bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 850: Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models
Authors: Devarakonda Vaishnavi , Williams LaTerrica , Seker Sinem , Lei Jonathan T. , Singh Purba , Han Airi , Anurag Meenakshi , Holloway Kimberly R. , Welm Alana L. , Ellis Matthew J. , Kavuri Shyam M. 
Published: August 2019

Abstract
Targeting HER2 is one of the greatest successes in oncology, and has resulted in the generation of a wide array of HER2-targeting agents. Our genomic approaches are revealing other mechanisms of HER2 activation, such as our discovery of activating HER2 mutations in different cancer types. From initial breast cancer and SUMMIT trial data, the pan-HER drug neratinib as monotherapy showed initial clinical response in ER+ breast cancer, but with frequent early relapse. This study investigates the preclinical efficacy of anti HER2 agents alone or in combination with endocrine therapy agents or in combination with CDK4/6 inhibitors using ER+/HER2 mutant cell lines and ex vivo HER2 mutant patient derived xenograft (PDX) model. ER+ breast cancer cell lines (T47D and MCF7) stably expressing HER2V777L, and ER+/HER2 mutant PDX model (HER2G778_P780 dup) were used to examine HER2 signaling. We found that MCF7/T47D cells expressing HER2V777L and HER2G778_P780 dup PDX tumors showed strongly activated autophosphorylation of HER2 and increased expression of CDK4, CDK6, phospho-Rb, and cyclin D1 as compared to MCF7/T47D cells expressing HER2WT or ER+/non-HER2mut PDX model, suggesting that HER2 mutations preferentially depend on CDK4/6 signaling for cell growth. Additionally, we showed that activating MCF7 HER2V777L cause resistance to endocrine therapy treatment (fulvestrant IC50 &gt;5μM). Further, we show that neratinib alone is effective at higher concentrations (IC50 &lt; 2μM) in MCF7/HER2V777L cells. Next we showed that abemaciclib alone exhibited moderate activity against MCF7 HER2V777L cells (IC50 &lt; 0.4μM) and additional activity in combination with neratinib (IC50 &lt; 0.06μM) was seen. Moreover, ex vivo HER2G778_P780 dup cells are relatively resistant to fulvestrant alone (IC50 &lt; 0.2μM), neratinib alone (IC50 &lt; 0.006μM), abemaciclib alone (IC50 &lt; 0.04μM), and neratinib in combination with abemaciclib (IC50 &lt; 0.005μM), suggesting that patients harboring ER+/HER2-mutant tumors may benefit from neratinib in combination with abemaciclib. Therefore, we propose that simultaneous targeting of both HER2 and the CDK4/6 axis is required for maximal inhibition of ER+ breast cancers harboring HER2 activating mutations.
Citation Format: Vaishnavi Devarakonda, LaTerrica Williams, Sinem Seker, Jonathan T. Lei, Purba Singh, Airi Han, Meenakshi Anurag, Kimberly R. Holloway, Alana L. Welm, Matthew J. Ellis, Shyam M. Kavuri. Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 850.
Abstract 865: Isolation of circulating tumors cells from genetically engineered mouse models of lung adenocarcinoma
Authors: Burton Liza J. , Koo Junghui , Tucker-Burden Carol , Zhou Wei , Gilbert-Ross Melissa , Huang Chunzi , Sica Gabriel , Marcus Adam 
Published: August 2019

Abstract
The major cause of cancer-associated mortality is tumor metastasis, but our understanding of this process is far from complete. During successful dissemination, tumor cells invade the surrounding tissue of the primary tumor, intravasate into blood and lymphatic vessels, translocate to distant tissues, extravasate, adapt to the new microenvironment, and eventually seed, proliferate, and colonize to form metastases. Because dissemination mostly occurs through the blood, circulating tumor cells (CTCs) that have been shed into the vasculature and may be on their way to potential metastatic sites are of obvious interest (1). KRAS mutations are the most frequent oncogenic drivers of non-small cell lung cancer and when associated with co-mutations lead to a decrease in overall survival. We have previously established a lenti-Cre-induced Kras and Lkb1 mutant and Kras and p53 mutant genetically engineered mouse modes (KLLenti) and (KPLenti) that develop 100% lung adenocarcinoma to conduct the first study to isolate and maintain primary, CTC and metastatic cells that are KLLenti or KPLenti. We are able to isolate TTF-1+ and pan-cytokeratin+ CTCs from the KLlenti and KPlenti mice and validated their mutational status by genotyping, western blot, and immunofluorescence. Moreover, lkb1-mutant or p53-mutant primary tumor cells have different 3-D invasive properties and patterns, as well as the respective CTCs and metastatic cells when compared across different genetic sub-types. To further study gene expression patterns between primary, CTC, and metastatic sites RNAseq will be employed to identify pathways that drive metastasis within the genetic sub-types.
