tbuckley/cabot-search huggingface dataset:
Abstract 2242: Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice
Authors: Chao Yang, Qing Jiang
Journal: Cancer Research (2017)

Abstract Nuclear factor-κB (NF-κB) plays a key role in inflammatory responses and cancer development. Inhibition of NF-κB has been shown to attenuate inflammation and cancer progression. δ-Tocotrienol (δTE) is a natural vitamin E form rich in annatto seeds and has been shown to inhibit NF-κB in pancreatic cells. However, potential effect of δTE on NF-κB activation in immune cells and the underlying mechanism have not been investigated. In the present study, we found that δTE inhibited TNF-α induced activation of NF-κB, as indicated by diminished phosphorylation and degradation of IκBα in the cytosol, and phosphorylation of p65 in the nucleus. Furthermore, δTE potently inhibited TNF-α-induced phosphorylation of TAK1, a key upstream kinase that is required for the activation of NF-κB. Interestingly, δTE significantly increased the expression of A20 and CYLD, both of which are negative regulators of NF-κB. Knockout of A20 partially diminished δTE's anti-NF-κB effect, supporting the notion that induction of A20 plays a key role in δTE’s anti-NF-κB effect. To translate mechanistic findings to a whole body environment, we further investigated the effectiveness of δTE and its metabolite, δTE-13’-COOH, against azoxymethane (AOM) induced and colitis-promoted colon tumorigenesis in male BALB/c mice. We found that δTE-rich mixed tocotrienols (δTE /γTE ~8/1, at 0.035% diet) inhibited colon tumorigenesis, as indicated by 36% reduction of multiplicity of large adenomatous polyps (&amp;gt;2mm(2), P=0.07) and decreased tumor surface area by 31% (P&amp;lt;0.05). δTE-13’-COOH (at 0.04% diet) significantly suppressed multiplicity of total polyps by 25% (P=0.06) and large polyps by 54% (P&amp;lt;0.01). Our study demonstrates that δTE has potent anti-NF-κB activity and this vitamin E form and its metabolite suppress colitis-promoted colon tumorigenesis in mice. Citation Format: Chao Yang, Qing Jiang. Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice [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 2242. doi:10.1158/1538-7445.AM2017-2242
Abstract #5572: Small molecular inhibitor of centromere-associated protein E (CENP-E), GSK923295A inhibits cell growth in breast cancer cells
Authors: Zhi Hu, Wen-lin Kuo, Debopriya Das, Safiyyah Ziyad, Shenda Gu, Sanchta Bhattacharya, Andy Wyrobek, Nicholas Wang, Heidi Feiler, Richard Wooster, Barbara Weber, Joe Gray
Journal: Cancer Research (2009)

Centromere-associated protein E (CENPE) is a kinesin-like motor protein which accumulates in the G2 phase of the cell cycle and then is degraded at the end of mitosis. CENPE is responsible for mitotic chromosomal alignment and the mitotic spindle check point. GSK923295A is a small molecule inhibitor targeting CENP-E. In this study, we measured cellular responses to GSK923295A in a panel of 50 well characterized breast cancer cell lines. With a three-day proliferation assay, GSK923295A inhibited cell growth with a GI50 range between 20nM to 9µM. Most of the breast cancer cell lines (40/48) showed very low GI50 of less than 200nM. Basal subtype breast cancer cells are sensitive to the compound with the GI50 range between 20nM to 200nM. The non-malignant cells are very resistant to GSK923295A with GI50 >500nM. However, the luminal subtype has a very wide range of GI50s (20nM-2000nM). Predictive biomarkers of response to GSK923295A treatment were discovered by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK923295A. Functional analysis of top predictive biomarkers indicates that PI3K/AKT signaling, Ephrin receptor signaling, PTEN signaling and apoptosis signaling pathways are involved in cellular response of GSK923295A in breast cancer cells (p   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5572.
Abstract 1296: Bayesian fine-mapping using summary data of 145,000 subjects refines common risk associations, discovers secondary signals and novel candidate genes for prostate cancer
Authors: Zsofia Kote-Jarai, Tokhir Dadaev, Ed Saunders, Paul Newcombe, Ezequiel Anokian, Daniel Leongamornlert, Ali Amin Al Olama, Christopher Haiman, Ros Eeles, David Conti
Journal: Cancer Research (2017)

