bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5253: Regulation of estrogen related receptor α by ING4 and its potential role in breast cancer pathogenesis
Authors: Shatnawi Aymen A. , Giguere Vincent 
Published: August 2019

Abstract
Breast cancer is one of the most frequently diagnosed tumors in the United States that affects one in eight women during their lifetime. It is second only to lung cancer as cause of cancer death in women. The orphan members of the nuclear receptor superfamily, estrogen-related receptors ERRα and γ (ERRs) isoforms are considered the master regulators of energy metabolism and their transcriptional pathways are highly associated with the cancer phenotype. Realizing the important function of co-regulators on ERRs transcriptional activity and their impact on cancer development and progression, we have identified the tumor growth family member 4 (ING4), a protein that has been implicated in several solid tumors and physically interacts with ERRα in breast cancer cellular models and modulates its transcriptional activity. Examination of the Oncomine database revealed that both ING4 and ERRα gene expression were significantly higher in invasive ductal and lobular breast carcinomas compared to normal ones, and their increased expression is inversely correlated with the overall patient survival rate in The Cancer Genome Atlas (TCGA) database. Knocking down ING4 in a breast cancer cell line using siRNA technology significantly decreased the expression of ERRα, and overexpression of ING4 upregulates the endogenous expression of ERRα. Well-defined ERRα target genes were also regulated by ING4 in the same manner as ERRα. Also, depleting ING4 expression significantly increased breast cancer cell migration in in vitro scratch assays, while both ING4 and ERRα knockdown decreased breast cancer cell proliferation. Collectively, these findings provide evidence for positive regulation of ERRα by ING4. Understanding the mechanism by which ING4/ERRα interaction regulates cellular pathways in breast cancer, underscores the impact of such regulation on biological and pharmacological actions. Thus, they can be used for the development of improved novel pharmaceuticals that target ERRα/ING4 complex or its downstream pathways.
Citation Format: Aymen A. Shatnawi, Vincent Giguere. Regulation of estrogen related receptor α by ING4 and its potential role in breast cancer pathogenesis [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 5253.
Abstract 5264: Metabolic reprogramming with β-alanine to overcome chemotherapy resistance in pancreatic cancer
Authors: Yakoub Danny , Totiger Smitha T. , Moran Alexandra , Suwal Sujit , Pimentel Julio , O'Donell Lauren , Walls Jamie , Nagathihalli Nagaraj , Merchant Nipun 
Published: August 2019

Abstract
Background: Increased aerobic glycolysis (Warburg effect) leading to acidic microenvironment confers chemoresistance to weakly basic Gemcitabine, the standard treatment in Pancreatic ductal adenocarcinoma (PDAC). Metabolomic perturbations in two PDAC cell lines having differential sensitivity to Gemcitabine was investigated by profiling over 40 metabolites using 1H-NMR spectroscopy. Notably, a significant decrease in the concentration of β-alanine (βA) was observed in Gem resistant compared to Gem sensitive cell line, suggesting βA may have a role in chemotherapy response. We aimed to evaluate the role of βA supplementation in improving Gem efficacy in Gem resistant cell lines
Methods: PDAC Panc-1 cell line extracts treated with Gem with and without βA supplementation were analysed via 1H-NMR spectroscopy. Aerobic glycolysis was quantified by measuring extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) using the Seahorse XF analyser platform. Global mRNA profiling was done by Next Generation Sequencing. Proliferation, migration and cell cycle analysis was measured by Xcelligence real time cell analysis system and flow cytometry, respectively. PANC-1 and BxPC-3 tumor xenografts treated with Gemcitabine with and without βA for 4 weeks and the tumor volumes and weights were measured.
Results: βA supplementation in Gem resistant cells results in: (1) decreased basal glycolytic rate, proton leak and ATP production; (2) increased pyruvate, decreased lactic acid and NAD+ concentrations with decreased LDH-A transcription; also increased carnosine levels with a more basic pH in the conditioned media; (3) enhanced sensitivity to Gem treatment, with a significant reduction in proliferation, cell migration, and increased apoptosis and relative hENt-1 mRNA levels and (5) xenograft tumor volumes and weights were significantly reduced upon βA supplementation.
Conclusion: βA supplementation reprograms cell metabolism by normalizing energy production and reducing microenvironment acidification, thus enhancing chemo-sensitivity in Gem resistant PDAC cells and xenografts. βA can be potentially used as a co-therapeutic in PDAC.
Note: This abstract was not presented at the meeting.
Citation Format: Danny Yakoub, Smitha T. Totiger, Alexandra Moran, Sujit Suwal, Julio Pimentel, Lauren O'Donell, Jamie Walls, Nagaraj Nagathihalli, Nipun Merchant. Metabolic reprogramming with β-alanine to overcome chemotherapy resistance in pancreatic cancer [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 5264.
Abstract 5267: Unbiased metabolic profiling of atypical teratoid/rhabdoid tumors predicts sensitivity to the glutamine metabolic inhibitor 6-diazo-5-oxo-L-norleucine
Authors: Wang Sabrina Z. , Poore Brad , Alt Jesse , Price Antoinette , Allen Sariah , Orr Brent , Rais Rana , Slusher Barbara , Eberhart Charles , Raabe Eric H. , Rubens Jeffrey H. 
Published: August 2019