Citation Format: Liza J. Burton, Junghui Koo, Carol Tucker-Burden, Wei Zhou, Melissa Gilbert-Ross, Chunzi Huang, Gabriel Sica, Adam Marcus. Isolation of circulating tumors cells from genetically engineered mouse models of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 865.
Abstract 868: Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network
Authors: XU Liangliang , WU Feng , CHEUNG Otto K.W. , SZETO Lemuel L.M. , MOK Myth T.S. , Yip Kevin Y.L. , To Ka F. , CHENG Alfred S.L. 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Parallel with the growing epidemics of obesity and diabetes, non-alcoholic fatty liver disease (NAFLD) has become the predominant cause leading to HCC in a dysregulated metabolic background. Recent HCC genomics studies present only a paucity of recurrent gene mutations, which lead to a sparkling interest in the epigenetic regulation of hepatic carcinogenesis. Chromatin modifications convert the metabolic insults from NAFLD to transcriptional program that contributes to HCC development. Super-enhancers (SEs) are subclass of regulatory elements with unusually strong enrichment for the binding of transcriptional coactivators to fulfill cell identity. Currently, it has been proposed that dysregulation of SEs underlies the development of diseases including cancers, but the role of SEs in NAFLD-associated HCC is still unknown.
In order to investigate the alterations of histone modifications in NAFLD-associated HCC development, nanoscale chromatin immunoprecipitation sequencing of multiple histone marks were performed. By integrating multiple epigenomic profiles from primary NAFLD-associated HCCs and matched non-tumor tissues, we identified recurrent SEs enriched that contribute to fatty liver, lipid metabolism and metabolic syndrome. Interestingly, we observed significant enrichment of recurrent active SEs in a number of target genes. Notably, through CRISPR/Cas9-induced knockout liver cell lines, we showed that deletion of two distinct SE regions significantly reduced the expression of a candidate target gene and attenuated the tumorigenic potential of HCC cells. In summary, our results show that the dysregulation of SEs contributes to human hepatic carcinogenesis, thus representing novel therapeutic targets for NAFLD-associated HCCs.
Citation Format: Liangliang XU, Feng WU, Otto K.W. CHEUNG, Lemuel L.M. SZETO, Myth T.S. MOK, Kevin Y.L. Yip, Ka F. To, Alfred S.L. CHENG. Epigenomic profiling of primary hepatocellular carcinoma reveals super-enhancer-associated chromatin regulator network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 868.