Abstract Genome-wide association studies (GWAS) have identified more than 160 prostate cancer (PrCa) genetic risk loci, however these variants rarely point directly to the true underlying functional variant driving the association. In this fine-mapping study to narrow the credible causal variant set for 80 PrCa regions representing 89 original independent GWAS signals, we performed Bayesian variable selection in combination with functional annotation and quantile regression. We used imputed data for 83,511 PrCa cases and 62,283 controls investigated with high-density genotyping arrays from the OncoArray, iCOGS and 5 previous GWAS studies from the PRACTICAL/ELLIPSE consortia. To facilitate fine-mapping from one-at-a-time SNP associations meta-analyzed over the consortia we first applied JAM, a novel Bayesian algorithm which searches multi-SNP models in summary data by imputing the correlation structure according to a reference panel. JAM provides inference on the number of independent signals, as well as the set of potential SNPs driving those signals. We utilized functional annotation and eQTL analysis (TCGA prostate tumor data) in combination with quantile regression to further prioritize the most likely causal variants within the credible set of SNPs and identify potential candidate genes and functional mechanisms. The median credible set size from JAM was 17 SNPs per region, shrinking the post-QC input set of variants by about 98%. In 13 regions evidence was found for multiple independent signals, up to a maximum of 5 SNPs. Within the single hit regions, almost half had less than 10 variants selected. In 34 regions the credible set included at least one SNP that was co-localized with a significant eQTL. Quantile regression highlighted enrichment for variants in promoters, DNase hypersensitivity site and eQTLs - representing candidate biological mechanisms underpinning disease development. This study has substantially reduced and prioritized the candidate causal PrCa risk variants within previously known GWAS regions, identifying a small subset of variants for further functional investigation and novel candidate genes at a number of loci. Citation Format: Zsofia Kote-Jarai, Tokhir Dadaev, Ed Saunders, Paul Newcombe, Ezequiel Anokian, Daniel Leongamornlert, Ali Amin Al Olama, Christopher Haiman, Ros Eeles, David Conti, The PRACTICAL/ELLIPSE Consortium. Bayesian fine-mapping using summary data of 145,000 subjects refines common risk associations, discovers secondary signals and novel candidate genes for 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 1296. doi:10.1158/1538-7445.AM2017-1296
Abstract 13: Chromatin unfolding small molecules as a novel type of anticancer agents
Authors: Katerina V. Gurova
Journal: Cancer Research (2017)

