bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A123: Structure-function studies and drug design on the histone lysine methyl methyltransferases NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1.
Authors: Di Luccio Eric , Morishita Masayo , Mevius Damiaan , Chen Yunpeng 
Published: August 2014

Abstract
Chromatin remodelers that include histone methyl transferases (HMTases) are becoming a focal point in cancer drug development. The NSD family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L are bona fide oncogenes found aberrantly expressed in several cancers, suggesting their potential role for novel therapeutic strategies.
Several histone modifiers including HMTase have clear roles in human carcinogenesis but the extent of their functions and regulations are not well understood, especially in pathological conditions. The extents of the NSDs biological roles in normal and pathological conditions remain unclear. In particular, the substrate specificity of the NSDs remains unsettled and discrepant data has been reported. NSD2/MMSET is a focal point for therapeutic interventions against multiple myeloma and especially for t(4;14) myeloma, which is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma. Herein, we investigated the in vitro mechanisms of histone mark recognition and modifications by the SET domain of the NSDs and identify novel HMTase inhibitors by virtual ligand screening that may pave the way to specific NSD2/MMSET inhibitors suitable for therapeutic efforts against malignancies that include multiple myeloma.
Our data highlights the versatility of NSD1, NSD2, and NSD3 in recognizing and methylating lysine marks on H3 and H4. We report for the discovery of LEM-07 an inhibitor of NSD2/MMSET with an IC50 of 11.2 μM against H3K36 methylation in vitro. LEM-07 would be useful to explore the biology of NSD2.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A123.
Citation Format: Eric Di Luccio, Masayo Morishita, Damiaan Mevius, Yunpeng Chen. Structure-function studies and drug design on the histone lysine methyl methyltransferases NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A123.
Abstract A132: Development of a small-molecule inhibitor targeting the Wnt signaling pathway.
Authors: Yamada Tesshi , Masuda Mari , Sawa Masaaki 
Published: August 2014

Abstract
Wnt signaling is a major force driving colorectal carcinogenesis, but only a small number of druggable target molecules in the Wnt pathway have been found. Our recent series of proteomic studies has revealed that various classes of nuclear proteins participate in the β-catenin and T-cell factor-4 (TCF-4) complex and modulate the activity of Wnt signalling. Those included fusion/translocated in liposarcoma (FUS/TLS) (1), poly(ADP-ribose) polymerase-1 (PARP-1) (2), Ku70/Ku80 (3), DNA topoisomerase IIα (Topo IIα) (4), splicing factor-1 (SF1) (5), Ran (ras-related nuclear protein), RanBP2 (Ran binding protein-2), and RanGAP1 (Ran GTPase-activating protein-1) (6), Traf2- and Nck-interacting kinase (TNIK) (7). Among these proteins, TNIK protein kinase attracted our current interest because various small-molecule kinase inhibitors have been applied successfully to cancer treatment. TNIK was an activating kinase for TCF-4, and colorectal cancer cells are highly dependent upon the expression and catalytic activity of TNIK for proliferation (7). High-throughput screening of a kinase-focused compound library (&gt;10,000 compounds) against recombinant TNIK identified a lead candidate that inhibited the kinase activity of TNIK with an IC50 value of 8.6 nM and the transcriptional activity of TCF-4. TNIK is a feasible drug target in the Wnt signaling pathway.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A132.
Citation Format: Tesshi Yamada, Mari Masuda, Masaaki Sawa. Development of a small-molecule inhibitor targeting the Wnt signaling pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A132.
Abstract A135: Concurrent MCL1 and JUN amplification in pseudomyxoma peritonei.
Authors: Mansfield Aaron S. , Sio Terence , Grotz Travis E. , Graham Rondell P. , Molina Julian R. , Que Florencia G. , Miller Robert C. 
Published: August 2014

