tbuckley/cabot-search huggingface dataset:
Abstract 3557: miR-155 positively regulates glucose metabolism via PI3K p85&amp;lt;alpha&amp;gt;-FOXO3a-cMYC axis in breast cancer
Authors: Sinae Kim, Eunji Lee, Suhwan Chang
Journal: Cancer Research (2017)

Abstract Breast cancer is the most common cancer for women worldwide. Although the oncogenic roles of miR-155 in cancer have been reported, the metabolic function of miR-155 in breast cancer has not been fully elucidated. In this study, we have investigated how the energy metabolic shift occurs after a genetic inactivation or knockdown of miR-155. To this end, we performed metabolic profiling of the miR-155ko/ko or miR-155+/ko primary cancer cells, obtained from mouse breast cancer model. We found, in the absence of miR-155, less glucose uptake and glycolysis in tumor cells. Mechanistically, we revealed PIK3R1(Phosphoinositide-3-Kinase, Regulatory Subunit1, p85&amp;lt;alpha&amp;gt;) and FOXO3a (Forkhead transcription factor of the O class 3a) are major targets that trigger the metabolic shift. Furthermore, we showed cMYC level was consequently decreased in the absence of miR-155 that results in the down-regulation of proteins playing in glucose uptake and Glycolysis. This finding is further confirmed in mouse allograft model. Finally, we show the miR-155 expression is positively correlates with either energy metabolite levels or standardized uptake values (SUV) of fluoro-deoxy glucose (FDG)-PET Images in triple negative breast tumors. Taken together, our study demonstrates a novel mechanism by which the miR-155 controls energy metabolism in breast cancer, through PI3K p85&amp;lt;alpha&amp;gt;-FOXO3a-cMYC axis. Citation Format: Sinae Kim, Eunji Lee, Suhwan Chang. miR-155 positively regulates glucose metabolism via PI3K p85&amp;lt;alpha&amp;gt;-FOXO3a-cMYC axis in 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 3557. doi:10.1158/1538-7445.AM2017-3557
Abstract 5251: Amentoflavone regulate Hh-Gli1 signaling pathway and inhibits tumorsphere formation in U251 glioblastoma cells
Authors: Jing Chen, Cheng Bao, Hong Jin Lee
Journal: Cancer Research (2017)

Abstract Cancer stem cells represent a rare population of cells with a self-renewal capacity, and potentially are involved in tumor progression, tumor relapse, and resistance to cancer chemotherapies. In this study, we investigated the effect of an active ingredient of chamaecyaris obtuse, amentoflavone, on stemness of U251 glioblastoma cells. We first found that amentoflavone from 1 to10 μM suppressed tumorsphere formation and inhibited the expression of glioblastoma stem cell markers CD133 and ALDH1 in a dose dependent manner. In addition, amentoflavone significantly reduced the expression of Nanog involved in cancer stem cells maintenance in tumorsphere culture. As an upstream modulator, Hedgehog (Hh) signaling mediator Gli1 was confirmed to be highly expressed in tumorsphere culture where the suppression of Gli1 by the treatment of Hh inhibitors (vismodegib and GANT 61) or Gli1-siRNA significantly suppressed the expression of stem cell markers CD133, ALDH1, and Nanog as well as tumorsphere formation in U251 glioblastoma cells. These results indicate that Hh signaling plays an important role in maintaining tumorsphere and stemness of U251 glioblastoma cells. Next, we also found that the treatment of amentoflavone from 1 to10 μM inhibited the expression of Gli1 and its downstream mediator Nanog in tumorsphere culture of U251 glioblastoma cells. Taken together, amentoflavone significantly suppressed Hh/Gli1 signaling which results in inhibition of stemness of U251 glioblastoma cells. Citation Format: Jing Chen, Cheng Bao, Hong Jin Lee. Amentoflavone regulate Hh-Gli1 signaling pathway and inhibits tumorsphere formation in U251 glioblastoma cells [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 5251. doi:10.1158/1538-7445.AM2017-5251
Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis
Authors: Rebecca F Baggaley, Michael A Irvine, Werner Leber, Valentina Cambiano, Jose Figueroa, Heather McMullen, Jane Anderson, Andreia C Santos, Fern Terris-Prestholt, Alec Miners, T Déirdre Hollingsworth, Chris J Griffiths
Journal: The Lancet HIV (2017)

Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care.We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment.Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years.Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted.NHS City and Hackney, UK Department of Health, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care.
Abstract LB-067: Design, synthesis and biological evaluation of novel selenocyanide histone deacetylase inhibitor as anti-triple negative breast cancer agents
Authors: Chu Tang, Yang Du, Jie Tian
Journal: Cancer Research (2017)

