bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1102: Integrated genomic analysis of clear-cell ovarian cancer identifies PRKCI as a therapeutic target
Authors: Tsang Tsun Yee , Mohapatra Gayatry , Itamochi Hiroaki , Mok Samuel C. , Birrer Michael J. 
Published: August 2015

Abstract
Clear-cell ovarian cancer (CCOC) is the third most common subtype of ovarian cancer. CCOC is more resistant to standard chemotherapy and has a poorer prognosis than serous and endometrioid histotypes. Through a comprehensive genomic approach, genes that are responsible for the aggressive behavior of CCOC were identified and their mechanism explored.
Genome-wide DNA copy number alterations were measured in 13 CCOC cell lines using high-resolution oligonucleotide array comparative genomic hybridization (Agilent 105k Human Genome CGH Microarray). Genomic identification of significant targets in cancer (GISTIC) analysis identified 16 amplicons containing 391 genes. Integrating whole genome expression data from human CCOC tumor specimens and normal ovarian surface epithelium specimen revealed 45 amplified genes showed mRNA overexpression in CCOC tumor specimens. Among the 45 genes, protein kinase C iota (PRKCI) was amplified in 9/13 CCOC cell lines and was overexpressed (6.7 fold) in CCOC tumor specimens. Cell proliferation, migration/invasion and tumorigenicity were suppressed by knockdown of PRKCI in PRKCI-overexpressing cells (KOC-7c and OVISE) and were enhanced by overexpression of PRKCI in cells with low endogenous levels of PRKCI (ES2 and TOV21G). Targeted inhibition of PRKCI with sodium aurothiomalate (ATM) suppressed cell growth, cell migration/invasion and tumorigenicity in CCOC cells. Western blot analysis revealed that PRKCI oncogenic function was mediated through MEK/ERK and PI3K/Akt signaling pathways. Thus, PKRCI can be considered as a potential novel CCOC-specific target; not only it inhibits malignant behavior of CCOC cells, but also induces the two major molecular pathways regulating cisplatin resistance. The results from the present study indicate that our comprehensive genomic analysis of CCOC allows identification of therapeutic targets responsible for the aggressive behavior specific of this ovarian cancer histotype and thus improve its therapeutic outcome.
Citation Format: Tsun Yee Tsang, Gayatry Mohapatra, Hiroaki Itamochi, Samuel C. Mok, Michael J. Birrer. Integrated genomic analysis of clear-cell ovarian cancer identifies PRKCI as a therapeutic target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1102. doi:10.1158/1538-7445.AM2015-1102
Abstract 1109: In vivo loss of function screening reveals carbonic anhydrase IX (CAIX) as a key modulator of tumor initiating potential in primary pancreatic tumors
Authors: Pore Nabendu , Jalla Sanjoo , Higgs Brandon , Liu Roger , Tice David A. , Hollingsworrth Robert , Michelotti Emil , Sorio Claudio , Scarpa Aldo 
Published: August 2015

Abstract
Re-programming of energy metabolism is one of the emerging hallmarks of cancer. Upregulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient derived pancreatic xenograft model. Lenti-viruses expressing shRNAs targeting twelve different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including CAIX, MCT4, and xCT were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation since shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient derived pancreatic tumor model.
Citation Format: Nabendu Pore, Sanjoo Jalla, Brandon Higgs, Roger Liu, David A. Tice, Robert Hollingsworrth, Emil Michelotti, Claudio Sorio, Aldo Scarpa. In vivo loss of function screening reveals carbonic anhydrase IX (CAIX) as a key modulator of tumor initiating potential in primary pancreatic tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1109. doi:10.1158/1538-7445.AM2015-1109
Abstract 1112: Loss-of-function genetic screening with shRNA and CRISPR libraries
Authors: Tedesco Donato , Makhanov Mikhail , Baron Sylvain , Suchkov Dmitry , Chenchik Alex 
Published: August 2015