Abstract Although targeted therapy was the major focus of anti-cancer drug development, recently revealed enormous heterogeneity of tumors planted a seed of doubt in it as a potential cure for cancer. Very few universal cancer targets are known and they lack cancer specificity. DNA is one of this sort, but activity of drugs targeting DNA was traditionally attributed to their ability to block DNA replication and cause DNA damage with a plethora of harmful long lasting effects in normal cells. We have found that reversible binding of DNA by non-DNA damaging small molecules, curaxins, has strong anticancer effect in different preclinical models without deleterious consequences associated with DNA damage (REF). In this study we explained the mechanism of activity of curaxin clinical lead, CBL0137, through alteration of chromatin organization in tumor cells. Intercalation of the curaxin carbazole moiety between base pairs and DNA major and minor groove binding with curaxin side chains cause an increase in inter base pair distance and untwisting of the double helix (~18o). Such alteration of DNA helical shape leads to decreased nucleosome stability and chromatin opening, creating sites for the high affinity binding of histone chaperone complex FACT. We named this phenomenon “chromatin trapping of FACT” or c-trapping. Consequences of C-trapping are much more deleterious for tumor, than for normal cells. First, c-trapping is an equivalent of functional inactivation of FACT. FACT is critical for oncogenic transformation and tumor, but not normal cell, viability and growth (REF). FACT is essential for the activity of several transcription factors, such as NF-kappaB, HSF1, MYC etc., with important roles in tumor cell proliferation and survival (REF). Further, deregulation of transcription caused by curaxin-dependent chromatin decondensation leads to upregulation of transcription from heterochromatin. This leads to the formation of double stranded RNAs from centromeric and pericentromeric repetitive elements, which mimics a viral infection and induces an IFN response, a powerful inhibitor of tumor cell growth. Additionally, c-trapping of FACT leads to casein kinase 2 mediated phosphorylation and activation of wild type p53 leading to p53-dependent death of cells. Thus non-DNA damaging DNA binding small molecules compromise cancer cell viability via alteration of nucleosome stability and chromatin organization. This is a novel mechanism of anti-cancer activity of small molecules with broad applicability to different types of cancer while lacking the harmful effects of DNA damaging chemotherapy. Citation Format: Katerina V. Gurova. Chromatin unfolding small molecules as a novel type of anticancer 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 13. doi:10.1158/1538-7445.AM2017-13
Abstract 1321: Transcriptome-wide association study of prostate cancer risk
Authors: Maxine Chen, Alexander Gusev, Massimo Loda, Lorelei A. Mucci, Meir J. Stampfer, Peter Kraft, Kathryn L. Penney
Journal: Cancer Research (2017)

Abstract Though more than 150 single nucleotide polymorphisms (SNPs) associated with prostate cancer have been identified through GWAS, we still do not understand the functional consequences of common genetic variation in this disease. Genetic variants may influence complex diseases like prostate cancer through gene expression. However, very large studies evaluating gene expression in prostate cancer are currently infeasible due to the limited availability of prostate cancer tissue and expense of collecting expression data. Alternative approaches have been developed to identify expression-trait associations in study populations without directly measured expression data. One such approach (Gusev et al. Nat Genet. 2016) uses a set of reference individuals with both gene expression and SNP data to develop genetic prediction models of gene expression values. These models are then used to impute cis genetic components of gene expression for a much a larger set of individuals with only genotype and phenotype information. We used Affymetrix gene expression microarray data from normal prostate and prostate tumor tissue and genotype data from prostate cancer patients in the Health Professionals’ Follow-up Study and the Physicians’ Health Study (N=187) as a reference panel for creating the predicted models of the genetic components of expression. We imputed gene expression values into Oncoarray GWAS summary statistics from the PRACTICAL consortium (N ~ 75,000) to assess the association between predicted expression and prostate cancer risk. We present the results of our transcriptome-wide association study in normal prostate and prostate tumor tissue, identifying genes significantly associated with prostate cancer risk after correcting for multiple testing. These genes may provide insight into how genetic variants influence prostate cancer through their effect on gene expression. Citation Format: Maxine Chen, Alexander Gusev, The PRACTICAL Consortium, Massimo Loda, Lorelei A. Mucci, Meir J. Stampfer, Peter Kraft, Kathryn L. Penney. Transcriptome-wide association study of prostate cancer risk [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 1321. doi:10.1158/1538-7445.AM2017-1321
Abstract 802: Loss of function of Arid1a synergizes with MYCN in neuroblastoma pathogenesis
Authors: Hui Shi, Ting Tao, Cigall Kadoch, Thomas Look
Journal: Cancer Research (2017)

