tbuckley/cabot-search huggingface dataset:
Abstract 5519: psiTPTE22-HERV functions as a tumor suppressor in gastric cancer and is associated with disease outcome
Authors: Jessie Qiaoyi Liang, Fei Xu, Shu Zheng, Jun Yu
Journal: Cancer Research (2017)

Abstract Background and aim: The novel gene psiTPTE22-HERV identified by us previously is a human endogenous retrovirus (HERV)-related gene located adjacent to the gene psiTPTE22. With a high GC content around the promoter region, expression of psiTPTE22-HERV can be regulated epigentically by DNA methylation. We aimed to elucidate the clinical significance of epigenetic alteration and biological function of psiTPTE22-HERV in gastric cancer. Methods and results: psiTPTE22-HERV was ubiquitously expressed in normal adult tissues including stomach, but was frequently silenced/down-reguated in gastric tumors and cancer cell lines as evidenced by RT-PCR. Bisulfite genomic sequencing results indicated that psiTPTE22-HERV was silenced by promoter DNA methylation, and its expression could be restored by demethylation treatments in gastric cancer cell lines. Ectopic expression of psiTPTE22-HERV significantly suppressed cell viability, clonogenicity and cell cycle progression, induced apoptosis, and inhibited migration and invasion of SGC7901 and MKN45 gastric cancer cells. In contrast, knock-down of psiTPTE22-HERV in the gastric cancer MKN1 cells significantly increased cell growth and migration ability, promoted cell cycle progress and inhibited cell apoptosis. psiTPTE22-HERV significantly suppressed subcutaneous tumorigenicity of SGC7901 cells in nude mice and metastasis (liver implantation) in tail vein injection models. Promoter methylation level of psiTPTE22-HERV was significantly higher in gastric tumors than in adjacent non-tumor tissues as revealed by bisulfite genomic sequencing (P&amp;lt;0.05); methylation levels in both tumors and adjacent non-tumor tissues of gastric cancer patients were significantly higher than in normal stomach tissues (both P&amp;lt;0.001). Multivariate Cox regression analysis demonstrated that promoter methylation of psiTPTE22-HERV in primary gastric tumors was an independent risk factor for poor survival. Kaplan-Meier survival curves showed that high-methylation of psiTPTE22-HERV promoter was significantly associated with shortened survival in gastric cancer patients from two independent cohorts (both P&amp;lt;0.05). Conclusion: psiTPTE22-HERV functions as a tumor suppressor that is commonly down-regulated by promoter methylation in gastric cancer, which may serve as a prognostic biomarker for gastirc cancer patients. Citation Format: Jessie Qiaoyi Liang, Fei Xu, Shu Zheng, Jun Yu. psiTPTE22-HERV functions as a tumor suppressor in gastric cancer and is associated with disease outcome [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 5519. doi:10.1158/1538-7445.AM2017-5519
Abstract 671: Prognostic importance of EGFR expression and Kras gene mutations in gallbladder carcinoma
Authors: Anjali Singh, Abul Kalam Najmi, Pramod Mishra, Majid Talikoti
Journal: Cancer Research (2017)

Abstract Gallbladder carcinomas involve multiple cascades of oncogenes like EGFR and Kras. Activation of Kras downstream pathways predict the sensitivity to anti EGFR treatment. In 2012, for the first time it was established that GBC and cholangiocarcinomas have their unique somatic genomic landscape and thus be studied independently. This study evaluates whether EGFR is a prognostic factor in GBC and identifies the frequency of codon 12 and codon 13 Kras mutations along with its association with subject survival. Seventy two GBC curative resections from North India were immunostained with anti EGFR monoclonal antibody and assessed for codon 12 and 13 KRAS mutation by real time PCR. Strong EGFR expression was observed in 25.4percent cases. About 28/72; G12C, 17/72; G12R, 10/72; G12D and 18/72; G13D cases harboured point mutations in Kras gene, which was significantly higher as compared to control tissues. Multivariate analysis revealed that EGFR expression (p=0.01; HR=3.14; 95percent CI=1.28-7.71) and codon-13 mutation (p=0.001; HR=38.34; 95percent CI=4.90-300.01) had a significant impact on survival and were independent prognostic factors in GBC. Our study suggests that EGFR expression and codon 13 mutations are independent prognostic factors in the selected GBC cohort and showed a high frequency of Kras codon 12 mutations as well. Citation Format: Anjali Singh, Abul Kalam Najmi, Pramod Mishra, Majid Talikoti. Prognostic importance of EGFR expression and Kras gene mutations in gallbladder 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 671. doi:10.1158/1538-7445.AM2017-671
Abstract 2312: Feasibility study of a fractionation method in the treatment of tumor treating fields
Authors: Yunhui Jo, Jiwon Sung, Hyo Sook Song, Eun Ho Kim, Myonggeun Yoon
Journal: Cancer Research (2017)