Abstract
Genome-wide loss-of-function screens provide a direct approach to identify the genes regulating biological responses and find new therapeutic targets. While RNAi screens have proven an effective tool for these screens, CRISPR/CAS9 provides an alternative approach to implement these screens. To complement our established shRNA screening platform, we have developed pooled format genome-wide modular sgRNA libraries for cost-effective functional CRISPR knockout screens. Pooled sgRNA and shRNA libraries were then run to identify lethal interactions in isogenic PDX-derived cell line pairs.
Citation Format: Donato Tedesco, Mikhail Makhanov, Sylvain Baron, Dmitry Suchkov, Alex Chenchik. Loss-of-function genetic screening with shRNA and CRISPR libraries. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1112. doi:10.1158/1538-7445.AM2015-1112
Abstract 1116: Oncogene signatures identify novel therapeutic targets and combinatorial strategies in breast cancer
Authors: Guest Stephen , Kratche Zachary , Irish Jonathan , Bollig-Fischer Aliccia , Garrett-Mayer Elizabeth , Ethier Stephen 
Published: August 2015

Abstract
During the course of tumorigenesis, cancer cells acquire a large number of genetic and epigenetic alterations. A subset of these alterations results in the generation of driver oncogenes that play critical roles in initiating and maintaining the transformed phenotype. We hypothesize that most solid tumors are simultaneously driven by multiple driver oncogenes that together form an oncogene network and that durable therapies for solid tumors will need to target multiple oncogenes. Identifying multiple driver oncogenes from among the large number of mutated/amplified genes present in most solid tumors is a nontrivial task that will require novel approaches. In this work, we have combined genome-wide, RNAi-based dropout screens with copy number, expression and exome sequencing analysis to identify the full complement of driver oncogenes that function in a panel of breast cancer cell lines. The panel of cell lines used for this study is the SUM panel of breast cancer cells which contains 10 cell lines and includes representatives of HER2 positive, ER positive, and triple negative breast cancer subtypes. For each line we have identified multiple activated driver oncogenes that when combined define a complete oncogene signature for the cell line. All of the oncogene signatures contain both well-characterized oncogenes that are known to play a role in breast cancer as well as novel driver genes that do not have a well-characterized role in breast cancer. Subsequent work has confirmed the role of several of the novel driver oncogenes including the epigenetic modifier KAT6A and the apoptotic regulator BCL2L1. Additionally, we show that the cell line oncogene signatures can be used to successfully predict sensitivity of individual cell lines to small molecule inhibitors. Predictions of sensitivity to inhibitors were confirmed through the integration of oncogene signatures with published data from large-scale drug screens across numerous cancer cell lines. Finally, we demonstrate the utility of oncogene signatures through their use in the design of novel therapeutic strategies that effectively reduce cancer cell viability.
Citation Format: Stephen Guest, Zachary Kratche, Jonathan Irish, Aliccia Bollig-Fischer, Elizabeth Garrett-Mayer, Stephen Ethier. Oncogene signatures identify novel therapeutic targets and combinatorial strategies in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2015-1116
Abstract 1121: Analysis of gene expression changes as a function of PBRM1, BAP1, and SETD2 mutation status clear cell renal cell carcinoma in TCGA tumors
Authors: Abbosh Philip H. , Ibragimova Ilsiya , Slifker Michael , Cairns Paul 
Published: August 2015