Abstract Approximate 70-80% of breast cancers are estrogen receptor positive (ER+), and the ERα plays essential role in breast cancer growth. Therefore, many ERα ligands have been developed for hormone drugs, such as tamoxifen, which is the first line drug for the treatment of ER(+) breast cancer. Unfortunately, endocrine therapy is ineffective for triple-negative breast cancer (TNBC), which lacks of expression of ER, PR and HER-2, representing about 20% of breast cancers. Current treatment option for TNBC is still limited to cytotoxic chemotherapy, and histone deacetylase inhibitor (HDACi) was used as novel therapeutic strategy for TNBC. HDACi can induce functional ERα re-expression and re-sensitize cells of TNBC to estradiol activator and tamoxifen antagonist. More than ten clinical trials of HDACi are underway for the treatment of TNBC, and most of HDAC inhibitors have the hydroxamic acid moiety, a typical zinc-binding group. However, these inhibitors do not show significant anticancer effects on TNBC compared to SAHA, which is the first HDACi approved by FDA. Hydroxamic acids usually have pharmacokinetic and metabolic problems, and also SAHA shows considerable toxicity to healthy cells. Therefore, much effort has been undertaken to develop an “ideal HDACi”, more effective and less toxic. We recently found that zinc-binding group of HDACi is selenocyanide (named as SelA), which shows strong anti-HDAC1, HDAC6 and HDAC8. These three isoforms have been found to be critical for the invasion and migration of both ER(+) breast cancer and TNBC activities, with a nanomolar range of IC50, and demonstrate high selectivity for HDAC6; moreover, SelA also displays significant anti-proliferative effect on both ER(+) breast cancer and TNBC both in vitro and in vivo. In summary, selenocyanide compound represents a novel HDACi for the treatment of TNBC, and the structure-activity relation is pursuing. Citation Format: Chu Tang, Yang Du, Jie Tian. Design, synthesis and biological evaluation of novel selenocyanide histone deacetylase inhibitor as anti-triple negative breast cancer 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 LB-067. doi:10.1158/1538-7445.AM2017-LB-067
Abstract 2472: Defining the role of the XAB2 complex during homologous recombination
Authors: David O. Onyango, Jeremy Stark
Journal: Cancer Research (2017)

Abstract Several factors associated with RNA processing are important for homologous recombination (HR), but the mechanistic links between these processes remain poorly understood. To this end, we have examined the function of the tetratricopeptide repeat factor XAB2 in HR, since this factor has a conserved function in RNA processing. We have found that XAB2 is important for chromosomal double strand break (DSB) repair via two pathways of HR that require end resection as an intermediate step, end resection of camptothecin (Cpt) induced DNA damage, and RAD51 recruitment to ionizing radiation induced foci (IRIF). Furthermore, XAB2 mediates CtIP hyperphosphorylation induced by Cpt and BRCA1 IRIF, as well as histone acetylation events linked to HR proficiency. The capacity for XAB2 to promote HR correlates with its ability to form a complex with ISY1 and PRP19, which show a similar influence as XAB2 on HR. Our recent efforts include examining other members of the XAB2 complex, as well as the transcription unit aberrations caused by loss of this complex, which may contribute to the defects in HR. Citation Format: David O. Onyango, Jeremy Stark. Defining the role of the XAB2 complex during homologous recombination [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 2472. doi:10.1158/1538-7445.AM2017-2472
Abstract 1998: Transcriptome analysis of hypoxic head and neck cancer cells uncovers intron retention in EIF2B5 as a mechanism to reduce protein synthesis
Authors: Lauren K. Brady, Hejia Wang, Caleb Radens, Milan Radovich, Amit Maity, Cristina Ivan, Mircea Ivan, Yoseph Barash, Constantinos Koumenis
Journal: Cancer Research (2017)