Abstract
Atypical teratoid rhabdoid tumors (AT/RT) are deadly tumors of infancy in need of new, targeted therapies. Molecular analyses have revealed 3 epigenetically distinct subgroups of AT/RT. High MYC-expressing tumors are a particularly aggressive subgroup, with a 5-year median survival of 18.5%. MYC is difficult to directly target given large, flat, featureless protein-protein binding sites. We performed the first unbiased metabolic profile of AT/RT cell models by high-performance liquid chromatography-mass spectrometry. This study revealed that high MYC-expressing AT/RT have a unique metabolic profile (Partial Least Squares-Discriminant Analysis). Pathway analysis highlights a dependence on glutamine metabolism in high-MYC expressing AT/RT. High MYC-expressing cell lines grow poorly in glutamine-free media compared to low-MYC cell lines (MTS assay, glutamine-free media vs normal media). Due to this dependence on glutamine metabolism, we hypothesized that high-MYC expressing AT/RT would be especially sensitive to glutamine metabolic inhibitors. We show that the glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON) slows high-MYC expressing AT/RT cell growth, induces high rates of apoptosis, and improves survival in orthotopic mouse models of high-MYC expressing AT/RT (p =0.0027 by log-rank test). In contrast, low-MYC expressing models are relatively insensitive to DON. In uniformly labeled glutamine metabolic analyses of AT/RT cells, DON treatment led to depletion of glutathione levels by preventing the production of glutamate. DON treatment synergized with carboplatin to kill AT/RT cells in vitro and extend the life of mice bearing AT/RT orthotopic xenografts (p&lt; 0.001 by log rank test). We aim to translate these findings into a new clinical trial to improve survival in this deadly disease.
Citation Format: Sabrina Z. Wang, Brad Poore, Jesse Alt, Antoinette Price, Sariah Allen, Brent Orr, Rana Rais, Barbara Slusher, Charles Eberhart, Eric H. Raabe, Jeffrey H. Rubens. Unbiased metabolic profiling of atypical teratoid/rhabdoid tumors predicts sensitivity to the glutamine metabolic inhibitor 6-diazo-5-oxo-L-norleucine [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 5267.
Abstract 5269: Discovery and validation of plasma acylcarnitines for the early diagnosis of hepatocellular carcinoma
Authors: Shen Eric Yi-Liang , U Abellona , Taylor-Robinson Simon , Thursz Mark , Holmes Elaine , Nicholson Jeremy 
Published: August 2019