Abstract
In addition to VHL, the most commonly mutated clear cell renal cell carcinoma (ccRCC)genes are the chromatin modifiers PBRM1, BAP1, and SETD2. Mutations in these genes predict loss-of-function and presumably exert cancer-related functions through changes in chromatin context and gene expression. Mining publicly available data from The Cancer Genome Anatomy (TCGA) allowed us to correlate mutation status and gene expression profiles, potentially suggesting roles for these mutations in ccRCC. Gene set enrichment analysis (GSEA)reveals that specific signaling and metabolic changes are common for each tumor mutation and may reveal the biologic mechanism of tumor-associated mutations. Work is underway to functionally validate the effect of loss-of-function ccRCC mutations in epigenetic modifiers.
Citation Format: Philip H. Abbosh, Ilsiya Ibragimova, Michael Slifker, Paul Cairns. Analysis of gene expression changes as a function of PBRM1, BAP1, and SETD2 mutation status clear cell renal cell carcinoma in TCGA tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1121. doi:10.1158/1538-7445.AM2015-1121
Abstract 1132: Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway
Authors: Hsu Wei-Hsiang , Jhuang Hong-Jhih , Huang Chi-Ying 
Published: August 2015

Abstract
Peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1α), a major metabolic regulator of gluconeogenesis and lipogenesis, is known to be strongly induced to coactivate HBV gene expression in the liver of fasting mice. In this study, we found that the combination of 8-Br-cAMP and glucocorticoids showed the synergistic induction of PGC-1α and its downstream gene expression, including the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, HBV corepromoter activity was synergistically enhanced by the combination of 8-Br-cAMP and glucocorticoid treatment. Graptopetalum paraguayense (GP), a herbal medicine, is commonly used in Taiwan to treat liver disorders. Here, we found that a partially purified fraction of GP (named HH-F3) dose dependently suppressed 8-Br-cAMP/glucocorticoid-induced G6Pase, PEPCKand PGC-1α expression as well as suppressed HBV core promoter activity. Additionally, HH-F3 blocked HBV core promoter activity via the inhibition of PGC-1α expression. The ectopic expression of PGC-1α effectively reversed the HH-F3-mediated inhibition of HBV core promoter activity.HH-F3-reduced HBV surface antigen expression, HBV mRNA production, core protein level, and HBV replication were drastically rescued by ectopically expressed PGC-1α. In addition, HH-F3 could also inhibit fatty acid synthase (FASN) expression as well as decrease lipid accumulation by the down-regulation of PGC-1α in human hepatocarcinoma cell lines. In conclusion, HH-F3 could inhibit HBV replication, gluconeogenesis, and lipogenesis through the down-regulation of PGC-1α. Our study indicates that targeting PGC-1α may be a novel therapeutic strategy for HBV infection. Together, HH-F3mighthave potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome.
Citation Format: Wei-Hsiang Hsu, Hong-Jhih Jhuang, Chi-Ying Huang. Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1132. doi:10.1158/1538-7445.AM2015-1132
Abstract 1134: N-Myc promotes glutamine anaplerosis and aggressive tumor progression through direct GLS2 activation
Authors: Xiao Daibiao , Ren Ping , Su Hexiu , Yue Ming , Xiu Ruijuan , Gan Lei , Liu Hudan , Qing Guoliang 
Published: August 2015

