bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B31: Establishment of a 5-fluorouracil-resistant esophageal squamous cell carcinoma cells with dihydropyrimidine dehydrogenase gene amplification
Authors: Kikuchi Osamu , Baba Kiichiro , Ohashi Shinya , Muto Manabu 
Published: May 2016

Abstract
5-Fluorouracil (5-FU) is the key drug for the treatment of esophageal squamous cell carcinoma (ESCC), however, resistance to 5-FU remains a critical limitation to the clinical use. To clarify the mechanisms of 5-FU resistance in ESCC, we have established a 5-FU-resistant ESCC cell line TE-5R from parental TE-5 cells, by treatment with the step-wise continuous increasing concentrations of 5-FU. The half maximal inhibitory concentration of 5-FU showed that TE-5R cells were 15.6-fold resistant to 5-FU in comparison with TE-5 cells. Intracellular 5-FU concentration was significantly lower in TE-5R cells than in TE-5 cells. TE-5R cells showed regional copy number amplification of chromosome 1p including the DPYD gene, as well as high mRNA and protein expressions of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU degradation, whereas copy number of the other 5-FU metabolism-related genes in TE-5R cells did not changed from TE-5 cells. Gimeracil, a DPD inhibitor, sharply restored 5-FU resistance and increased intracellular 5-FU concentration in TE-5R cells. Next, to investigate whether other 5-FU metabolism-related genes contributed to 5-FU resistance in TE-5R cells, we added microarray gene expression assay and no significant differences in the expression of 5-FU metabolism-related genes were detected. These results indicate that 5-FU resistance in TE-5R cells is based on a DPD-dependent rapid degradation of 5-FU. Taken together, we established novel 5-FU-resistant TE-5R cells, which may have obtained 5-FU resistance with DPD copy number amplification and consequent overexpression, providing a critical insight to explore a new strategy against 5-FU-resistant ESCC using DPD inhibitor.
Citation Format: Osamu Kikuchi, Kiichiro Baba, Shinya Ohashi, Manabu Muto. Establishment of a 5-fluorouracil-resistant esophageal squamous cell carcinoma cells with dihydropyrimidine dehydrogenase gene amplification. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B31.
Abstract B43: Quantitative PCR and in-situ-hybridization analysis to determine tissue concentration and localization of MRX34
Authors: Martin Desiree , Kelnar Kevin , Bader Andreas G. 
Published: May 2016

Abstract
MRX34, a liposomal microRNA (miRNA)-based therapy for cancer, has recently entered clinical trials as a potential first clinical candidate in its class. MRX34 is a mimic of naturally occurring microRNA-34 (miR-34) encapsulated in a liposomal nanoparticle formulation. Preclinical animal studies have shown that intravenous delivery of MRX34 can increase miR-34 levels in liver tumor cells more than 100-fold when analyzing whole-tissue RNA extracts by quantitative PCR (qPCR). MRX34-induced tumor regression has enhanced the survival of mice by inhibiting the growth of both hepatic and non-hepatic tumors. We have established a chromogenic in situ hybridization (CISH) method to track the cellular location of the miR-34 mimic in tissues after systemic MRX34 administration. In contrast to conventional biodistribution approaches that cannot distinguish between spatial differences in tissue accumulation, CISH in conjunction with microscopy allows the detection of the miRNA mimic on a cellular level and may provide new insights into cell-type specific accumulation. Here, we evaluated the localization and tissue concentrations of systemically delivered MRX34 in mice bearing orthotopic Huh7 tumors by CISH followed by image correlation to a formalin-fixed and paraffin-embedded tissue equivalent, and isolation-free qPCR analysis. Our results show that the CISH procedure is a reproducible and robust assay capable of over 2 logs of miR-34 detection when correlated to qPCR data from matching micro-dissected samples. Systemic MRX34 delivery leads to accumulation of miR-34 mimics in tumor cells with Cmax reached approximately 2 hrs post dosing. In addition, the CISH data reveal how biodistribution data generated from whole-tissue extracts can be biased due to minute impurities and suggests that these methods should be used in combination with CISH for an accurate assessment of tissue concentrations.
Citation Format: Desiree Martin, Kevin Kelnar, Andreas G. Bader. Quantitative PCR and in-situ-hybridization analysis to determine tissue concentration and localization of MRX34. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B43.
Abstract B46: Rac1 inhibition as a therapeutic strategy in breast cancer
Authors: Senderoff Dana , Azzi Georges , Goka Erik , Lippman Marc 
Published: May 2016