Abstract
Introduction:
Hepatocellular carcinoma (HCC) is one of the commonest and the leading cause of cancer death globally. The main cause of this high mortality rate is that patients with HCC are usually diagnosed at late stages since they have only subtle clinical presentations at early stages. This late diagnosis is a result of the requirement of high-end imaging modalities, the use of invasive procedures, and the lack of reliable tumour biomarkers. Metabolomics is the study of metabolites in an organism in response to the changes in health status. The purpose of this study was to identify and validate plasma acylcarnitines as potential diagnostic biomarkers of HCC by using techniques in the field of metabolomics.
Methods:
228 EDTA-plasma samples of healthy controls, cirrhotic patients, or treatment-naïve patients with HCC, collected from Imperial College Healthcare Tissue Bank, were used as a discovery and training set. Patient factors, including basic patient characteristics, aetiologies of HCC, and Child-Pugh scores, and data relating to tumours, such as the multiplicity, the sizes in diameter, the status of macro-vascular invasion, were collected. A targeted assay was adapted to measure concentrations of carnitine and acylcarnitines with different chain length using the TQ-S tandem quadrupole mass spectrometer. Non-parametric univariate analyses were applied to evaluate the statistical difference between HCC and cirrhosis. Logistic regression was preferred to develop diagnostic models. A Gambian cohort of 165 plasma samples was then used as an external validation.
Results:
Among sixteen measured carnitine and acylcarnitines, three acylcarnitines, namely acetylcarnitine, succinylcarnitine, and hexanoylcarnitine, statistically increased in HCC patients comparing to cirrhotic patients. A linear model incorporating these three acylcarnitines and alpha-fetoprotein was then developed. The area under the ROC curve of this multivariable regression model was 0.782 (95% C.I., 0.695-0.870) in the training set. When applied to the validation cohort, the sensitivity and specificity of this model at identifying HCC patients from cirrhosis were 82.2% and 67.8%, respectively.
Conclusion:
This report provides a comprehensive profile of the changes of carnitine and acylcarnitines among HCC, cirrhotic patients and healthy controls, and determines the value of acylcarnitines as diagnostic biomarkers for HCC.
Citation Format: Eric Yi-Liang Shen, Abellona U, Simon Taylor-Robinson, Mark Thursz, Elaine Holmes, Jeremy Nicholson. Discovery and validation of plasma acylcarnitines for the early diagnosis of hepatocellular carcinoma [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 5269.
Abstract 5272: Sensitive bioluminescent assays for monitoring changes in tumor and immune cell metabolism
Authors: Leippe Donna Marie , Karassina Natasha , Valley Michael P. , Vidugiris Gediminas , Cali James J. , Vidugiriene Jolanta 
Published: August 2019

Abstract
The tumor microenvironment is complex, containing diverse cell populations with individual nutrient requirements. Tumor and immune cells must respond to the dysregulated and changing conditions of the tumor microenvironment, as well as compete for fuels, to remain functional and viable. As metabolism is critical for proper cell function, e.g. for effective immune cell activity, understanding the metabolic needs of these cells is essential. We have developed a series of bioluminescent metabolite detection assays for monitoring cell metabolism. The assays share a common NAD(P)H bioluminescent detection technology that can be coupled with specific dehydrogenases to monitor key metabolic pathways such as: glycolysis with glucose and lactate detection; glutamine metabolism with glutamine and glutamate measurements; and lipolysis and lipogenesis with glycerol and triglyceride measurements. The assays were developed to have high sensitivity permitting detection of low levels of metabolites (femtomole detection limit), an important feature when samples contain only a few cells or small volumes. The assays can be used in a non-lytic format by analyzing metabolites in samples of collected cell culture medium. In this way changes over time can be monitored and the cells remain intact for additional measurements, such as multiplexing with viability or cytotoxicity assays. We have used these assays to study the metabolic activity of tumor cell lines and T cells. The induction of aerobic glycolysis is an early step in the activation of T cells. Here we present an example of detecting T cell activation in vitro by monitoring glycolysis and quantitating the increase in lactate secretion over time. Activation was observed only in the presence of both glucose and glutamine, confirming the requirements for both fuels and biochemical pathways for activation. In addition to understanding fuel requirements of cells, we also used the assays to follow changes of metabolic pathways in cancer cell lines treated with small molecule compounds. Treatment with such compounds could provide a means of manipulating tumor nutrient usage and metabolite secretion in the tumor microenvironment. In our experiments, metabolite levels were found to be altered by effectors of glycolysis, oxidative phosphorylation and glutamine metabolism. Multiplexing with viability and cytotoxicity assays provided information about cell health during the experiments.
Citation Format: Donna Marie Leippe, Natasha Karassina, Michael P. Valley, Gediminas Vidugiris, James J. Cali, Jolanta Vidugiriene. Sensitive bioluminescent assays for monitoring changes in tumor and immune cell metabolism [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 5272.
Abstract 5277: Glutamine antagonists synergize with L-asparaginase in MYCN-driven rhabdomyosarcoma
Authors: Maxwell Micah J. , Poore Brad A. , Hanaford Allison , Alt Jesse , Rais Rana , Slusher Barbara S. , Eberhart Charles G. , Raabe Eric H. 
Published: August 2019