Abstract Hypoxia is a key feature of solid tumors that contributes to resistance to therapy and reduced overall survival. Cellular adaptation to the hypoxic tumor microenvironment involves attenuation of energy-consuming processes such as macromolecular synthesis. We have identified RNA processing as another major process which is globally downregulated under hypoxic stress. By sequencing RNA of normoxic and hypoxic head and neck cancer cells, we observed widespread repression of genes that regulate RNA splicing and processing. As a result, we observed over 1,000 changes in relative mRNA isoform expression, including a significant increase in hypoxia-induced intron retention in nearly 100 genes. Genes observed to undergo intron retention in hypoxia included major regulators of RNA processing and protein synthesis, such as the translation initiation factor EIF2B5. Surprisingly, hypoxia-induced intron retention in EIF2B5 creates a premature termination codon, which results in a truncated protein isoform of eIF2Bϵ. We provide evidence that this isoform acts in opposition to the full-length protein to inhibit translation under stringent hypoxic conditions. Moreover, this intron is expressed in solid cancers known to contain hypoxic fractions and is overexpressed in head and neck cancer in a stage-dependent manner compared to normal tissue. To investigate how this intron is retained, we are examining the role of hypoxia-mediated changes in phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Our data suggest that increased phosphorylation of the CTD may lead to transcriptional pausing and subsequent retention of intron 12 in EIF2B5. Furthermore, distinct sequence features at this locus, such as a weak splice site at the intron12:exon13 junction, may explain how this intron is selectively retained in hypoxic cells. These results implicate mRNA splicing as a key mechanism to induce alternate transcripts and subsequent protein isoforms under hypoxia that influence cellular adaptation to stress. Citation Format: Lauren K. Brady, Hejia Wang, Caleb Radens, Milan Radovich, Amit Maity, Cristina Ivan, Mircea Ivan, Yoseph Barash, Constantinos Koumenis. Transcriptome analysis of hypoxic head and neck cancer cells uncovers intron retention in EIF2B5 as a mechanism to reduce protein synthesis [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 1998. doi:10.1158/1538-7445.AM2017-1998
Abstract 4096: Transglutaminase 2(TG2) induces the intrinsic EGFR-TKI resistance in EGFR-mutant NSCLC
Authors: Junyoung Choi, Hannah Yang, Sang-We Kim, Kyung Hae Jung, Kang-Seo Park, Dae Ho Lee
Journal: Cancer Research (2017)

Abstract The non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib. Unfortunately, even though the intrinsic EGFR-TKI resistant patients harboring the EGFR-sensitizing mutation, a part of those are still resistant to EGFR-TKI. And, it has been reported that both PTEN loss and NF-kB activation contribute to intrinsic EGFR-TKI resistance in EGFR-mutant lung cancer. Transglutaminse 2 (TG2) is post-translational modification enzyme and known to induce degradation of tumor suppressors including PTEN and IκB-α with peptide cross-linking activity. Because TG2 was known as a regulator of PTEN and IκB-α (NF-κB inhibitor) level in cytosol, we have explored if TG2 can be another key regulator to the intrinsic resistance of EGFR-TKI in the intrinsic EGFR-TKI resistant NSCLC cell. In NSCLC with EGFR-sensitive mutations, we first found that higher TG2 expression level and lower PTEN and IκB-α expression levels in the intrinsic EGFR-TKI resistant NSCLC compare with EGFR-TKI sensitive NSCLC. TG2 stably expressing EGFR-TKI sensitive NSCLC cells harboring EGFR mutations showed reduction of both PTEN and IκB-α and exhibited EGFR-TKI resistance. In reverse, TG2 stably downregulated H1650, intrinsic EGFR-TKI resistant NSCLC cell harboring EGFR sensitive mutation, restored EGFR-TKI sensitivity via PTEN and IκB-α restoration by TG2 loss. Xenograft study using TG2 overexpressed and downregulated NSCLC cells also verified our in vitro results. Therefore, we have demonstrated that TG2 elicits the intrinsic EGFR-TKI resistance via PTEN loss and activation of NF-κB pathway. These results suggest that TG2 may be a useful target for overcoming the intrinsic EGFR-TKI resistance of NSCLC harboring EGFR sensitive mutations. Citation Format: Junyoung Choi, Hannah Yang, Sang-We Kim, Kyung Hae Jung, Kang-Seo Park, Dae Ho Lee. Transglutaminase 2(TG2) induces the intrinsic EGFR-TKI resistance in EGFR-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 4096. doi:10.1158/1538-7445.AM2017-4096
Abstract 3562: A novel TGF-β signaling pathway promotes a slow growing phenotype of cancer cells in response to glutamine insufficiency
Authors: Dan He, Chengqian Yin, Shuo Qie, Shuyang Chen, Nianli Sang
Journal: Cancer Research (2017)

Abstract Glutamine is a critical nutrient for proliferating cells and most tumor cells. Glutamine addiction as one of the dramatic tumor cell adaptive metabolisms is characterized by increased glutaminolysis. To better understand how tumor cells respond to glutamine deficiency, we cultured Hep3B cells in glutamine free media supplemented with ammonia, and isolated survival clones (MM01). These clones are capable of perpetual survival in glutamine free media with ammonia, but assume a slow growing phenotype, which represents the model adapted to long-term glutamine insufficiency. Comparing MM01 and Hep3B by microarray-based genome-wide gene expression profiling, we identified functional activation of Smad2/3 in MM01 cells, suggesting that long-term glutamine insufficiency activates a TGF-β signaling pathway. We have validated that glutamine insufficiency triggers Samd2 phosphorylation, which in turn, stimulates the expression of p15INK4B, providing a link to the slow growing phenotype. To elucidate how glutamine insufficiency triggers TGF-β signaling, we examined the effects of glutamine insufficiency on the expression levels of TGF-β family ligands, and found that Inhibin-βE, a newly discovered inhibin subunit isoform in the TGF-β superfamily, is up-regulated at both mRNA and protein levels in MM01. Luciferase assays demonstrate that glutamine insufficiency enhances the activity of Inhibin-βE promoter. Furthermore, we show that overexpressing Inhibin-βE is sufficient to induce Smad2/3 activation and growth inhibition in Hep3B cells. Taken together, our data suggest that Inhibin-βE likely plays a crucial role in cell adaptation to metabolic stress, facilitating cancer cell survival by slowing down biosynthesis and proliferation. A better understanding of the novel Inhibin-βE-triggered TGF-β signaling pathway may provide potential new therapeutic targets for cancer treatment. Citation Format: Dan He, Chengqian Yin, Shuo Qie, Shuyang Chen, Nianli Sang. A novel TGF-β signaling pathway promotes a slow growing phenotype of cancer cells in response to glutamine insufficiency [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 3562. doi:10.1158/1538-7445.AM2017-3562
Abstract 2508: Profiling the metabolic effects of AGI-5198 treatment on IDH1-mutated gliomas
Authors: Victor Ruiz Rodado, Adrian Lita, Tyrone Dowdy, Mark R. Gilbert, Mioara Larion
Journal: Cancer Research (2017)

