as readouts for primary screen and changes in cell number as confirmation, our unbiased screen identified two novel lncRNAs that drastically reduced cell proliferation when depleted. In addition to cell growth, the two lncRNAs also contribute to cancer cell migration and invasion. Interestingly, our gene profiling analyses and RNA immunoprecipitation studies show the two lncRNAs are involved in signaling cascades known to promote mammary tumorigenesis including EGF and β-catenin. We are now trying to delineate the detailed molecular mechanism(s) by which the two lncRNAs contribute to TNBC tumorigenesis. Together, our current results suggest a possibility for the two novel lncRNAs as drug targets in triple-negative breast cancer. Citation Format: Tse-Chun Kuo, Sheng-Chieh Hsu, Hui-Ju Chou, Pei-Shan Li, Szu-Huei Wu, Yen-Ling Yu, Jen-Shin Song, Hsing-Jien Kung. RNAi screen identified novel long non-coding RNAs involved in cell growth control, migration, and invasion [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 3502. doi:10.1158/1538-7445.AM2017-3502
Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)
Authors: Anouar Fanidi, David C Muller, Jian-Min Yuan, Victoria L Stevens, Stephanie J Weinstein, Demetrius Albanes, Ross Prentice, Cynthia A Thomsen, Mary Pettinger, Qiuyin Cai, William J Blot, Jie Wu, Alan A Arslan, Anne Zeleniuch-Jacquotte, Marjorie L McCullough, Loic Le Marchand, Lynne R Wilkens, Christopher A Haiman, Xuehong Zhang, Jiali Han, Meir J Stampfer, Stephanie A Smith-Warner, Edward Giovannucci, Graham G Giles, Allison M Hodge, Gianluca Severi, Mikael Johansson, Kjell Grankvist, Arnulf Langhammer, Steinar Krokstad, Marit Næss, Renwei Wang, Yu-Tang Gao, Lesley M Butler, Woon-Puay Koh, Xiao-Ou Shu, Yong-Bing Xiang, Honglan Li, Wei Zheng, Qing Lan, Kala Visvanathan, Judith Hoffman Bolton, Per Magne Ueland, Øivind Midttun, Arve Ulvik, Neil E Caporaso, Mark Purdue, Regina G Ziegler, Neal D Freedman, Julie E Buring, I-Min Lee, Howard D Sesso, J Michael Gaziano, Jonas Manjer, Ulrika Ericson, Caroline Relton, Paul Brennan, Mattias Johansson
Journal: JNCI Journal of the National Cancer Institute (2017)

Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.
Abstract 3865: Targeting the epigenetic modifier HMGA2 in lethal adult and pediatric gliomas inhibits invasion, growth and tumorigenicity
Authors: Harpreet Kaur, Sabeen Z. Ali, Huizi Guo, Sepehr Akhtarkhavari, Fausto Rodriguez, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are highly infiltrative, incurable adult and pediatric brain tumors characterized by the presence of tumor stem-like cells. Although GBM and DIPG have different epigenetic drivers, we found increased expression of an epigenetic modifier and stem cell factor HMGA2 in both tumors by immunohistochemistry and western blotting. HMGA2 is a DNA-binding protein that regulates transcription during normal embryogenesis and in cancer stem cells. We hypothesized that HMGA2 contributes to high grade glioma tumorigenicity through its ability to alter the transcription of many genes. Lentiviral short hairpin RNA (shRNA)-mediated reduction of HMGA2 in multiple patient-derived GBM cell lines significantly reduced invasion in transwell assay (shHMGA2 vs. shControl, P&amp;lt;0.01). Similarly, shRNA mediated suppression of HMGA2 in DIPG cell lines reduced proliferation (BrdU incorporation), reduced invasion (transwell assay), inhibited clonogenicity (soft agar assay) and increased apoptosis (cleaved caspase-3 immunofluorescence, shHMGA2 vs. shControl, P&amp;lt;0.001). Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug Netropsin significantly inhibited invasion (transwell assay), decreased proliferation (BrdU incorporation) and increased apoptosis of DIPG neurospheres (P&amp;lt;0.01). Mice bearing orthotopic GBM xenografted cells transduced with HMGA2 shRNA lived significantly longer (108 days) compared to control shRNA (67.5 days, P&amp;lt;0.0001 by log-rank analysis). To investigate the mechanism of HMGA2-mediated malignancy, we discovered high levels of CD44 (a known mediator of invasion and stemness) that correlated with high HMGA2 expression in DIPG and GBM tumors. Suppression of HMGA2 led to decreased CD44 expression while ectopic expression of HMGA2 increased CD44 expression in GBM cell neurospheres. Knockdown of CD44 in HMGA2-high GBM neurospheres reduced invasion (P&amp;lt;0.01). Our studies suggest an oncogenic role of HMGA2 and its downstream effectors in gliomas and identify this important pathway as a potential therapeutic target. We conclude that minor groove binding agents similar to Netropsin may be effective agents for HMGA2-expressing pediatric and adult high grade gliomas. Citation Format: Harpreet Kaur, Sabeen Z. Ali, Huizi Guo, Sepehr Akhtarkhavari, Fausto Rodriguez, Charles G. Eberhart, Eric H. Raabe. Targeting the epigenetic modifier HMGA2 in lethal adult and pediatric gliomas inhibits invasion, growth and tumorigenicity [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 3865. doi:10.1158/1538-7445.AM2017-3865
Abstract 2008: Intestinal microbiota may dynamically facilitate the anti-PD-L1 immunotherapy
Authors: Jia Xue, Zhun Wang, Sheng Guo, Jie Cai, Davy Ouyang, Bin Cai, Gang Chen, Jie Liu, Xin Dong, Henry Li
Journal: Cancer Research (2017)

Abstract Cancer immunotherapies, e.g. the antibody against programmed death ligand 1 (PD-L1), a checkpoint inhibitor, have witnessed great successes in treating certain cancers in recent years. Recent data have also demonstrated that gut microbiota are important modulators on anticancer immunotherapy1,2. Heterogeneity in patient outcome seems to suggest complex communications between microbiota and host antitumor immunity. To this end, we tested an engineered chimeric MC38 mouse cell line, hPDL1-MC38-HuCELL™ via human PD-L1 knock-in procedure, where MC38 CRC syngeneic cell is derived from C57BL/6. After treatment of PD-L1 antibodies (cD7A8 and BMS PD-L1 of different dose regimens), we observed significantly different drug responses among the mice from three different Chinese rodent suppliers: the mice from Vendor 1 showed no tumor progression after treatment with a variety of doses while no favorable response was observed in mice from Vendor 2 and Vendor 3. To deeply study the gut microbiota of these mice, we performed 16S ribosomal RNA sequencing on untreated mice from three groups (5 replicates for each). Global diversity analysis by Quantitative Insights Into Microbial Ecology (QIIME) tool revealed a clear separation in the three sources of mice: the microbiota composition of Vendor 2 and Vendor 1 are relatively closer to each other whereas the Vendor 3 mice are different, suggesting that the main difference seen between Vendor 1/2 and 3 in the original composition of gut microbiota is not the key impact for the observed anti-PD-L1 efficacy, and there should be other complex dynamics impacted anti-PD-L1 treatment, which remains unknown. Moreover, a group of 27 taxa were identified with significant difference in abundance (Kruskal-Wallis test, p-value &amp;lt; 0.05) across the groups, such as Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae, which confirmed the previous data1. In conclusion, intestinal microbiota dynamically facilitate anti-PD-L1 efficacy and reversely anti-PD-L1 treatment could influence reconstruction of gut microbiota. References 1. Sivan A, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084-9. 2. Vétizou M, et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350(6264):1079-84. 3. Caporaso JG, et al., QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335-6. Citation Format: Jia Xue, Zhun Wang, Sheng Guo, Jie Cai, Davy Ouyang, Bin Cai, Gang Chen, Jie Liu, Xin Dong, Henry Li. Intestinal microbiota may dynamically facilitate the anti-PD-L1 immunotherapy [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 2008. doi:10.1158/1538-7445.AM2017-2008