Abstract 880: Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin
Authors: Vučetić Milica , Daher Boutaina , Durivault Jerome , Parks Scott K. , Pouyssegur Jacques 
Published: August 2019

Abstract
The lethality of pancreatic ductal adenocarcinomas (PDAC) calls for improved therapeutic strategies. Chemoresistance remains a primary challenge in PDAC treatment, and exploiting oxidative stress might offer novel therapeutic clues. In this regard, we explored the cystine/glutamate exchanger (SLC7A11/xCT) that contributes to the maintenance of the intracellular glutathione (GSH). We deleted xCT via CRISPR-Cas9 in two PDAC cell lines (MiaPaCa-2 and Capan-2) and cultivated xCT-KO clones in the presence of N-acetylcysteine (NAC). In both cell lines, xCT-deletion abolished &gt;90% of 14C-cystine uptake and induced a rapid depletion of GSH following NAC removal. Although several cystine/cysteine transporters have been identified in human cells, our finding demonstrates that, in vitro, xCT is the major actor for GSH synthesis. Consequently, both xCT-KO cell lines exhibited amino-acid stress with ATF4 and GCN2 kinase activation, mTORC1 inhibition, and proliferation arrest followed by ferroptotic cell death. Importantly, tumor growth was also abolished in both KO cell lines indicating the key role of xCT in cellular cysteine availability in vivo. Moreover, the rapid depletion of intracellular GSH in xCT-KO cells led to accumulation of lipid peroxides and cell swelling, both being prevented by vitamin E or iron chelation, two hallmarks of cell death by ferroptosis. Finally, in vitro pharmacological inhibition of xCT by erastin (1μM) phenocopied xCT-KO and potentiated the cytotoxic effects of both gemcitabine and cisplatin in these PDAC cell lines. In conclusion, our findings strongly support the concept that xCT inhibition, by its dual induction of nutritional and oxidative cellular stresses, has the great potential of a successful anticancer strategy.
Note: This abstract was not presented at the meeting.
Citation Format: Milica Vučetić, Boutaina Daher, Jerome Durivault, Scott K. Parks, Jacques Pouyssegur. Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 880.
Abstract 892: Alterations of vitamin B1 homeostasis following oxidative stress in breast cancer and impact of supplementation on cellular redox homeostasis
Authors: Jonus Hunter C. , Ray Ashley E. , Zastre Jason A. 
Published: August 2019

Abstract
Vitamin B1, or thiamine, has been demonstrated to enhance the development and growth of breast tumors in vivo. In addition, alterations in the expression of critical thiamine homeostasis genes have been extensively described in pre-clinical models of breast cancer as well as in clinical breast tumor tissue. Despite the effort that has been placed on delineating alterations to thiamine homeostasis that occur during breast cancer, there remains little evidence demonstrating a molecular advantage for supplemental thiamine in breast cancer cells. Our previous work in colorectal cancer suggests that the proliferative benefits of thiamine may be related to the maintenance of oxidative stress. This appears to be facilitated through the adaptive regulation of the thiamine activating enzyme thiamine pyrophosphokinase-1 (TPK1) for thiamine pyrophosphate production. Here, using MCF7 cells as a model of breast cancer, we also identified a relationship between thiamine homeostasis and oxidative stress. Similar to previous findings in colorectal cancer, Western blot analysis revealed that TPK1 expression was up-regulated in response to enhanced levels of ROS induced by hypoxia and chemotherapeutic treatment. TPK1 knockdown mediated by shRNA reduced the proliferation of MCF7 cells, while the presence of supplemental thiamine promoted proliferation as determined by cell counting. The effect of supplemental thiamine on MCF7 proliferation corresponded with a direct impact to the antioxidant status of tumor cells measured by reduced nuclear accumulation of the transcription factor nuclear factor- erythroid 2-related factor 2 by Western blot analysis. Molecular probes detecting intracellular ROS revealed that supplemental thiamine did not reduce the basal level of ROS in MCF7 cells. However, enhanced thiamine reduced intracellular superoxide levels following stimulation with the electron transport chain inhibitor Antimycin A. These findings support that during supplemental thiamine conditions thiamine homeostasis may be exploited in breast cancer for a redox advantage contributing to tumor progression.
Citation Format: Hunter C. Jonus, Ashley E. Ray, Jason A. Zastre. Alterations of vitamin B1 homeostasis following oxidative stress in breast cancer and impact of supplementation on cellular redox homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 892.
