bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A200: Galectin-1-exposed dermal and tumor-associated fibroblasts produce biologically active extracellular matrix which improves growth of endothelial cells in vitro
Authors: Varinska Lenka , Mojzis Jan , Gabius Hans-Joachim , Smetana Karel , Gal Peter 
Published: May 2016

Abstract
The tumor microenvironment is formed by both malignant and non-malignant cells as well as by extracellular matrix (ECM) components. Stromal cells located in the tumor are primarily considered as sources of promalignant factors. Toward this end, we here address the issue of testing whether ECM affects vessel growth, considering the impact of a potent effector for conversion of fibroblasts to myofibroblasts and ECM production, i.e. the adhesion/growth-regulatory galectin-1. This endogenous lectin, known for triggering diverse cellular responses such as growth modulation, invasion or motility and production of vascular endothelial growth factor-C, is here studied for its impact on the qualities of ECM to sustain proliferation of human umbilical vein endothelial cells (HUVECs). Fibroblasts had been cultured for 10 days with the lectin, followed by removing cellular constituents after an osmotic shock. Freshly isolated HUVECs were placed on the ECM. In parallel, HUVECs were seeded on untreated and gelatin-coated surfaces as controls. A positive control for growth of HUVECs culture using medium supplemented with vascular endothelial growth factor completed the test panel. Cells were kept in contact to the substratum for two days and then processed for immunocytochemistry. HUVECs seeded on fibroblast-generated ECM presented a comparatively high degree of proliferation. Furthermore, contact to substratum produced by tumor-associated fibroblasts led to generation a meshwork especially rich in fibronectin. Galetctin-1 is apparently capable to trigger ECM production favorable for growth of HUVECs, prompting further work on characterizing structural features of the ECM and in situ correlation of lectin presence, ECM constitution and neo-angiogenesis.
Acknowledgement
This study was supported in part by the Agency for Science and Research under the contract no. APVV-0408-12 and by VEGA-1/0299/13.
Citation Format: Lenka Varinska, Jan Mojzis, Hans-Joachim Gabius, Karel Smetana, Jr., Peter Gal. Galectin-1-exposed dermal and tumor-associated fibroblasts produce biologically active extracellular matrix which improves growth of endothelial cells in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A200.
Abstract A23: CancerNet biomarker profiling panel
Authors: Chenchik Alex , Diehl Paul , Iakoubov Leonid , Frangou Costa 
Published: May 2016

Abstract
Background: Next-generation sequencing (NGS) is playing a transformational role in cancer discovery research; providing a powerful way to study DNA and/or RNA from clinical specimens. Unfortunately, the cost and complexity of whole genome sequencing approaches represent major barriers to use of these methodologies in routine molecular diagnostic testing. Nonetheless, a comprehensive catalog of all types of mutations in cancer opens unique opportunities for understanding the mechanism of cancer onset or progression and facilitates a more personalized approach to clinical care, including improved risk stratification and treatment selection.
Methodology: Recently developed targeted approaches reduce NGS data complexity and generate qualitative sequencing information by measurement of a subset of targets per technical replicate with minimal sample usage. To this end, we have developed a novel, multiplex PCR target enrichment-based NGS pipeline (Driver-Map) designed to comprehensively assess the genomic landscape of both solid tumors and hematologic malignancies from clinical samples. Importantly, CancerCore analyzes the genomic alterations for 569 pan-cancer driver genes. Simultaneous quantitative target gene expression analysis using multiplex quantitative RNA-Seq (Q-RNA-Seq) for ∼2,000 additional genes (CancerNet) and computational network modeling facilitates the rapid identification of cancer gene and/or pathway models to identify commonalities across tumor type(s) and supporting pharmacogenetics information.
Results: To determine the broad utility of this methodology and determine whether Driver-Map captures biologically relevant information, we apply it to clinical samples from triple-negative breast cancer (TNBC) patients and demonstrate that our approach identifies novel therapeutically tractable genes.
Conclusion: In summary, Driver-Map provides both strand-specific sequencing at single-base resolution and ‘digital’ gene expression profiling, resulting in better detection of both rare genetic variants and low abundance mRNA transcripts. Moreover, Driver-Map results in unparalleled specificity and sensitivity while increasing the cost-effectiveness for high-throughput clinical Next-Gen applications.
Citation Format: Alex Chenchik, Paul Diehl, Leonid Iakoubov, Costa Frangou. CancerNet biomarker profiling panel. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A23.
Abstract A28: NFATC3-PLA2G15 fusion transcript identified by RNA-sequencing promotes tumor progression in colorectal cancer cells
Authors: Jang JE , Kim HP , Lee SH , Lee DW , Lim YJ , Han SW , Kim TY 
Published: May 2016