Abstract Tumor treating fields (TTFs) treatment has been reported to have great potential to treat various cancers. Inspired by a similarity between TTFs and radiotherapy in electromagnetic property, TTFs using a fractionated treatment scheme originally designed for radiotherapy were applied to cancer (Human glioblastoma, U373) and normal cells (intestinal epithelial, IEC-6) for three days with durations of 3, 6, 9, or 24 hours/day. As the treatment time of TTFs increases from 3 to 24 hours/day, the relative cancer cell growth rates in both cell lines were reduced. While the difference in cancer cell growth rate compared to control was ~25% (decreased from 100% to ~75%) for the treatment time of 6 hours/day, the growth rates of cells treated for additional 6 hours (i.e., 12 hours/day) and additional 18 hours (i.e., 24 hours/day) differed only ~5% and ~8% from that of cells treated for 6 hours/day, respectively. Our results suggested that the dependence on treatment time in cancer cell inhibition is weakened distinctly at treatment times over 6 hours/day. For normal cells, the relative growth rates corresponding to the treatment time of TTFs was not decreased much for the treatment time of 3, 6, 12 hours/day revealing 93.3%, 90.0%, 89.3% of cell growth rates compared to control, respectively, but it suddenly reduced to ~73% for 24 hours/day of treatment. The experimental results indicated that the effects of TTFs on growth rates of cancer cells are higher than the effects of TTFs on growth rates of normal cells for treatment times of 3-12 hours/day, but the difference became minimal for treatment times of 24 hours/day. Our results suggest that the fractionated scheme in the treatment of tumor treating fields may reduce treatment time while maintaining efficacy, suggesting that this method can increase patients’ quality of life. Citation Format: Yunhui Jo, Jiwon Sung, Hyo Sook Song, Eun Ho Kim, Myonggeun Yoon. Feasibility study of a fractionation method in the treatment of tumor treating fields [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 2312. doi:10.1158/1538-7445.AM2017-2312
Abstract 1784: Early feasibility and development of multiplexed, single-reaction assays for ALK, ROS1 and RET novel ddPCR RNA fusions
Authors: Hestia Mellert, Kristin Alexander, Leisa Jackson, Galen Roda, Samantha Cooper, Dianna Marr, Stephen J. Jones, Nia Charrington, Gary Pestano
Journal: Cancer Research (2017)