Abstract 893: The cofilin-TEAD1-p27Kip1 pathway ablates cell senescence
Authors: Lee Yi-Jang , Tsai Cheng-Han , Chang Chun-Yuan 
Published: August 2019

Abstract
Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remain to be addressed. Here we demonstrated, after a survey of various actin-binding proteins, that up-regulation of cofilin-1 was essential for the reduced rate of actin depolymerization in senescent cells, as well as their morphological enlargement . Additionally, the up-regulated cofilin-1 mainly existed in the serine-3 phosphorylated form according to the 2D gel immunoblotting assay. Accumulation of cofilin-1 in senescent cells depended on the post-translational mechanism, as the ubiquitin-proteasomal degradation of cofilin-1 was reduced without any change in mRNA level. Up-regulation of cofilin-1 was not only found in replicative senescence but also in oxidative stress- and K-Ras oncogene-induced senescence. Over-expression of wild-type cofilin-1 and constitutively phosphorylated cofilin-1 promoted cell senescence with increased cell size. Additionally, senescent phenotypes were reduced by knockdown of total cofilin-1. The senescence induced by over-expression of cofilin-1 was dependent on p27Kip1 but not p53 and p16INK4 expression. Knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that over-expression of cofilin-1 induced expression of p27Kip1 through transcriptional suppression of the TEAD1 transcription factor. The TEAD1 transcription factor played a transrepressive role on the p27Kip1 gene promoter as determined by the promoter deletion reporter gene assay. Interestingly, TEAD1 down-regulation was accompanied by up-regulation of cofilin-1 in senescence. Knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and cell senescence, respectively. Furthermore, senescence induced by the over-expression of cofilin-1 could be alleviated by ectopic expression of TEAD1. Taken together, current data suggest that cofilin-1/TEAD1/p27Kip1 signaling is involved in senescence-related morphological change and growth arrest.
Keywords: Cofilin-1, TEAD1, p27Kip1, morphology, growth arrest, senescence
Citation Format: Yi-Jang Lee, Cheng-Han Tsai, Chun-Yuan Chang. The cofilin-TEAD1-p27Kip1 pathway ablates cell senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 893.
Abstract 894: A Self-Immobilizing NIR Probe for in vivoImaging of Chemotherapy Induced Senescence
Authors: Ma Xiaowei , Liu Jun , Wang Ying , Cui Chao , Deenik Philip 
Published: August 2019

Abstract
Post-treatment relapse and distant metastasis are significant causes of mortality by cancers. Previous research has demonstrated that cancer treatments, such as chemotherapy, can sometimes stimulate tumor spread. This phenomenon is associated with an essential process that some cells are resistant to apoptosis by entering premature senescence after therapy. Thus, chemotherapy-induced cellular senescence may play a critical role in cancer recurrence and metastasis. To monitor the cellular senescence induced by chemotherapy, we developed a self-immobilizing near infrared (NIR) probe (4-152) that can be activated by senescence-associated beta-galactosidase (β-gal) and get immobilized at site of activation, allowing the monitoring of chemotherapy-induced senescence in vivo. We first verified our approach in vitro, when cervical cancer cells (HeLa) were treated with camptothecin (CPT), followed by fluorescence imaging with 4-152. The results demonstrated that our designed probe exhibited a dramatic NIR fluorescent response in cells receiving CPT treatment. The fluorescent western blot showed that the probe could be activated by β-gal and attached to the enzyme. The confocal microscopy imaging and flow cytometry results further demonstrated the 4-152 could accumulate in the CPT-induced senescent cancer cells. We then investigated the in vivo imaging ability of the probe for senescence detection in tumor xenografts treated with CPT. After treatment with CPT or saline (as control), 4-152 was administrated to the mice by tail vein injection. NIR imaging was then performed on the IVIS Spectrum in vivo imaging system. The imaging showed that the 4-152 could quickly distribute to the tumor and accumulated for over 24 hours. The fluorescence intensity of the CPT treated tumors was significantly higher than the untreatment tumors. After imaging, tumors and major organs were resected for ex vivo imaging. The fluorescent intensity of tumors showed 6.27-fold higher than liver. Ex vivo immunofluorescence staining and X-gal staining further confirmed the correlation of probe 4-150 and senescence cells.In conclusion, we have developed an activatable self-immobilizing NIR probe for the monitoring of chemotherapy-induced cellular senescence in vivo. This probe may be used for the treatment effect monitoring and therapeutic regimen optimization in the future.