Abstract
Background: Pseudomyxoma peritonei (PMP) is a rare abdominal malignancy. We hypothesized that next generation exomic sequencing would identify recurrent mutations that may have prognostic or therapeutic implications.
Methods and Materials: Ten patients were selected based on availability of tissue and adequate follow-up. Mutations were tested for in 236 cancer-related genes in formalin-fixed paraffin-embedded (FFPE) slides using next-generation exomic sequencing (Foundation Medicine, Cambridge, MA). Immunohistochemistry (IHC) was used to detect MCL1 expression.
Results: Detectable mutations were found in 80% of patients. Seventy percent harbored a KRAS mutation, most commonly involving codon 12 (G12D in four cases, and one case each of G12V, G12A and A59T). Four GNAS mutations (R201H/R201C substitutions) were also detected. MCL1 and JUN were concurrently amplified in three patients. One patient with MCL1 and JUN amplification had concurrent amplification of MYC and NFKBIA. ZNF703 was amplified in one patient. Patients with MCL1 amplification were also found to express MCL1 by IHC, but MCL1 expression was also detected in some patients without amplification.
Conclusions: We are first to report MCL1 and JUN co-amplification in PMP. Expression of MCL1 may not be completely dependent upon amplification. The prognostic and therapeutic implications of these recurrent mutational events are the subject of ongoing investigation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A135.
Citation Format: Aaron S. Mansfield, Terence Sio, Travis E. Grotz, Rondell P. Graham, Julian R. Molina, Florencia G. Que, Robert C. Miller. Concurrent MCL1 and JUN amplification in pseudomyxoma peritonei. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A135.
Abstract A138: Identification of PKM2 as a potential biomarker of high-grade ovarian serous tumor.
Authors: Poersch Aline , Souza Lucas Oliveira , Faça Vitor Marcel , Greene Lewis Joel , Candido dos Reis Francisco Jose 
Published: August 2014

Abstract
The M2 splice isoform of pyruvate kinase (PKM2), that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species [1]. Furthermore, studies indicate that the PKM2 expression might be an early event in carcinogenesis [2]. Thus, PKM2 can be a useful biomarker for the early detection of tumors. Although the presence of PKM2 is described for different types of cancer, there is no information specific PKM2 in ovarian cancer. Thus, to investigate the presence of PKM2 in ovarian cancer, we performed proteomic analysis in a pool of ovarian serous adenocarcinoma (malignant) fluids (n=10) and in a pool of ovarian serous cystadenoma (benign) fluids (n=10) using immunodepletion of albumin and IgG, isotopic labeling with acrylamide, separation by SDS-PAGE, in situ digestion with trypsin and liquid chromatography ion exchange followed by reverse phase coupled to a mass spectrometer LTQ-ORBITRAP (LC-MS/MS). Moreover, evaluated the expression of PKM2 in plasma and tumor fluid of ovarian serous adenocarcinoma (n=14) and of ovarian serous cystadenoma (n=13) using the kit ELISA EDTA-Plasma Test (ScheBo® Biotech AG), and evaluated the expression of PKM2 in tissue microarrays of 71 ovarian serous adenocarcinoma samples (different stages and grades) using Tumor M2-PK Antibodies (monoclonal, ScheBo®, Biotech AG). The PKM2 protein was detected in proteomic analysis of ovarian serous adenocarcinoma. In ELISA test, PKM2 can be confirmed in both plasma and tumor fluid of ovarian serous adenocarcinoma and ovarian serous cystadenoma, with significant difference between fluids (p&lt;0.0001). Concentrations of PKM2 in plasma and tumor fluid are higher in ovarian serous adenocarcinoma. The tissue microarrays analysis confirmed that PKM2 is highly expressed in adenocarcinoma of all stages and grades. The presence of PKM2 in different biological samples of ovarian cancer and in all stages and grades suggests that your inhibition is a viable strategy in the treatment of this malignancy and conducting research in tumor metabolism will benefit cancer treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A138.
Citation Format: Aline Poersch, Lucas Oliveira Souza, Vitor Marcel Faça, Lewis Joel Greene, Francisco Jose Candido dos Reis. Identification of PKM2 as a potential biomarker of high-grade ovarian serous tumor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A138.
Abstract A150: A methodology for the isolation, culture, and immortalization of human breast epithelial and myoepithelial cells.
Authors: Fuster Gemma , Zubeldia-Plazaola Arantzazu , Mancino Mario , Fernández-Nogueira Patricia , Ametller Elisabet , Gascón Pedro , Almendro Vanessa 
Published: August 2014