Abstract
Over the past few decades, targeted therapies have accounted for most of the therapeutic advances in breast cancer. The purpose of this approach is to discover new, actionable therapeutic strategies for breast cancer. We previously used a forward genomic screening approach to identify novel genes capable of cooperating with HER2, and found that loss of HACE1 was prevalent in breast cancer, identifying it as a tumor suppressor gene. HACE1 had significantly lower expression in breast cancer patients compared to normals. HACE1 is an E3 ubiquitin ligase that ubiquitinates Rac1, marking it for degradation. Rac1, a Rho GTPase, is a central component of key signaling pathways in breast cancer. While we identified HACE1 in a HER2 cooperating screen, the observation that HACE1 levels were consistently low across different subtypes of breast cancer led us to suggest that Rac1 is commonly hyperactivated in breast cancer and therefore has potential as a therapeutic target. We tested a Rac1 inhibitor, EHT 1864, on 8 different breast cancer cell lines, starting with an initial soft agar assay screen for sensitivity versus resistance and found that 4 cells lines were sensitive to the Rac1 inhibitor in soft agar cloning assays (MCF7, T47D, BT549, and BT474), while 4 other cell lines were resistant (MDA231, MDA436, MDA468, HS578T). These results were confirmed in 2D proliferation assays. The majority of the cell lines that were resistant to Rac1 inhibition overexpressed EGFR, suggesting that overexpression of EGFR confers resistance to Rac1 inhibition via the MAP Kinase pathway. Isogenic cell lines (MCF7) that express multiple activating proteins of the MAPK signaling pathway including EGFR, HER2, and MEK were treated with EHT1864 to determine if MAPK signaling was capable of overcoming Rac1 inhibition. Interestingly, the expression of EGFR conferred resistance to the Rac1 inhibitor. We further showed that molecular knockdown of EGFR in HS578T cells (EGFR-overexpressing, Rac1 inhibitor-resistant cells) resensitizes this cell line to Rac1 inhibition. Pharmalogical inhibition of EGFR using Gefitinib, an EGFR tyrosine kinase inhibitor, demonstrated the same resensitization to the Rac1 inhibitor. Our results suggest that Rac1 inhibition may be a therapeutic strategy in the treatment of breast cancer, as a single agent alone or in the case of EGFR overexpressing (triple-negative) breast cancers, in combination with EGFR targeted therapies.
Citation Format: Dana Senderoff, Georges Azzi, Erik Goka, Marc Lippman. Rac1 inhibition as a therapeutic strategy in breast cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B46.
Abstract IA04: Multifaceted functions of the PD-1 pathway
Authors: Sharpe Arlene H. 
Published: May 2016

Abstract
The PD-1 co-inhibitory pathway is a key regulator of the critical balance between stimulatory and inhibitory signals needed for effective immune responses to microbes and tumors, as well self-tolerance. This pathway consists of the inhibitory Programmed Death (PD)-1 receptor and its two ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). PD-1 is inducibly expressed on T cells, and its ligands have distinct expression patterns. PD-L1 is broadly expressed on hematopoietic and non-hematopoietic cells, whereas PD-L2 is inducibly expressed primarily on DCs and macrophages. In this talk, mechanisms by which the PD-1:PD-L pathway regulates optimal immune homeostasis and tolerance will be discussed. In addition, the functions of PD-1 pathway in controlling humoral immune responses will be discussed, and compared to the functions of CTLA-4 in regulating humoral immunity.
Citation Format: Arlene H. Sharpe. Multifaceted functions of the PD-1 pathway. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA04.
Abstract IA06: Angiogenesis revisited: Role and (therapeutic) implications of endothelial metabolism
Authors: Carmeliet Peter 
Published: May 2016