Abstract We have previously described a targeted genomic Laboratory Developed Test (LDT) that includes variant specific Droplet Digital™ PCR (ddPCR) testing for EGFR, KRAS and BRAF in plasma. This test supports the rapid delivery of molecular diagnostic test results, with &amp;gt;95% of tests results delivered in 72 hours of receipt in our Laboratory. This test then meets the key clinical need for the delivery of results that can result in faster treatment decisions. Additionally, the test may be of utility for those patients who need mutation results quickly or for whom tissue may be unavailable or insufficient for molecular testing. This is especially true for patients diagnosed with non-small cell lung cancer (NSCLC). In this report we will update on new test concepts created using the recently available design software engine for ddPCR assays. Specifically, we will describe studies on the development of single-reaction, multiplexed assays for the respective detection of ROS1 (up to 11 variants), RET (up to 8 variants) and EML4-ALK (v1 - v3). Design considerations, specificity and sensitivity, as well as reproducibility and robustness studies for these complex assays will be reviewed. Similar studies were conducted for the development of the commercially available test for the EML4-ALK fusion variants. EML4-ALK concordance studies compared the fusions found in blood with known positives and negatives found using FISH and PCR based methods (n=24 evaluable matched pair samples). Clinical sensitivity, specificity and concordance were 85%, 100% and 92% respectively. In this study we also report on test performance of the ALK RNA fusion test over 3 consecutive months of testing. Of note, we have delivered greater than 95% of tests (n = 272 samples) with an observed positive sample frequency of 2%. The robust detection of rare variant, RNA fusions from plasma within 72 hours represents a molecular testing option of value to patients with NSCLC and their physicians. Citation Format: Hestia Mellert, Kristin Alexander, Leisa Jackson, Galen Roda, Samantha Cooper, Dianna Marr, Stephen J. Jones, Nia Charrington, Gary Pestano. Early feasibility and development of multiplexed, single-reaction assays for ALK, ROS1 and RET novel ddPCR RNA fusions [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 1784. doi:10.1158/1538-7445.AM2017-1784
Abstract 5264: Chemoprevention of rat oral carcinogenesis by black raspberry phytochemicals
Authors: Steve Oghumu, Thomas Knobloch, Jennifer Ahn-Jarvis, Logan Weghorst, Kyle Horvath, Paul Geuy, Christopher Weghorst
Journal: Cancer Research (2017)

Abstract It is expected that in 2016, there will be an estimated 48,330 new cases and 9,570 deaths due to oral cancer in the US, which is about one person every hour every day. Due to the epithelial field defects associated with oral carcinogenesis, tumor recurrence and second primary tumor incidence are common. Recently conducted Phase I Clinical trials demonstrate the ability of black raspberries (BRBs) to modulate inflammatory biomarkers of molecular efficacy that supports a chemopreventive strategy against oral cancer. From these human trials we have established a molecular signature of BRB responsive biomarkers. However, it is essential that a preclinical animal model of BRB chemoprevention which recapitulates the fundamental features of human oral carcinogenesis be developed, so that we can evaluate potential mechanisms of action and validate molecular biomarkers of BRB efficacy. We therefore established the ability of BRB to inhibit oral lesion formation in a rat model of 4-nitroquinoline 1-oxide (4NQO) induced oral carcinogenesis and examined molecular efficacy using a clinically relevant transcriptional signature. Oral cancer was induced in F344 rats using 4NQO in drinking water for 10 weeks followed by regular drinking water for 16 weeks. Rats were administered a diet containing 5 or 10 percent lyophilized BRBs. Tongue tissues were examined for lesion multiplicity, incidence and histopathological features. Clinically derived pro-inflammatory and pro-survival molecular biomarkers were also determined by real-time PCR and ELISA. Dietary administration of 5 and 10 percent BRBs reduced combined lesion incidence and multiplicity by -39.3% and -28.6% respectively. Histopathological analyses of tongue sections further demonstrate the chemopreventive ability of dietary BRB administration in the rat model. Pro-survival and pro-inflammatory biomarkers were downregulated in BRB administered 4NQO induced rats compared to untreated 4NQO induced rats. Our study shows that dietary administration of BRB inhibits oral carcinogenesis in the rat 4NQO model. The rat 4NQO model is suitable for interrogating mechanisms of action of BRB-mediated oral cancer chemoprevention. Citation Format: Steve Oghumu, Thomas Knobloch, Jennifer Ahn-Jarvis, Logan Weghorst, Kyle Horvath, Paul Geuy, Christopher Weghorst. Chemoprevention of rat oral carcinogenesis by black raspberry phytochemicals [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 5264. doi:10.1158/1538-7445.AM2017-5264
Abstract 3391: Next generation sequencing paves the way for personalized medicine in pheochromocytoma and paraganglioma patients and their families
Authors: Laura Gieldon, Susan Richter, Andreas Rump, Karl Hackmann, Andreas Tzschach, Graeme Eisenhofer, Mariola Pęczkowska, Aleksander Prejbisz, Evelin Schröck, Barbara Klink
Journal: Cancer Research (2017)