Abstract
Introduction: Breast tissue is composed by different cell types including epithelial and myoepithelial cells, macrophages, fibroblasts, adipocytes, and cells from the immune system. Two main lineages, epithelial and myoepithelial cells, are the most essential cell populations in the normal mammary gland and also in breast cancer. Traditionally, cancer research has been performed using commercial cell lines, but primary cell cultures suppose a powerful tool to study with a higher reliability new aspects of mammary gland biology including normal and diseased tissue. However, normal primary human epithelial cells in culture achieve senescence at 10 to 40 population doubling, hampering their long-term culture. In addition, some studies have described lineage-specific marker limitations to be used in order to isolate these two cell types, since some of the markers tend to change during cell culture.
Experimental Procedures: In this protocol we compared two different methodologies in an effort to improve isolation, culture and immortalization of different cell populations of human normal mammary epithelium. We based our approaches in previously described methods incorporating additional steps to improve cell survival, to preserve cellular antigens used for isolation and validation of cell subpopulations and to enhance cellular transformation. For these purposes, we determined cell growth and viability, and also cell-lineage specific markers of cytospinned cells in both methodologies used.
Results: One of the goals of the present work to yield on cell survival and antigens preservation is in fact overnight digestion at low enzymatic concentration. Other crucial steps are cell immortalization and also addition of critical compounds to the cell culture media.
Conclusions: In the present work, we propose some guidelines to establish more efficiently mammary epithelial cell lines allowing long-term cell culture system and providing us a strong instrument to better understand the role of the different epithelial cell types and the origins of breast cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A150.
Citation Format: Gemma Fuster, Arantzazu Zubeldia-Plazaola, Mario Mancino, Patricia Fernández-Nogueira, Elisabet Ametller, Pedro Gascón, Vanessa Almendro. A methodology for the isolation, culture, and immortalization of human breast epithelial and myoepithelial cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A150.
Abstract A156: CrkI and CrkII adaptor proteins promote invasiveness and metastasis via epithelial-mesenchymal transition (EMT) in A549 lung adenocarcinoma cells.
Authors: Elmansuri Aiman , Tanino Mishie , Mahabir Roshan , Wang Lei , Tsuda Masumi , Kimura Taichi , Nishihara Hiroshi , Tanaka Shinya 
Published: August 2014

Abstract
Epithelial-to-mesenchymal transition (EMT) is a leading phenomenon implicated in morphogenesis, invasiveness and metastasis of cancer cells. Likewise, Crk adaptor proteins described to promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions in MDCK kidney epithelial cells. In this study we show that overexpression of CrkI and CrkII; members of Crk adaptor family of signalling proteins in A549 lung adenocarcinoma cells induce morphological changes resemble mesenchymal cells with high motility and invasiveness potential in both in vitro and in vivo. Furthermore, CrkI and CrkII both induce EMT but mostly through different pathways, while CrkI had a significant effect on TGFβ1-SMAD pathway which might be the inducer of EMT, more than CrkII, CrkII which had a higher Rac1 activity in the other hand showed a prominent effect on the expression of transcriptional factors regulating EMT like Snail and Slug, leading to almost total loss of the cell-cell adhesion glycoprotein E-cadherin expression, as well as remarkable increases in the production of extracellular matrix metalloproteinase (MMP) 2. These effects were opposed by inhibiting Rac1 activity. In conclusion, we could describe that CrkI and CrkII have a differential effect on the EMT process via activating Rac1, MMPs production, and the potential effect on TGF-β signalling, highlighting novel regulatory mechanisms of the adaptor protein Crk, and its involvement in cancer metastasis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A156.
Citation Format: Aiman Elmansuri, Mishie Tanino, Roshan Mahabir, Lei Wang, Masumi Tsuda, Taichi Kimura, Hiroshi Nishihara, Shinya Tanaka. CrkI and CrkII adaptor proteins promote invasiveness and metastasis via epithelial-mesenchymal transition (EMT) in A549 lung adenocarcinoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A156.
Abstract A158: DAXX/ATRX and MEN1 genes are stong prognostic markers in pancreatic neuroendocrine tumor.
Authors: Park Joo Kyung , Paik Woo Hyun , Ryu Ji Kon , Kim Yong-Tae , Lee Se-Hoon 
Published: August 2014