Abstract
In order to identify novel fusion transcripts in colorectal cancer, we carried out paired-end RNA sequencing in 28 human colorectal cancer cell lines. Fusion transcript candidates were identified using ChimeraScan and FusionMap tools. We obtained 1380 candidates having 4 or more read counts and spanning reads. Among the candidates, we selected 27 candidates for validation which harbors genes related to the Wnt signaling pathway or kinases according to KEGG or DAVID. After the targeted gene filtering step, validation using RT-PCR with fusion specific primers finally resulted in 2 intra- and 1 inter-fusion transcripts. Intra-fusion transcripts were NFATC3-PLA2G15 and AKAP13-PDE8A and inter-fusion transcript was KRT8-PKM2 each identified in colo-320, SW-480 and SNU-1235, respectively. The fusion junctions were confirmed by Sanger sequencing. NFATC3-PLA2G15 fusion transcripts consisted of exon 1-9 of NFATC3 (nuclear factor of activated T-cells, cytoplasmic 3) gene and exon 2-6 of the PLA2G15 (Phospholipase A2, Group 5) gene and both located on the same chromosome 16q. NFATC3 is known as transcription factor in the Wnt signaling pathway and regulates function of the target genes like cell proliferation, invasion and epithelial-to-mesenchymal transition (EMT). Under the experiments using siRNA in the colo-320 cell carrying fusion transcript, knockdown of the NFATC3-PLA2G15 fusion transcript decreased mRNA and protein expression of mesenchymal markers, namely vimentin (VIM), Twist-related protein 1 (TWIST1) and fibronectin (FN), and increased epithelial markers, E-cadherin (CDH1) and claudin-1 (CLDN1). Fusion transcripts knockdown also led to decrease of the invasion ability regulated by above markers. Moreover, soft agar assay showed inhibition of colony formation after fusion transcript knockdown. Fusion transcript downregulation also resulted in decrease of cell proliferation and mRNA and protein expression of cyclin D but increase in p27 level. The knockdown did not have influence in the fusion negative cell line. Collectively, these results suggest that the NFATC3-PLA2G15 fusion transcript is involved in invasion and proliferation of colorectal cancer cells.
Citation Format: JE Jang, HP Kim, SH Lee, DW Lee, YJ Lim, SW Han, TY Kim. NFATC3-PLA2G15 fusion transcript identified by RNA-sequencing promotes tumor progression in colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A28.
Abstract A36: Circulating cell-free DNA as a marker for response and resistance to BRAF and EGFR inhibition in BRAF-mutated metastatic colorectal cancer
Authors: Morris Van , Janku Filip , Huang Helen , Fu Siqing , Overman Michael , Piha-Paul Sarina , Subbiah Vivek , Kee Bryan , Tsimbierdou Apostolia , Fogelman David , Shurieqi Imad , Manuel Shanequa , Scamardo Antonio , Lanman Richard , Sommer Nicolas , Hong David , Kopetz Scott 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:15 PM ET Friday, November 6.
Citation Format: Van Morris, Filip Janku, Helen Huang, Siqing Fu, Michael Overman, Sarina Piha-Paul, Vivek Subbiah, Bryan Kee, Apostolia Tsimbierdou, David Fogelman, Imad Shurieqi, Shanequa Manuel, Antonio Scamardo, Richard Lanman, Nicolas Sommer, David Hong, Scott Kopetz. Circulating cell-free DNA as a marker for response and resistance to BRAF and EGFR inhibition in BRAF-mutated metastatic colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A36.
Abstract A38: In vitro and in vivo characterization of a novel NEK2 inhibitor MBM5 for the treatment of gastrointestinal cancer
Authors: Fang Yanfen , Zhang Xiongwen , Hu Wenhao , Kong Yannan , Wang Hong , Zhu Mengli 
Published: May 2016