Abstract ARID1A is a key component of the SWI/SNF-A (BAF) chromatin-remodeling complex that is known to modulate chromatin structure and gene transcription. Recent exome and whole-genome resequencing has identified SWI/SNF as the most frequently mutated chromatin remodeler in human cancers, and ARID1A as the most highly mutated component among the SWI/SNF subunits, primarily in solid tumors. In high-risk neuroblastoma, ARID1A is mutationally inactivated in one allele in ~1% of patient tumors. In addition, ARID1A is deleted in one allele in at least 85% of cases with chromosome 1p deletions, which is the most common deletion found in neuroblastoma. Thus, ARID1A appears to function as a haploinsufficient tumor suppressor in a substantial fraction of high-risk neuroblastomas. The arid1a gene is duplicated in zebrafish, and the two genes are hence named arid1aa and arid1ab. We targeted each allele of the two genes using CRISPR/Cas genome editing system and recovered stable lines with loss-of-function mutations in each arid1a gene. arid1ab but not arid1aa homozygous mutation showed embryonic lethality. We bred these lines with a transgenic zebrafish line expressing high levels of MYCN in the peripheral sympathetic nervous system driven by the dopamine beta-hydroxylase promoter. Loss of one copy of either arid1aa or arid1ab dramatically accelerated the onset and increased the penetrance of MYCN-induced neuroblastoma. Loss of additional copies of arid1aa or arid1ab accelerated the tumor onset even futher, with the most rapid onset in compound heterosygotes of both genes. The compound heterosygotes showed increased fraction of sympathoadrenal cells in active cell cycle compared to the MYCN transgenic fish with wild type arid1a allales. Our long-term goal is to use the zebrafish model to elucidate the mechanisms underlying the highly dose-dependent tumor suppressor role of this component of the BAF chromatin remodeling complex in neuroblastoma, as a first step toward designing targeted therapies synthetic lethal with reduced expression levels of ARID1A. Citation Format: Hui Shi, Ting Tao, Cigall Kadoch, Thomas Look. Loss of function of Arid1a synergizes with MYCN in neuroblastoma pathogenesis [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 802. doi:10.1158/1538-7445.AM2017-802
Frequent programmed death-ligand 1 expression in gastric cancer associated with Epstein-Barr virus or microsatellite instability: Implications for predictive biomarker development.
Authors: Changqing Ma, Krishna Patel, Fyza Y Shaikh, Bing Ren, Aatur D. Singhi, Weijing Sun
Journal: Journal of Clinical Oncology (2016)

e15579 Background: Immune checkpoint blockade of the programmed death-ligand 1 (PD-L1) pathway has emerged as a novel therapeutic approach for cancer. Therefore development of predictive biomarkers, such as PD-L1 expression by immunohistochemistry, may help stratifying patients. However, while PD-L1 expression can be seen in a subset of gastric cancers, it is unclear if it correlates with molecular subtypes, which may be potential confounding factors for patient stratification. Methods: Forty-four resected gastric cancer cases were collected and classified as Epstein-Barr virus positive (EBV+, N = 7), microsatellite unstable (MSI, N = 16), or microsatellite stable tumors without EBV (EBV-/MSS, N = 21). Positive PD-L1 expression was defined as membranous staining in either tumor cells or tumor immune infiltrates. T-cells in immune infiltrates at the tumor invasive front were characterized. Results: Positive PD-L1 expression was seen in 32 (72%) cases. Compared with EBV-/MSS tumors, significantly higher proportions of EBV+ or MSI tumors were positive for PD-L1 (11/21, 53%; 7/7, 100%; 14/16, 87%, respectively; P = 0.013). EBV+ or MSI tumors also had significantly more CD8 T-cells at invasive front than did EBV-/MSS tumors (P < 0.001). PD-L1 expression did not correlation with depth of invasion (P= 0.534) or positive lymph node metastasis (P = 0.2879). Conclusions: Positive PD-L1 expression was predominantly seen in MSI and EBV+ gastric cancers and associated with increased CD8 T-lymphocytes in tumor immune infiltrates. EBV and MSI status should be further investigated for predicting response to PD-1/PD-L1 blockade. Furthermore, since PD-L1 expression is often seen in EBV+ or MSI tumors, clinical application of immune checkpoint inhibitors may need to focus on these selected populations.
Abstract 3493: LncRNA as potential target in drug-resistant melanomas
Authors: Rosaura Esteve-Puig, Martina Sanlorenzo, Igor Vujic, Kevin Lai, Marin Vujic, Dallas Mould, Kevin Lin, Juan Oses-Prieto, Shreya Chand, Christian Posch, Alma Burlingame, Susana Ortiz-Urda
Journal: Cancer Research (2017)