Abstract More than 35% of pheochromocytomas and paragangliomas (PPGL) are thought to occur due to an underlying genetic predisposition. 18 susceptibility genes have been identified for PPGL, which explain app. 30% of familial cases. Further PPGL predisposition genes, however, remain to be discovered. In addition, identification of biomarkers for malignancy also remains a current challenge since histologic assessment does not suffice discrimination of malignant PPGLs. Personalized screening protocols, risk stratification measures and surveillance guidelines are needed for PPGL patients and their family members at risk. We performed panel sequencing for 94 tumor predisposition syndrome (TPS) genes and identified 12 pathogenic germline mutations in 60 PPGL patients. Two of these patients were identified with NF1-mutations although they did not meet the diagnostic criteria for Neurofibromatosis. Thus, TPS gene panel sequencing proved superior to routine Sanger sequencing since mutations were identified in genes that would have routinely been excluded from analysis. Combining results of immunohistochemistry as well as biochemical profiling by measuring Krebs-cycle metabolites and genetic analyses of tumors we were able to reclassify variants of uncertain significance (VUS) as either pathogenic mutations or polymorphisms in several patients. Three incidentally found pathogenic mutations in CHEK2 and MSH2 prompted further analyses such as testing for microsatellite instability in order to evaluate possible effects on PPGL development. For patients in whom no underlying mutation could be detected we performed custom candidate gene panel sequencing of tumor derived-DNA. Whole exome sequencing (WES) was carried out in 15 cases highly suspicious for a genetic background in order to identify new candidate predisposition genes that will further be evaluated in the patient cohort and in functional studies. We will also present guidelines for diagnostics, surveillance and prevention of PPGL for patients and their family members. Citation Format: Laura Gieldon, Susan Richter, Andreas Rump, Karl Hackmann, Andreas Tzschach, Graeme Eisenhofer, Mariola Pęczkowska, Aleksander Prejbisz, Evelin Schröck, Barbara Klink. Next generation sequencing paves the way for personalized medicine in pheochromocytoma and paraganglioma patients and their families [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 3391. doi:10.1158/1538-7445.AM2017-3391
Abstract 1427: Investigating role of RECQ1 in response to gemcitabine treatment in triple negative breast cancer
Authors: Swetha Parvathaneni, Xing Lu, Sudha Sharma
Journal: Cancer Research (2017)

Abstract The response of cancer cells to therapeutic drugs aimed at causing DNA damage is dependent on proteins that play roles in DNA repair. Single nucleotide polymorphism in RECQ1 (also known as RECQL or RECQL1), a DNA helicase involved in DNA damage and replication stress response, is reported to influence patient’s response to gemcitabine in pancreatic cancer leading to poor survival. Gemcitabine is also used as a chemotherapeutic against triple negative breast cancer; however resistance to gemcitabine is reported. The mechanism by which gemcitabine chemoresistance is obtained is poorly understood. Given the importance of RECQ1 in replication fork restart and it being categorized as a breast cancer susceptibility gene, we wish to investigate the role of RECQ1 in modulating cellular response to gemcitabine in triple negative breast cancer cells. To study RECQ1 functions, we developed isogenic pairs of RECQ1-proficient and RECQ1-deficient cells by CRISPR-Cas9-mediated targeted inactivation of RECQ1 in breast cancer cell lines as in vitro model system. RECQ1-knockout MDA-MB-231 cells displayed reduced cell growth and proliferation, and increased DNA damage as compared to the MDA-MB-231 cells expressing wild type RECQ1. As compared to RECQ1-proficient MDA-MB-231 cells, RECQ1-deficient cells were more sensitive to gemcitabine treatment, incurred significantly greater load of double strand breaks upon gemcitabine treatment, and displayed aberrant cell cycle progression following recovery from gemcitabine treatment. Our ongoing experiments are investigating the detailed mechanism of RECQ1’s role in response to gemcitabine and its implications in therapeutic response. Funding: This work was funded by the NIGMS/NIH grant SC1GM093999 to Sudha Sharma. We also acknowledge support from the NIMHD/NIH award number G12MD007597 and NIA/NIH award number 1R25 AG047843-02. We thank Drs. Ritu Chaudhary, Xiaoling Li and Ashish Lal (NCI) for their help and support. Citation Format: Swetha Parvathaneni, Xing Lu, Sudha Sharma. Investigating role of RECQ1 in response to gemcitabine treatment 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 1427. doi:10.1158/1538-7445.AM2017-1427
Abstract 3084: Therapeutic implications of sex hormone signaling in melanoma
Authors: Christopher Natale, Junqian Zhang, Ankit Dahal, Todd Ridky
Journal: Cancer Research (2017)