Abstract
NEK2 is a conserved mitotic regulator critical for centrosome splitting and correct chromosome segregation. Aberrant expression of NEK2 has been found in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. Here we report the discovery of a novel small molecule NEK2 inhibitor, MBM5, for the treatment of gastrointestinal cancer cells. A series of compounds have been synthesized to determine their potency against NEK2. Through in vitro kinase assay, we found that compound MBM5 exhibited a significant inhibitory effect on the kinase activity of NEK2. MBM5 also demonstrated strong inhibition on proliferation of a broad spectrum of tumor cells, especially gastrointestinal cancer cells (IC50&lt;1 μM). Treating cells with MBM5 triggered a significant accumulation of cells at G2/M phase and a modest accumulation of cells with &gt;4N DNA content. By releasing cells from the G1/S boundary, we found that the progression from G2/M to G1 phases were completely abrogated in the presence of MBM5. In consistence, we further observed that MBM5 induced chromosomal misalignment in metaphase and slightly increased the level of multinucleated cells, confirming the perturbed mitotic progression. And these was correlated with MBM5-inhibited phosphorylation of Hec1 and Histone 3. Over time, the accumulation of chromosomal abnormalities led to apoptosis, as evidenced by the increased population of Annexin-V/PI positive cells, the up-regulated expression of cleaved-caspase 3 and the cleavage of PARP. In vivo daily treatment with MBM5 (ip, 20 mg/kg, 3 weeks) significantly inhibited the growth of MGC-803 gastric tumor and HCT-116 colonal tumor xenografts. Altogether, this study demonstrates that MBM5 interfered with NEK2 functions both in cells and tumor xenografts, thus showing its potential in anti-cancer treatment regimens.
Citation Format: Yanfen Fang, Xiongwen Zhang, Wenhao Hu, Yannan Kong, Hong Wang, Mengli Zhu. In vitro and in vivo characterization of a novel NEK2 inhibitor MBM5 for the treatment of gastrointestinal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A38.
Abstract A59: Exploration of Tid1 and mitochondrial EGFR in non-small cell lung carcinoma tumorgenesis
Authors: Chen Chi-Yuan , Lin Yu-Han , Pi Wen-Chieh 
Published: May 2016

Abstract
The epidermal growth factor receptor (EGFR) over activity has been associated with a number of cancers, including non-small cell lung carcinoma (NSCLC). Known the critical role of EGFR in NSCLC and the recent findings that mitochondrial accumulation of EGFR could contribute to tumorigenesis, several interesting oncology questions related with the intracellular trafficking of EGFR to mitochondria need to be addressed. Tid1 (also known a mitochondrial Hsp40) has 2 isoforms, Tid1-L and Tid1-S, which may function differently. Since we have recently shown that Tid1 can interact with EGFR and that Tid1 is a mitochondrial protein, we postulate that Tid1 may participate in the mitochondrial localization of EGFR and play a role in NSCLC tumorigenesis. Using immunofluorescence microscopy, we observed that EGFR and Tid1 co-located within mitochondria in NSCLC cells. Moreover, mitochondria EGFR (mtEGFR) interact with both Tid1 isoforms directly under EGF stimulation, although there is a stronger association with the Tid1-S. In NSCLC patient tumors have shown mtEGFR and Tid1-S to be an indicator for poor clinical outcomes in cancer patients. Moreover, EGFR mitochondrial translocation can be decreased by erlotinib treatment in H3255 cells and greatly decline of cell viability. From the above observations, we believe that an adequate quantity of mitochondrial EGFR is critical for survival in NSCLC. Additional experiments are needed to further explore if Tid1 plays a role in the mitochondrial accumulation of EGFR in NSCLC cells.
Citation Format: Chi-Yuan Chen, Yu-Han Lin, Wen-Chieh Pi. Exploration of Tid1 and mitochondrial EGFR in non-small cell lung carcinoma tumorgenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A59.
Abstract A63: Role of the metastasis suppressor, NDRG1, in regulating the EGFR and ErbB family of receptors and its effects on key oncogenic signaling pathways in pancreatic cancer
Authors: Menezes Sharleen V. , Kovacevic Zaklina , Richardson Des R. 
Published: May 2016