Abstract
The past 40 years of research in the angiogenesis field have focused on identifying genetic signals such as VEGF and Notch, which determine vessel sprouting. However, the role and therapeutic potential of targeting endothelial cell (EC) metabolism have been largely overlooked. We have recently reported that ECs are glycolysis addicted and that glycolysis importantly co-determinine vessel sprouting downstream of VEGF and other pro-angiogenic signals. In addition, we documented that ECs are rather unique in utilizing fatty acid-derived carbons for the de novo synthesis of deoxyribonucleotides for DNA synthesis during EC proliferation when vessels sprout. Moreover, targeting (blocking) glycolysis and fatty acid oxidation inhibit pathological angiogenesis and induce tumor vessel normalization (thereby reducing metastasis and improving chemotherapy), suggesting that these metabolic pathways are new targets for anti-angiogenic drug development without evoking systemic side effects. Furthermore, lymphatic ECs differ from other EC subtypes in their metabolic requirements for lymphangigoenesis. Since many of these metabolic targets are pharmacologically druggable, these metabolic pathways represent a new promising target for therapeutic anti-angiogenesis.
Citation Format: Peter Carmeliet. Angiogenesis revisited: Role and (therapeutic) implications of endothelial metabolism. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA06.
Abstract IA07: Metabolic heterogeneity in cancer cells and tumors
Authors: DeBerardinis Ralph J. 
Published: May 2016

Abstract
Most diseases are accompanied by altered metabolism at the cellular level. In cancer, metabolic reprogramming that is, the regulated alteration of metabolism as a consequence of tumorigenic mutations and other factors is viewed as an essential component of malignant transformation. It is unknown to what extent cell-autonomous vs. non-cell autonomous factors influence metabolic pathway choice. We performed metabolic profiling in a large panel of molecularly annotated non-small cell lung cancer (NSCLC) cell lines grown in standard monolayer culture in order to define the scope of cell-autonomous metabolic variability in this disease and to understand the mechanisms by which metabolic phenotypes are established. We then identified a new pathway that allows cells to tolerate a cell-extrinsic stress: the loss of anchorage dependence. Regardless of the intrinsic metabolic preferences in monolayer culture, NSCLC cells activated an unconventional pathway allowing reducing equivalents to shuttle from the cytosol to the mitochondria to counteract oxidative stress during anchorage loss. Finally, we performed clinical studies involving a combination of pre-surgical imaging and intra-operative 13C infusions to assess metabolic heterogeneity between individual NSCLC tumors in human patients, and to characterize the extent of metabolic heterogeneity within individual tumors. These studies revealed enhanced glycolysis and glucose oxidation in tumors compared to adjacent lung, regardless of driver mutation. Surprisingly, we also found that regional metabolic heterogeneity could be mapped prior to surgery by examining tissue perfusion using contrast MRI, and that glucose’s contribution to central carbon metabolism is inversely proportional to tumor perfusion. Together, these efforts identify a complex but finite set of metabolic phenotypes that support cell growth and may predict therapeutic vulnerabilities. They also underscore the potential for both existing and novel imaging approaches to inform about metabolic phenotypes in vivo, including phenotypes specified by both cell-intrinsic and cell-extrinsic factors.
Citation Format: Ralph J. DeBerardinis. Metabolic heterogeneity in cancer cells and tumors. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA07.
Abstract IA08: Hypoxia, metabolism, and tumor progression
Authors: Simon M Celeste 
Published: May 2016

Abstract
Solid tumors typically develop hostile microenvironments characterized by irregular vascularization and poor oxygen (O2) and nutrient supply. Whereas normal cells modulate anabolic and catabolic pathways in response to changes in nutrient availability, cancer cells exhibit unregulated growth even under nutrient scarcity. Recent studies have demonstrated that constitutive activation of growth-promoting pathways results in dependence on unsaturated fatty acids for survival under O2 deprivation. In cancer cells, this dependence represents a critical metabolic vulnerability that could be exploited therapeutically. I will review how this dependence on unsaturated lipids is affected by the microenvironmental conditions faced by cancer cells.
Citation Format: M Celeste Simon. Hypoxia, metabolism, and tumor progression. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA08.
Abstract IA13: Clonal dynamics of normal and malignant human mammary cell growth in xenografts
Authors: Eaves Connie J. , Nguyen Long , Pellacani Davide , Kannan Nagarajan , Lefort Sylvan , Balani Sneha , Cox Claire , Osako Tomo , Aparicio Samuel , Hirst Martin 
Published: May 2016