Abstract
Rhabdomyosarcoma is the most common soft tissue sarcoma in children. Chromosomal translocations producing fusion transcription factors (PAX-FOXO1) are associated with poor prognosis. A subset of fusion-positive rhabdomyosarcomas have downstream activation of the transcription factor MYCN, a known oncogenic driver. Attempts to inhibit directly either PAX-FOXO1 or MYCN have been unsuccessful. MYCN is known to drive tumor cell reliance on glutamine metabolism. 6-diazo-5-oxo-L-norleucine (DON) is a well-characterized glutamine analog that irreversibly inhibits glutamine-utilizing enzymes. DON was well tolerated in a phase I pediatric clinical trial, but it has never been systematically tested in rhabdomyosarcoma. We show that high MYCN confers sensitivity to DON therapy in vitro. We have also developed a targeted glutamine antagonist compound, JHU083, which is similarly effective against MYCN-driven rhabdomyosarcoma cell lines. Furthermore, DON administered by intraperitoneal injection twice weekly significantly reduces flank tumor volume in a murine xenograft MYCN-driven rhabdomyosarcoma model (mean tumor volume 757 mm3 vs. 2167 mm3 in control animals, p-value 0.0000197 by t-test). In stable isotope resolved metabolomics experiments, DON primarily prevents asparagine synthesis, depleting intracellular asparagine levels by at least 50% in MYCN-driven cell lines (p-value = 0.0003). Finally, DON combined with L-asparaginase synergistically inhibits growth of MYCN-driven rhabdomyosarcoma cell lines (CI &lt;&lt; 1 by the Chou-Talalay method, indicating strong synergy; p-value = 0.0001). We conclude that DON depletes cellular pools of asparagine, and combination therapy with DON and L-asparaginase synergistically inhibits the growth of MYCN-driven rhabdomyosarcoma. These studies provide the preclinical justification for potential clinical trials for the use DON or DON prodrugs in combination with L-asparaginase as new therapeutic options for patients with MYCN-driven rhabdomyosarcoma.
Citation Format: Micah J. Maxwell, Brad A. Poore, Allison Hanaford, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Glutamine antagonists synergize with L-asparaginase in MYCN-driven rhabdomyosarcoma [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 5277.
Abstract 5292: Cell-autonomous suppression of colon carcinogenesis by type-2 cGMP-dependent protein kinase
Authors: Islam Bianca N. , Hou Yali , Sharman Sarah K. , Browning Darren D. 
Published: August 2019

Abstract
A growing body of evidence demonstrates that cGMP signaling has anti-tumor effects in the colon, and could harbor novel targets for colon cancer prevention. The tumor suppressive components that function downstream of cGMP remain largely understudied. In the present work we have characterized the expression of cGMP-dependent protein kinases (PKG1, PKG2) in normal and cancerous tissue from humans. PKG1 was highly expressed in both normal and tumor tissue, where it localized to supportive cells in the lamina propria and stroma (respectively). In contrast, PKG2 expression was notably decreased in tumors compared to matched normal tissue, where it was identified in the epithelium by IHC. Neither PKG isoform was detected at the RNA or protein level in colon cancer cell lines. To interrogate a potential tumor-suppressor role of PKG2 in the colon epithelium we bred PKG2 knockout (KO) mice into a C57BL/6J background. These animals exhibited increased intestinal turnover as reflected by crypt hyperplasia (Ki67) and elevated luminal apoptosis (cleaved caspase 3). When subjected to AOM/DSS treatment, the PKG2 KO mice developed almost twice the number of polyps per mouse as wild type siblings (1.75-fold, p=0.0037). Mouse colon organoids were used to confirm that PKG2 was the only isoform expressed in the epithelium, where it was observed in both proliferating and differentiating epithelial compartments. Colon organoids derived from PKG2 KO mice exhibited more rapid proliferation, and a reduced ability to differentiate compared to wild type controls. Taken together our results show that PKG2 is the central target of cGMP in the colon epithelium, where it suppresses carcinogenesis by controlling proliferation in a cell autonomous manner.
Citation Format: Bianca N. Islam, Yali Hou, Sarah K. Sharman, Darren D. Browning. Cell-autonomous suppression of colon carcinogenesis by type-2 cGMP-dependent protein kinase [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 5292.
Abstract 5302: Interplay of Parkin, a 'tumor suppressor’ in metabolic deregulation of cancer
Authors: Bhat Zafar I. , Imtiyaz Khalid , Rizvi M. Moshahid 
Published: August 2019