Abstract Melanoma is the most common lethal form of skin cancer. Activating mutations in BRAF and RAS oncogenes account for over 80% of all melanomas and hyper-activate the MAPK cascade. Despite major advances in targeted melanoma therapies over the past decade, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are a new class of genes that do not encode proteins, which have been characterized as epigenetic regulatory molecules. LncRNAs have emerged as important players in cancer, potential predictors of therapeutic responses and targets for new treatments; however, their functions and precise molecular mechanisms remains largely unexplored. Our study aims to find novel potential targets involved in the acquisition of resistance to MAPK inhibitors. We identified an intergenic lncRNA (lincRNA) highly differentially expressed in drug-resistant melanoma samples, called MAPK Inhibitor Resistance Associated Transcript (MIRAT). We determined that MIRAT is localized mainly in the cytoplasm and plays a role in modulating the signal transduction pathways without regulating the genomic neighborhood. We discovered that MIRAT is upregulated in early drug tolerance to MAPK inhibition. Mechanistically, the gene overexpression and silencing of MIRAT, as well as preliminary RNA-protein interaction results, showed that it modulates the MAPK signal transduction pathway by binding to a downstream target of MEK. Collectively, these results highlight the relevance of cytoplasmic lincRNA’s and their role in oncogenic signaling pathways, and further suggest that lncRNAs and their protein-binding partners may serve as novel potential targets for overcoming drug resistance in melanoma. Note: This abstract was not presented at the meeting. Citation Format: Rosaura Esteve-Puig, Martina Sanlorenzo, Igor Vujic, Kevin Lai, Marin Vujic, Dallas Mould, Kevin Lin, Juan Oses-Prieto, Shreya Chand, Christian Posch, Alma Burlingame, Susana Ortiz-Urda. LncRNA as potential target in drug-resistant melanomas [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 3493. doi:10.1158/1538-7445.AM2017-3493
Abstract 4007: Differential macrophage programming is associated with the aggressiveness of gliomas
Authors: Nai-Wei Yao, Fang Liao, Chen Chang, Joanne Jeou-Yuan Chen
Journal: Cancer Research (2017)

Abstract Tumor-associated macrophages (TAMs), a major component of immune cells in the tumor microenvironment, have been shown to be associated with enhanced malignancy of gliomas. The polarization of macrophages toward a pro-inflammatory phenotype M1 or an anti-inflammatory phenotype M2 governed by niche factors in the tumor microenvironment may dictate the malignant outcome of gliomas. In this study, we examined the effects of differential programming of TAMs on the development of C6 gliomas in different host microenvironment using SD and Wistar rats. Using multi-parametric MRI measurements, we show that C6 cells implanted into SD rats developed larger tumors as compared to those in Wistar rats (p = 0.0199), which was accompanied with a shorter survival of SD rats (p = 1.06×10-9). The increased tumor growth in SD rats was associated with increased angiogenesis and higher levels of VEGF and VEGFR2 expression. We also observed a significantly increased ratio of M2/M1 in the tumors of SD rats while a decreased ratio of M2/M1 in those of Wistar rats, suggesting that the milieu of C6 gliomas in SD rats favors for the polarization of macrophages toward the pro-tumorigenic M2 phenotype. Most importantly, Induction of M1 polarization by IFNγ treatment greatly reduced tumor burden in SD rats, and induction of M2 polarization by IL-4/IL-10 treatment or blockade of M1 polarization by anti-IL12 treatment significantly promoted tumor growth in Wistar rats. These results demonstrate an important role of TAMs in glioma pathogenesis and the crucial role of microenvironment in dictating the polarization of TAMs into M1 or M2 phenotypes. We conclude that macrophage programming plays an important role in glioma development and that targeting glioma-associated macrophages may serve as a promising therapeutic approach. Citation Format: Nai-Wei Yao, Fang Liao, Chen Chang, Joanne Jeou-Yuan Chen. Differential macrophage programming is associated with the aggressiveness of gliomas [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 4007. doi:10.1158/1538-7445.AM2017-4007