Abstract
Introduction: The incidence and prevalence of pancreatic neuroendocrine tumors (PNET) are increasing; these tumors represent approximately 1.3% of all cases of pancreatic cancer in incidence and 10% of cases in prevalence. PNET has usually better prognosis compared to that of pancreatic ductal adenocarcinoma, however, some of PNETs are diagnosed as in advanced stage with distant metastasis. Accurate prediction of its prognosis and the proper treatment may be very important in patients with PNETs.
Aims and Methods: The aim of this study was to explore prognostic markers based on genetic basis of PNETs and they were known as the most frequently mutated genes MEN1, DAXX/ATRX. The pathologically confirmed 111 patients with PNETs were enrolled and the following clinical and pathologic factors were evaluated; AJCC stage, treatment modalities, differentiation and mitosis. Also, immunohistochemical staining of MEN1, DAXX/ATRX genes, Ki-57, chromogranin, synaptophysin, CD56, somatostatin, insulin and glucagon were done.
Results: The median age of study patients was 55 yrs and AJCC staging of the patients were as follows:IA;41 patients, IB;30 patients, IIA;13 patients, IIB;8 patients, IV; 19 patients. The median OS was 55.5 months and 81 patients underwent R0 resection. There were 23 patients (27%), 17 patients (20%) and 27 patients (31%) were positive for MENIN, ATRX and DAXX respectively. In addition, DAXX and ATRX are known to be mutually exclusive genes. Mutations in the MEN1 and DAXX/ATRX genes were resulted in negative immunohistochemical staining and it was significantly associated with longer DFS and OS (33 mo. vs. 65 mo., p &lt; 0.01; 63 mo. vs. 124 mo., p &lt;0.001 respectively). AJCC staging and grade of differentiation were the statistically significant prognostic factors among other clinical variables.
Conclusion: Mutations in the MEN1 and DAXX/ATRX genes (negative immunohistochemical staining results) were associated with better clinical prognosis. This study was the first one to investigate prognostic markers based on genetic basis of PNETs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A158.
Citation Format: Joo Kyung Park, Woo Hyun Paik, Ji Kon Ryu, Yong-Tae Kim, Se-Hoon Lee. DAXX/ATRX and MEN1 genes are stong prognostic markers in pancreatic neuroendocrine tumor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A158.
Abstract A16: A drug combination screen identifies taxanes as synergistic agents with the oral IAP inhibitor Debio 1143 in non-small cell lung cancer cells.
Authors: Langdon Casey G. , Wiedemann Norbert , Held Mathew A. , Platt James T. , Lévy Frédéric , Zanna Claudio , Vuagniaux Grégoire , Sorensen Mel , Wang Shaomeng , Bosenberg Marcus W. , Stern David F. 
Published: August 2014