Abstract
Most human breast cancers have diversified genomically and biologically by the time they become clinically evident and little is known about their origin from normal human mammary cells, or the cellular and molecular mechanisms that lead to their genesis and evolution. We have developed methods to quantify, purify and characterize different subsets of normal human mammary cells and have used these to identify properties that may influence their propensity for transformation. We have also developed methods for inducing the rapid transformation in vivo of these purified subsets following their transplantation into immunodeficient mice. The results demonstrate the ability of a single oncogene (KRASG12D) to induce the formation of serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. Both primary and secondary tumors are phenotypically heterogeneous and transcriptome analyses of primary tumors assign them to a “normal-like” category. DNA barcoding of the cells at the time of their initial transduction with KRASG12D has revealed a dramatic change in the numbers and sizes of clones they generate after 2 weeks in vivo. DNA barcoding also showed the unexpected appearance of many “new” clones in tumors generated upon passage into secondary recipients, thus recapitulating some features of in vivo passaged human breast cancer cell lines and patients’ tumor xenografts. This system challenges previous concepts about the process of human mammary oncogenesis and provides a new system for analyzing factors that can influence its speed, efficiency and heterogeneity of outcomes.
Citation Format: Connie J. Eaves, Long Nguyen, Davide Pellacani, Nagarajan Kannan, Sylvan Lefort, Sneha Balani, Claire Cox, Tomo Osako, Samuel Aparicio, Martin Hirst. Clonal dynamics of normal and malignant human mammary cell growth in xenografts. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA13.
Abstract IA16: Clonal evolution in breast cancer patients and patient derived xenografts
Authors: Aparicio Samuel 
Published: May 2016

Abstract
The notion that most cancers are ecosystems of evolving clones has implications for biological understanding and clinical application. The evolution of clonal composition has particular significance when evidence of positive or negative selection can be associated with the clonal genotype or epigenotype. Over the last 4 years next generation sequencing of tumors and methods for single cell analysis have opened up this approach for solid epithelial malignancies. I will discuss the implications of clonal evolution for cancer medicine and biological studies of cancer with reference to breast cancers. We have developed informatics approaches to population level clonal analysis and extended these to single cell measurements of genotypes. I shall discuss our more recent data from single cell sequencing and clonal analysis applied to clonal evolution of patient derived tumor xenografts, to illustrate the impact of clonal evolution on biological studies of cancer in model systems.
Citation Format: Samuel Aparicio. Clonal evolution in breast cancer patients and patient derived xenografts. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA16.
Abstract IA19: Cancer epigenomics: From knowledge to applications
Authors: Esteller Manel 
Published: May 2016

Abstract
For the last twenty-five years an increasing amount of evidence has shown the relevance of epigenetics in cell biology and tissue physiology, being DNA methylation aberrations in cancer the flag-ship for the recognition of its disturbance in human diseases. From the candidate gene approaches, new powerful technologies such as comprehensive DNA methylation microarrays and whole genome bisulfite sequencing has recently emerged that have reinforced the notion of epigenetic disruption in the crossroad of many sickness. From the poster-boy cases of MGMT and GSTP1 hypermethylation in the prediction of alkylating drug response and prostate cancer detection, respectively, to the personalized treatment of leukemia with small molecules targeted to fusion proteins involving histone modifiers such as DOT1L and MLL, the field has walked a long path. The current talk will focus in the epigenetic profiling, basically at the level of DNA methylation and histone modifications, that is starting to provide clinical value in the diagnosis, prognosis and prediction of response to drug therapies, with an emphasis in neoplasia, but without forgetting the novel advances in other human disorders. For cancer, we have already a wide view of the undergoing DNA methylation events that expand beyond classical promoter CpG islands of tumor suppressor genes and we have a growing list of mutated chromatin remodeler genes that contributes to the tumorigenesis process. It is time to apply this knowledge in practical clinical situations like the diagnosis of cancers of unknown primary, the screening of malignancies in high-risk populations or a biomarker selection of the patients that should receive treatment with epigenetic drugs.
Citation Format: Manel Esteller, Sr. Cancer epigenomics: From knowledge to applications. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA19.
Abstract IA21: Ras oncogene in cancer pathogenesis and therapy
Authors: Bar-Sagi Dafna 
Published: May 2016

Abstract
Mutations in ras genes are highly prevalent in human cancers and are universally predictive of resistance to virtually all anti-cancer therapeutic modalities. Mutant Ras proteins are endowed with a diverse set of biological capabilities that impinge on homeostatic mechanisms that control cell growth and survival. We have been interested in defining the molecular basis of these capabilities and delineating their contribution to the execution of the oncogenic program. Specifically, our recent efforts have focused on the impact of Ras-dependent oncogenic output on key elements of tumor evolution - metabolic reprogramming, immune evasion and genomic stability. The presentation will provide updates pertaining to these efforts highlighting newly identified Ras-dependent vulnerabilities that could potentially be exploited in the design of therapeutic interventions.
Citation Format: Dafna Bar-Sagi. Ras oncogene in cancer pathogenesis and therapy. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA21.