Abstract Background: AGI-5198 (a specific IDH1mut inhibitor) inhibits the formation of D-2-hydroxyglutarate (D-2HG) typically produced in millimolar quantities by the R132H mutation of isocitrate dehydrogenase I (IDH1). AGI-5198 was found to delay growth, to promote differentiation in cells and to decrease tumor volume in IDH1-mutant (IDH1mut) mice xenographs, and as a result, has been advanced to clinical trials in humans with IDH1mut glioblastomas. However, no metabolic study of this drug has been reported to date. Here, we investigated the metabolic changes induced by AGI-5198 treatment in order to determine if the drug restores the normal metabolic status once D-2HG concentration is decreased. Methods: We treated glioma cells carrying an IDH1 mutation with 10 μM AGI-5198 for 72 h. Metabolic changes were explored using an untargeted metabolomics approach. Cell viability analysis verified that the concentration of drug does not lead to significant cell death. NMR and MS-linked metabolomics together with in vivo cell imaging using RAMAN were used. Principal component analysis was employed to explore the differences in the metabolic profiles comparing treated and untreated glioma cells. Results and Conclusions: We confirmed that AGI5198 treatment reduced D-2HG levels in the cell lines investigated, validating previous reports. Moreover, we observed a decrease in phospholipid levels upon AGI-5198 treatment, which suggests a decreased proliferative potential for these cells; of particular importance for clinical application. Our preliminary analysis also suggests that metabolites involved in one carbon metabolism are altered upon AGI-5198 treatment. This pathway provides the methyl group for the DNA methylation by DNA methylases producing a hypermethylated phenotype. Our findings suggest that combining the AGI-5198 treatment with a DNA methylase inhibitor may improve outcomes in IDH1-mutated gliomas. Citation Format: Victor Ruiz Rodado, Adrian Lita, Tyrone Dowdy, Mark R. Gilbert, Mioara Larion. Profiling the metabolic effects of AGI-5198 treatment on IDH1-mutated 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 2508. doi:10.1158/1538-7445.AM2017-2508
Abstract 783: Cancer cell-derived extracellular vesicles stimulate tumor angiogenesis by delivering VEGF to endothelial cells
Authors: Song Yi Ko, Honami Naora
Journal: Cancer Research (2017)

Abstract Angiogenesis is essential for tumor growth and metastasis, and is orchestrated by a repertoire of growth factor signaling pathways that stimulate endothelial cell growth, migration and vessel formation. Recent studies have shown that angiogenesis can also be regulated by cell-derived extracellular vesicles. Exosomes are small endosomal-derived membrane vesicles that contain various biomolecules such as RNA and proteins, and are increasingly thought to play important roles in transferring informational cargo between cancer cells and stromal cells. In the majority of studies to date, the effects of cancer cell-derived exosomes have been attributed to their RNA cargo. In this study, we identified that exosomes derived from ovarian, colon and renal cancer cells contain abundant vascular endothelial growth factor (VEGF). Cancer cell-derived exosomes were found to activate the VEGF signaling pathway in endothelial cells and to stimulate endothelial cell migration and tube formation. Furthermore, our studies using inhibitors of VEGF signaling demonstrated that the stimulatory effects of cancer cell-derived exosomes on endothelial cells depend on the presence of VEGF in exosomes and are mediated via the VEGF signaling pathway. These findings indicate that cancer cell-derived exosomes promote tumor angiogenesis by delivering VEGF to endothelial cells. Citation Format: Song Yi Ko, Honami Naora. Cancer cell-derived extracellular vesicles stimulate tumor angiogenesis by delivering VEGF to endothelial cells [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 783. doi:10.1158/1538-7445.AM2017-783