Abstract Female gender, early age of first birth, and multiparity are associated with less aggressive melanoma; however, the mechanisms underlying the apparent clinical benefit are undefined. Previously we reported that 17β-estradiol drives melanocyte differentiation through G-protein coupled estrogen receptor (GPER), a nonclassical sex hormone receptor. Here, we use genetically-defined human skin xenograft melanoma to show that pregnancy antagonizes oncogenic BRAF and inhibits melanomagenesis. Transient GPER activation drives stable melanocyte differentiation that persists after removal of the activating ligand. Consistent with this, brief exposure of melanoma cells to GPER agonists prior to xenografting inhibited subsequent tumor growth. Systemic treatment with GPER agonists cooperated with PD-1 blockade in melanoma bearing mice to greatly prolong survival longer than that observed with either agent alone. The combination of differentiation-based therapies with immunotherapy may have significant therapeutic benefit for melanoma. Citation Format: Christopher Natale, Junqian Zhang, Ankit Dahal, Todd Ridky. Therapeutic implications of sex hormone signaling in melanoma [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 3084. doi:10.1158/1538-7445.AM2017-3084
Abstract 4857: TAK1 mediated IL1 expression as autocrine signaling to promote breast cancer metastasis
Authors: Oihana Iriondo, Mostafa Elhodaky, Yarong Liu, Grace Lee, Julie E. Lang, Pin Wang, Min Yu
Journal: Cancer Research (2017)

Abstract TGFβ-activated kinase 1 (TAK1), a serine/threonine kinase from the MAPKKK family, is regulated by different cytokines such as IL1, TGFβ, TNFα and BMPs, and it is therefore a key player in the cellular responses induced by changes in the microenvironment. TAK1 regulates cell survival, differentiation and inflammatory responses by activating other intracellular kinases such as p38, JNK or IKK. TAK1 activation is thought to influence the progression of several types of cancer, including lymphomas and pancreatic, colon, liver and breast cancer. In this study, we aimed to investigate the mechanisms by which TAK1 regulates breast cancer progression. (5Z)-7-Oxozeanol is a compound that inhibits the kinase activity of TAK1. Treatment of mice injected with MDA-MB-231 cells with (5Z)-7-Oxozeanol containing nanoparticles reduced metastasis formation, while growth of the primary tumor was not affected. TAK1 involvement in metastasis was confirmed by xenotransplantation experiments done with MDA-MB-231 cells overexpressing wild type or dominant negative forms of TAK1. Using these stable cell lines, we confirmed that TAK1 is required for p38 activation induced by several cytokines. Interestingly, cells cocultured with macrophages showed a TAK1-dependent increase in the expression levels of IL1α and IL1β, which can lead to TAK1 activation themselves. These cytokines were also detected in cancer cells that colonized the mouse lung, suggesting that the lung microenvironment could promote the initiation of a positive feedback loop by cancer cells, promoting the growth of metastatic lesions. Disruption of this positive autocrine feedback loop may be a potential therapeutic approach to suppress breast cancer metastasis to the lung. Citation Format: Oihana Iriondo, Mostafa Elhodaky, Yarong Liu, Grace Lee, Julie E. Lang, Pin Wang, Min Yu. TAK1 mediated IL1 expression as autocrine signaling to promote breast cancer metastasis [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 4857. doi:10.1158/1538-7445.AM2017-4857