Abstract
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that has been shown to affect numerous signaling pathways that control oncogenesis. In this study, the role of NDRG1 was investigated on a key upstream effector, namely epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor 2 (HER2) and human epidermal growth factor receptor 3 (HER3). This is of interest, as the ErbB family of receptor tyrosine kinases are involved in regulating multiple cell responses, being key regulators of down-stream oncogenic-signaling.
We demonstrate that NDRG1 is able to significantly reduce the expression, localisation and activation of EGFR, HER2 and HER3, while also inhibiting the formation of EGFR/HER2 and HER2/HER3 heterodimers. This investigation also showed that a novel class of anti-cancer agents, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), were able to markedly up-regulate NDRG1. These agents were found to inhibit EGFR, HER2 and HER3 expression and phosphorylation in PANC-1 pancreatic cancer cells in vitro. Moreover, these compounds led to a significant reduction of the expression of these proteins in PANC-1 tumour xenografts in vivo.
Due to the limitations of current anti-cancer therapeutics, these agents were also compared to a clinically used EGFR inhibitor, Erlotinib. Our study showed that in comparison to Erlotinib, both Dp44mT and DpC displayed higher anti-proliferative activity in pancreatic cancer cells. This could be significant, as DpC is due to enter clinical trials this year for the treatment of aggressive solid tumours (http://www.colmeddev.com/oncochel/).
Together, these findings reveal the molecular mechanisms that underlie the anti-cancer effects of NDRG1, and in turn, demonstrate the potential origin of the extensive down-stream effects attributed to this molecule.
Citation Format: Sharleen V. Menezes, Zaklina Kovacevic, Des R. Richardson. Role of the metastasis suppressor, NDRG1, in regulating the EGFR and ErbB family of receptors and its effects on key oncogenic signaling pathways in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A63.
Abstract A93: The Smac mimetic Debio 1143 synergizes with radiotherapy and immune checkpoint inhibitors to enhance antitumor immunity
Authors: BARKHOUSE Darryll , TAO Zhen , MYERS Carey , WIEDEMANN Norbert , GAVILLET Bruno , HARSHYNE Larry , DICKER Adam , HOOPER D.Craig , VUAGNIAUX Gregoire , Lu Bo 
Published: May 2016

Abstract
Introduction: Radiotherapy (RT) kills cancer cells, increases tumor antigenicity, and stimulates the immune response which can be further augmented by systemic immune-modulating agents. Debio 1143 is an oral antagonist of the inhibitors of apoptosis proteins (IAPs) currently in clinical development, which sensitizes tumor cells to RT- or chemotherapy-induced apoptosis, and modulates NFκ-B signalling. We hypothesized that, in addition to its activity on apoptosis, Debio 1143 could improve antitumor immunity by increasing the effects of RT and anti-PD1 treatment.
Experimental procedures: Using immunocompetent mouse models of lung cancer (Lewis lung cancer) and melanoma (B16F10), the anti-tumor activity of RT and anti-PD-1 was tested either alone or in combination with Debio 1143. The effects of the treatment on the immunological components were determined by FACS.
Results: Combining radiotherapy and Debio 1143 in vivo potently prevented tumor growth and increased the local accumulation of cytotoxic T cells. Activation of cytotoxic T cells proved to be mediated through the release of tumor necrosis factor alpha in the tumor microenvironment. In addition, Debio 1143 was able to potently stimulate the ability of an anti-PD1 antibody to kill tumor cells in vivo.
Conclusions: These data offer a new paradigm to improve the tumor immune response elicited by RT and immune checkpoint inhibitors and serve as the foundation for future clinical translation of combination therapy between Debio 1143, radiotherapy and immune-oncology agents.
Citation Format: Darryll BARKHOUSE, Zhen TAO, Carey MYERS, Norbert WIEDEMANN, Bruno GAVILLET, Larry HARSHYNE, Adam DICKER, D.Craig HOOPER, Gregoire VUAGNIAUX, Bo Lu. The Smac mimetic Debio 1143 synergizes with radiotherapy and immune checkpoint inhibitors to enhance antitumor immunity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A93.
Abstract B114: Combination of BGJ398 with either a pan-PI3K inhibitor or a specific PIK3CA inhibitor shows synergy in FGFR2 mutant endometrial cancer cell lines
Authors: Pollock Pamela M. , Geng Xinyan , Bonazzi Vanessa F. , Mahon Clare , Stephenson Sally , Packer Leisl 
Published: May 2016