Abstract
Cancer is a disease of uncontrolled proliferation which initially arises as a result of dysregulation in some gene candidates responsible for maintaining a normal cellular state. Some genes are suppressed with a concomitant increase in the expression of certain dormant ones. The former group constitutes the tumor suppressors while as the later- the oncogenes. Parkin a PARK 2 gene product is a potent tumor suppressor, has been well reported to be down regulated in many cancer types. Besides its tumor suppressor role, it regulates the redox state of the cell and recently it was reported to be an important factor in TP53 (a master tumor suppressor protein) mediated tumor suppression provides a clue about the role of Parkin in metabolic deregulation- an emerging hallmark of cancer! To this end, here we present that how Parkin is regulated under different environmental conditions and how it governs metabolic plasticity- glycolytic phenotype and hence cellular migration.
To conclude, the results show that Parkin differentially regulates metabolism by modulating certain potent marker candidates responsible for Warburg effect and associated carcinogenesis.
[MMA Rizvi is the corresponding author for this work.]
Note: This abstract was not presented at the meeting.
Citation Format: Zafar I. Bhat, Khalid Imtiyaz, M. Moshahid Rizvi. Interplay of Parkin, a 'tumor suppressor’ in metabolic deregulation of cancer [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 5302.
Abstract 5307: Androgen Receptor promotes localization of E-cadherin to cell-cell junctions through Abi1 signaling
Authors: Porter Baylee , Nath Disharee , Krum Susan A. , Bratslavsky Gennady , Kuznetsov Vladimir A. , Kotula Leszek 
Published: August 2019

Abstract
According to American Cancer Society, prostate cancer is a slow progressing disease that affects nearly 50 percent of males over the age of 60. Every year, 165,000 new cases are diagnosed and 30,000 deaths are reported. Current therapies such as Androgen Depravation Therapy (ADT) and Anti-Androgen treatments such as Enzalutamide increase quality of life and extend survival but do not provide a definitive treatment and are ineffective in highly metastatic prostate cancer. Castrate Resistant Prostate Cancer (CRPC) is an untreatable highly metastatic form of prostate cancer and once diagnosed the survival rate is 1-2 years. Hence, the understanding of molecular mechanisms of CRPC is of critical importance. We previously linked prostate cancer to Abi1 gene. Abl interactor 1 (Abi1) is a scaffolding protein and an integral member of the WAVE Regulatory Complex (WRC). WRC is actin nucleation promoting factor that acts upstream of Arp2/3 to enhance the speed of actin polymerization and is critical for various cellular functions including cell-cell junction formation. Our previous research using a prostate cancer mouse models shows that loss of Abi1 expression leads to down-regulation of cellular adhesion proteins such as E-cadherin. Studies using our CRISPR KO RWPE cell line indicate that loss of Abi1 disrupts cell-cell junction formation via decreased levels of E-cadherin. Analysis of patient data demonstrated loss of Abi1 in a subset of CRPC patients. Castrate resistant tumor growth is androgen independent therefore anti-androgen therapy is ineffective. In search of a link between the androgen signaling and the role of Abi1 in prostate cancer we found that Abi1 gene contains androgen receptor (AR) binding sites. Consistent with the idea that Abi1 is an AR responsive gene, expression levels of Abi1 are increased following AR stimulation with the synthetic androgen, R1881, of the hormone sensitive cell line LNCaP. We also observed increased levels of E-cadherin at the cell-cell junctions. In contrast, cells lacking Abi1 do not form proper cell junctions neither respond to AR stimulation in the same way as wild type cells. We propose that Abi1 is a critical part of androgen signaling by promoting cell-cell junctions and tissue integrity. Supported by NCI R01 CA161018 (LK).
Citation Format: Baylee Porter, Disharee Nath, Susan A. Krum, Gennady Bratslavsky, Vladimir A. Kuznetsov, Leszek Kotula. Androgen Receptor promotes localization of E-cadherin to cell-cell junctions through Abi1 signaling [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 5307.