Abstract
Elevated glutamine metabolism is an essential feature for malignant transformation. Glutaminase-catalyzed deamidation of glutamine to glutamate is a key step in both glutaminolysis and synthesis of ROS-scavenging glutathione. Two predominant human isozymes of glutaminase, kidney-type GLS1 (also called GLS) and liver-type GLS2, are involved in regulation of glutaminolysis. It has been shown the Myc family member, c-Myc, specifically potentiates elevated expression of GLS1 and promotes the downstream utilization of glutamine carbon in anaplerosis in liver cancer, whereas p53 tumor suppressor specifically activates GLS2 to support cellular defense against oxidative stress, suggesting GLS1 promoted tumorigenesis whereas GLS2 may inhibited it. However, whether cancer cells of different origins use a common or unique signal pathways to regulate glutamine metabolism remains largely unexplored. Using MYCN-amplified neuroblastoma as a model system, we identified GLS2 expression dramatically increased while that of GLS1 substantially decreased in the tumorigenic process of N-Myc transformed neuroblastoma. GLS2 depletion profoundly inhibited glutaminolysis concomitant with a substantial decrease in cell proliferation and viability in vitro and inhibition of tumorigenesis in vivo. Mechanistically, N-Myc, but not p53, selectively activates GLS2 transcription by direct binding to a conserved Myc-binding site within GLS2 promoter. In support of this notion, we found significant elevation of GLS2 expression concomitant with considerable GLS1 down-regulation in primary tumors obtained from MYCN-amplified neuroblastoma patients (invariably with poor prognosis) in comparison with those from MYCN non-amplified patients. In aggregate, these studies suggest that the metabolic regulation of c-Myc induced liver tumors differs from that of N-Myc induced neuroblastoma tumors which is likely to depend on both the genotype and the tissues of origin and have implications regarding the design of selective therapies targeting tumor metabolism.
Citation Format: Daibiao Xiao, Ping Ren, Hexiu Su, Ming Yue, Ruijuan Xiu, Lei Gan, Hudan Liu, Guoliang Qing. N-Myc promotes glutamine anaplerosis and aggressive tumor progression through direct GLS2 activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2015-1134
Abstract 1139: Tumor-associated fibroblasts facilitate head and neck cancer metabolism
Authors: Kumar Dhruv , Kasturi Partha , Houten Bennett Van , Thomas Sufi 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy affecting 40,000 cases in the USA annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic with up to 80% fibroblasts. We reported that tumor associated fibroblasts (TAFs) facilitate HNSCC progression. However, the molecular mechanisms that facilitate TAF-mediated tumor growth and metastasis remain unknown. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in lactic acid (LA) production. It has been reported that HNSCC tumors have high LA levels that correlate with reduced survival. The mechanisms whereby HNSCC tumors survive in highly acidic conditions remain unknown. We reported that activation of the receptor tyrosine kinase, c-Met, by TAF-secreted hepatocyte growth factor (HGF) contributes to HNSCC progression. The role of TAFs-secreted HGF in HNSCC metabolism remains unknown. In addition, we were unable to detect HGF secretion by HNSCC indicating paracrine activation of c-Met. In nasopharyngeal carcinoma, c-Met inhibition down regulates the TP53-induced glycolysis and apoptosis regulator (TIGAR) and NADPH production. We hypothesized that TAF-secreted HGF regulates HNSCC glycolysis via c-Met. Further, HNSCC cells regulate metabolism in TAFs. We found that PF2341066, a c-Met inhibitor significantly decreased glycolysis (p = 0.0023) and hexokinase-II levels in HNSCC cells. These data demonstrate that c-Met regulate glycolysis in HNSCC through modulation of hexokinase-II. In admixed cultures, HNSCC and TAFs demonstrate higher expression of the bi-directional lactate transporter monocarboxylate transporter 1 (MCT-1). Our data demonstrate that TAFs have a higher capacity to proliferate than HNSCC in the presence of LA. Others have reported that NFκB increases MCT-1 levels in tumor associated stroma under high LA conditions. In ongoing studies, we will determine the role of HNSCC in regulating MCT-1 levels in TAFs. Further, the role of c-Met in regulating expression of MCT-1 in HNSCC will be elucidated. Based on the cumulative data we conclude that TAF-secreted HGF regulates HNSCC metabolism and TAFs utilize LA as a carbon source making the microenvironment more conducive to tumor progression.
Keywords : HNSCC, TAFs, HGF, Glycolysis, OXPHOS
Citation Format: Dhruv Kumar, Partha Kasturi, Bennett Van Houten, Sufi Thomas. Tumor-associated fibroblasts facilitate head and neck cancer metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1139. doi:10.1158/1538-7445.AM2015-1139
Abstract 1170: TTP inhibits insulin receptor signals in cancer cell
Authors: Yoon Ji Eun , TRAM VO MAI , Yoon Nal Ae , Back Jin Ho , Min Young Joo , Cho Wha Ja 
Published: August 2015