Abstract
Background: Drug resistance is a major problem in cancer therapy. The combination of drugs targeting simultaneously multiple critical nodes of the signalling networks controlling growth and survival of cancer cells is necessary to achieve long-lasting responses. The members of the Inhibitor of apoptosis protein (IAP) family are key negative regulators of programmed cell death. Their frequent overexpression in most cancer types contributes to tumor cell survival and resistance to cancer therapy making IAPs attractive therapeutic targets. The oral monovalent SMAC mimetic, Debio 1143/AT-406, functions as an antagonist of multiple IAP proteins (cIAP1/2 and XIAP) and is currently in clinical development for cancer treatment. The goal of this study is to identify novel synergistic combination partners with Debio 1143 in non-small cell lung cancer (NSCLC).
Material and Methods: An in vitro high-throughput combination screen was performed using 6 human NSCLC cell lines bearing various genetic alterations. Debio 1143 was pairwise combined with 128 commercially available oncology compounds in a cell viability assay. To identify supra-additive drug combinations, the dose-response curves were analysed using the Bliss independence method. Synergistic combinations were further studied using tumor xenograft mouse models.
Results: Among several interesting combinations, we observed strong synergism of Debio 1143 combined with docetaxel or paclitaxel, two standard-of-care drugs in NSCLC. The beneficial effect of the combination between Debio 1143 and taxanes was further validated in multiple mouse cancer xenografts where the combination caused marked anti-tumour activity that was superior to either monotherapy.
Conclusion: These findings underline the feasibility of using in vitro high-throughput screening for the discovery of novel drug combinations with increased anti-tumour efficacy in vivo. Furthermore, they provide a rationale for the combination of the SMAC mimetic Debio 1143 with taxanes and are the basis for ongoing clinical trials in several cancer types.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A16.
Citation Format: Casey G. Langdon, Norbert Wiedemann, Mathew A. Held, James T. Platt, Frédéric Lévy, Claudio Zanna, Grégoire Vuagniaux, Mel Sorensen, Shaomeng Wang, Marcus W. Bosenberg, David F. Stern. A drug combination screen identifies taxanes as synergistic agents with the oral IAP inhibitor Debio 1143 in non-small cell lung cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A16.
Abstract A160: Characterization of novel regulators for epithelial-mesenchymal transition.
Authors: Li Linna , Lu Emily , Chang Jeffrey , Li Wenliang 
Published: August 2014

Abstract
The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits of breast cancer cells. Recently, a few kinases, such as FYN and c-Met, were reported to participate in regulating EMT. However, the roles of the majority of &gt;700 human kinases in EMT and breast cancer progression are still unknown. Here we carried out human kinase cDNA screens to identify novel regulators of EMT. Many unknown EMT regulators and a few known ones such as PI3K, PDGFRA, FYN and c-Met, were found to up-regulate mesenchymal marker vimentin. Some also increase expression of fibronectin and N-cadherin, as well as EMT transcriptional regulators, such as ZEB1/2, Snail and Slug. At the same time, the cells acquired mesenchymal phenotypes, such as increased migration/invasion activity, enhanced capability to survive and proliferate in growth factor deprivation condition or under drug treatments. Interestingly, FACS analysis also showed a substantial increase in CD44hiCD24low population in kinase-transducted mammary gland epithelial cells. The increase of CD44hi population could be attributed to increase of a CD44 mesenchymal variant - the standard form CD44s and decrease of the epithelial variant CD44 v8-10. And this alternation was associated with down-regulation of ESRP1 and ESRP2, two splicing factors that regulate CD44 splicing and EMT. Furthermore, the mammary gland epithelial cells undergoing EMT showed increase capability of forming mammosphere and differentiating into other lineages, such as osteoblast and adipocyte. Importantly, some of these novel EMT regulators are associated with TNBC, stemness and poor prognostics of human breast cancers. One novel regulator, a poorly studied serine/threonine protein kinase, was tested in vivo and found to be capable of generating primary tumor and metastasis at much higher efficiency. Further study of these novel EMT regulators promises to provide new mechanisms of breast cancer progression, and may also lead to development of new prognostic markers and therapeutics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A160.
Citation Format: Linna Li, Emily Lu, Jeffrey Chang, Wenliang Li. Characterization of novel regulators for epithelial-mesenchymal transition. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A160.