Abstract
Background: Our lab has identified FGFR2 mutations in 12% of over 1500 endometrioid endometrial cancers (ECs) analyzed. The majority of these tumors harbor genetic aberrations in the PI3K/AKT pathway resulting in constitutive activation. In other tissue types, PTEN loss has been shown to provide resistance to specific PIK3CA inhibition. We have previously reported that FGFR inhibition with PD173074 induced cell death despite loss of PTEN. We hypothesize that dual inhibition of FGFR2 and the PI3K pathway will lead to increased cell death and more effective tumor growth inhibition.
Materials and Methods: Two FGFR2 mutant EC cell lines were treated with BGJ398 (pan FGFR inhibitor) alone or in combination with either a pan-PI3K inhibitor (GDC0941) or a specific PI3KA inhibitor (BYL719). Synergy was assessed using the fixed ratio method proposed by Chou and Talalay. Cell death was determined by Annexin V staining and colony formation assays using low clinically relevant drug concentrations. Downstream signaling pathways were analyzed by Western blot analysis and BGJ398 in combination with either GDC0941 or BYL719 was assessed in vivo.
Results: Synergy was observed between BGJ398 and either the pan-PI3K inhibitor (GDC0941), or the specific PI3KA inhibitor (BYL719). Regression of tumor xenografts was observed in mice treated with BGJ398 and GDC0941 as well as BGJ398 and BYL719, despite PTEN inactivation.
Conclusions: Dual targeting of the FGFR and PI3K pathways is more effective than targeting either of them alone. PTEN loss does not provide resistance to PIK3CA inhibition in our EC models suggesting context dependent differences in PI3K signaling.
Citation Format: Pamela M. Pollock, Xinyan Geng, Vanessa F. Bonazzi, Clare Mahon, Sally Stephenson, Leisl Packer. Combination of BGJ398 with either a pan-PI3K inhibitor or a specific PIK3CA inhibitor shows synergy in FGFR2 mutant endometrial cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B114.
Abstract B115: Design and development of a novel series of PI3K-p110beta/delta-selective inhibitors with combined tumor immunotherapeutic, growth inhibition and anti-metastatic activity
Authors: Shuttleworth Stephen 
Published: May 2016

Abstract
The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of solid and hematological malignancies. In solid tumor therapy, the majority of clinical activity has centered on pan-class I (p110alpha, beta, delta and gamma) inhibitors of limited selectivity, or pan-class I/mTOR dual inhibitors, whereas targeting p110delta and p110gamma has been the main focus for hematological cancer treatment. Our research at Karus has focused on the emerging role of p110beta and p110delta in both cancer types, though increasingly in solid tumors, in which overexpression, mutation and PTEN-defectiveness have been shown to be key features in disease pathogenesis and progression. We have designed and developed a uniquely-selective series of orally-active molecules that inhibit the p110beta/delta isoforms, and which display extremely high specificity in the human kinome. The design of such molecules has enabled us to interrogate the function of p110delta in solid tumor immunotherapy and p110beta in primary tumor growth and metastasis, with our lead compounds showing promising oral activity in syngeneic models, in which they inhibit tumor growth and metastatic spread whilst also impacting on downstream biomarker levels. Additionally, through our ability to tune selectivity over p110alpha and p110gamma, elimination of the mechanism-related toxicities associated with those isoforms can be realized, making selective dual p110beta/delta inhibition, described herein for our lead compound, KA2237, potentially more conducive to combination therapy than for pan-inhibitors, including with signal transduction pathway inhibitors and other immunotherapeutics. KA2237, an orally-active, potent and selective small molecule p110beta/delta inhibitor, has completed GLP toxicology and will enter Phase I studies in 2015.
Citation Format: Stephen Shuttleworth. Design and development of a novel series of PI3K-p110beta/delta-selective inhibitors with combined tumor immunotherapeutic, growth inhibition and anti-metastatic activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B115.