Abstract
Insulin receptors (IRs) belong to the large class of tyrosine kinase receptors and are activated by insulin, IGF-I, IGF-II and. The binding of ligands to the IR initiates a cascade of events leading to activation of signal transduction pathways, mainly PI3K and AKT pathways, and induce glucose uptake and cell proliferation. IR signaling pathway has been reported to be deregulated in cancer cells resulting in a range of clinical manifestations including cancer. It has been shown that the presence of IR was required for transformation induced by many oncogenes and over-expression or constitutive activation of IR gave rise to transformed phenotypes. Here, we report an unexpected role of a tumor suppressor tristetraprolin (TTP) in inhibiting IR. TTP bound to the AU-rich element (ARE) within the mRNA 3′UTRs of IR, enhanced the decay of their mRNAs and inhibited the metabolism of cancer cells. The ectopic expression of IR without their 3′UTRs blocked the inhibitory effects of TTP on the Warburg effect cancer. Our data propose a new model whereby the TTP down-regulates IR and plays an important role as a negative regulator of both the energy metabolism and proliferation of cancer cells.
Citation Format: Ji Eun Yoon, VO MAI TRAM, Nal Ae Yoon, Jin Ho Back, Young Joo Min, Wha Ja Cho. TTP inhibits insulin receptor signals in cancer cell. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2015-1170
Abstract 1175: Curcumin may have anticancer effect by normalizing cancer metabolic pathway
Authors: Takeyama Hideaki , Hayashi Hiromitsu , Kaida Takayoshi , Arima Kota , Taki Katsunobu , Higashi Takaaki , Okabe Hirohisa , Nitta Hidetoshi , Hashimoto Daisuke , Chikamoto Akira , Beppu Toru , Baba Hideo 
Published: August 2015

Abstract
Background: Cancer metabolism is a new and exciting field of biology that provides a fundamentally different approach to treating cancer. The characteristic of cancer metabolism is Warburg effect formation that is the glucose metabolism in the glycolytic pathway in aerobic environments. Specific high expression of PKM2 (Pyruvate kinase type M2) is indispensable to the Warburg effect formation. Curcumin is an ingredient of Termeric, and has a variety of bioactivity with less toxicity. Recently, an anti-cancer effect of Curcumin attracts attention, and various studies are conducted to investigate the bio-mechanisms as an anti-cancer agent. While Curcumin has been reported to provide an anti-cancer effect by suppressing NF-κB-COX pathway and/or the oxidative stress, its effect on cancer metabolism still remains unclear. Here, we investigated the mechanism of anti-cancer effects derived by Curcumin by focusing on cancer metabolism.
Method: The anti-cancer effect of Curcumin was examined by growth-assay in HCC cell lines (HepG2 and HLF). To further assess the biological mechanism of Curcumin on cancer cells, the changes in cancer metabolic pathways such as pyruvate kinase type M2 (PKM2), glucose transporter1 (Glut1), glucose-6-phosphate dehydrogenase deficiency (G6PD), and Transketolase (TKT).
Result: In growth assay, Curcumin treatment significantly suppressed cell growth of HepG2 cell. For the cancer metabolic pathways, Curcumin treatment induced a shift into PKM1 from PKM2 expression represented by decreased PKM2/1 ratio by real time PCR in HepG2 and HLF cells. Indeed, Glut1 and G6PD expressions were also suppressed by Curcumin treatment, whereas TKT expression was increased in HepG2 cell.
Conclusion: Curcumin displayed anti-proliferative effects on HCC cell lines, and its anti-cancer effects may be due to normalize the cancer metabolic pathway represented by a shift into PKM1 from PKM2 expression.
Citation Format: Hideaki Takeyama, Hiromitsu Hayashi, Takayoshi Kaida, Kota Arima, Katsunobu Taki, Takaaki Higashi, Hirohisa Okabe, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba. Curcumin may have anticancer effect by normalizing cancer metabolic pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1175. doi:10.1158/1538-7445.AM2015-1175