Reference1. Ebos JM. Prodding the beast: assessing the impact of treatment-induced metastasis. Cancer Res 2015; 75: 3427-3435.
Citation Format: Xiaowei Ma, Jun Liu, Ying Wang, Chao Cui, Philip Deenik. A Self-Immobilizing NIR Probe for in vivoImaging of Chemotherapy Induced Senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 894.
Abstract 897: Lipid metabolism is involved in mitotic slippage-induced SASP upon treatment with anti-mitotic drugs
Authors: Crasta Karen C. , Wong Alex , Lim Bryan 
Published: August 2019

Abstract
Aberrant lipid accumulation is a hallmark of cancer. However, there is little known regarding mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug-treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets. Interestingly, we found that TOFA, an inhibitor that targets acetyl-CoA carboxylase (ACC) and blocks lipid accumulation enhanced survival of antimitotic-treated cells. Our work previously revealed that cells that survive slippage become senescent and confer pro-tumourigenic effects through non-cell-autonomous effects. Modulating lipid biosynthesis in cells post-slippage by TOFA amplified their inflammatory secretion profiles and accelerated development of tumourigenic behavior. In contrast to TOFA, inhibition of lipid accumulation by C75, a drug targeting fatty acid synthase, significantly reduced the production of pro-tumourigenic factors. This suggests that discrete lipid biosynthesis pathways could contribute differentially to the regulation of pro-tumourigenic inflammation.
Note: This abstract was not presented at the meeting.
Citation Format: Karen C. Crasta, Alex Wong, Bryan Lim. Lipid metabolism is involved in mitotic slippage-induced SASP upon treatment with anti-mitotic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 897.
Abstract 911: UCSC Xena for cancer genomics visualization and interpretation
Authors: Goldman Mary , Craft Brian , Zhu Jingchun , Haussler David 
Published: August 2019

Abstract
UCSC Xena (http://xena.ucsc.edu/) is a web-based visual integration and exploration tool for multi-omic data and associated clinical and phenotypic annotations. Our unique Visual Spreadsheet shows multiple data types side-by-side enabling discovery of correlations across and within genes and genomic regions. We offer dynamic Kaplan-Meier survival analysis, powerful filtering and subgrouping, charts, statistical analyses, genomic signatures, comparative transcript views, and bookmarks. We link out to the UCSC Genome Browser, giving users additional genomic context for any gene or coordinate, as well as MuPIT/CRAVAT and TumorMap, to give users complementary views of the same data.
Xena showcases seminal cancer genomics datasets from TCGA, the Pan-Cancer Atlas, PCAWG, GDC, GTEx, ICGC, and more; a total of more than 1500 datasets across 50 cancer types. We support virtually any type of functional genomics data. In addition to the commonly available SNPs, INDELs, copy number variation, and gene expression datasets, we support DNA methylation, exon-, transcript-, miRNA-, lncRNA-expression and structural variants. We also support clinical data such as phenotypes, subtype classifications and biomarkers. A recompute of TCGA, TARGET and GTEx datasets through the same bioinformatics pipeline allows users to compare expression between tumor and normal tissues. All of our data is available for download via our python API or through AWS S3 buckets.
A researcher can host their own data securely via private hubs running on a laptop or behind a firewall, with visual and analytical integration occurring only within the Xena Browser. The lightweight Xena Data Hubs are straightforward to install on Windows, Mac and Linux. Loading data is easy using either our application or command line interface.
Our newest features include:
* a new, more intuitive wizard to load your data into a local Hub
* URL bookmarks to save interactive views for yourself or to share with collaborators
* genomic signatures: dynamically build as a weighted sum over a set of genes
* hierarchically cluster a list of genes, regulons or probes
* upper vs lower quartile in a KM plot
Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler. UCSC Xena for cancer genomics visualization and interpretation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 911.