bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B289: Inhibition of platelet-derived growth factor receptors by ARQ 087, a multi-tyrosine kinase inhibitor.
Authors: Yu Yi , Lee Jennifer , Dransfield Daniel T. 
Published: August 2014

Abstract
Background: The platelet-derived growth factor (PDGF) receptors are receptor tyrosine kinases which contain two isoforms, PDGFRα and β. They form homo- or hetero-dimers and exert different biological functions including organ development and vascularization. Dysregulation of PDGF receptors has been implicated in tumor initiation and progression in addition to playing a major role in epithelial-mesenchymal transition, metastasis, and tumor angiogenesis. ARQ 087, a pan FGF receptor inhibitor inhibits FGFR1, 2, and 3 with IC50 from 2 to 4 nM.
Methods: We have performed in vitro kinase profiling to determine percent inhibition of selected kinases and IC50 for PDGFRα and its mutated form. siRNA knockdown was applied to evaluate cell proliferation of the PDGFRα-dependent cancer cell lines NCI-H1703 and A-204. Western blot analysis including phospho PDGFRα/β, pSTAT3, pAKT, pERK together with cell migration and invasion analysis was performed on NCI-H1703 and NIH-3T3 cells.
Results: ARQ 087 is an inhibitor of PDGF receptors which is supported by the in vitro kinase profiling results. ARQ 087 but not Imatinib, was equally potent against wild-type PDGFRα and the mutated form of PDGFRα (D842V), indicating a potential clinical implication for Imatinib-resistant PDGFR-driven cancers. Knockdown of PDGFRα using siRNA suppressed PDGFRα-dependent cancer cell line proliferative activity. ARQ 087 inhibition of cell proliferation was accompanied by the reduction of phosphorylation of PDGFRα and its downstream proteins. In addition to the anti-proliferative activity, ARQ 087 suppressed migration and invasion of NCI-H1703 cells through targeting PDGFRα and migration of NIH-3T3 cells through targeting PDGFRβ.
Conclusions: ARQ 087 is not only an inhibitor of the FGFR family but also of the PDGFR family, suggesting that targeting cancers driven by PDGF receptors or mutated forms may provide an additional clinical path for ARQ 087.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B289.
Citation Format: Yi Yu, Jennifer Lee, Daniel T. Dransfield. Inhibition of platelet-derived growth factor receptors by ARQ 087, a multi-tyrosine kinase inhibitor. [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 B289.
Abstract B300: Discovering immune-mediated therapy for cancer biologics is informed by in vitro cellular assays.
Authors: Williams Geoff , Poon Edmund , Ireland Samantha , Dillon Janette , Stewart Ross , Wilkinson Robert 
Published: August 2014

Abstract
Immune-mediated therapy for cancer (IMT-C) biologics are an emerging class of cancer drugs which target cells of the immune system to enhance the immune response to cancer. Cross-reactivity of IMT-C mAbs and other biologics to rodents is rare, emphasizing the importance of human in vitro assays in IMT-C discovery and development. Typically there is a trade-off between the physiological relevance of an assay and its throughput, hence higher-throughput assays are used in the early stages of drug discovery, and more complex, lower-throughput assays are subsequently used to profile lead candidates. Here, we review a panel of in vitro cellular assays currently used for IMT-C drug programs at MedImmune including transgenic reporter cell systems, bead-based assays, and multi-cellular systems using cell-lines and primary human immune cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B300.
Citation Format: Geoff Williams, Edmund Poon, Samantha Ireland, Janette Dillon, Ross Stewart, Robert Wilkinson. Discovering immune-mediated therapy for cancer biologics is informed by in vitro cellular assays. [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 B300.
Abstract B34: Development of a urine microvesicle/exosome RNA biomarker panel to identify prostate cancer.
Authors: Skog Johan , Noerholm Mikkel , Bentink Stefan , Romain Charlotte , Fishbeck Jillian , Sinclair Ian , Scott Anna , Mueller Romy , Koestler Tina , Belzer Susan 
Published: August 2014

Abstract
Introduction: Prostate cancer is diagnosed utilizing anywhere from 10-12 transrectal prostate needle biopsy specimens (PNB). The decision to biopsy is driven in part by the PSA test, which is known to have marginal accuracy in appropriate patient selection. As a result, between 40 to 60% of patients will have a benign biopsy with approximately 20% having false negative results. Exosomal RNA is stable in urine and can be easily extracted from a random urine sample. A novel molecular assay with an improved ability to predict the likelihood of having prostate cancer on a needle biopsy is being developed through isolation of RNA from urine exosomes and subsequent identification of an accurate prognostic gene signature.
Methods: A multicenter study was designed to collect first catch random urine, without a prior digital rectal exam (DRE) from men presenting for a PNB. Urine samples were processed at Exosome Diagnostic's clinical laboratory under quality control using the EXO70 Urine Microvesicle RNA Isolation Kit. The exosomal RNA was reverse transcribed and qPCR assays for specific genes performed. The results of those assays along with collected clinical data and PNB histopathology were subjected to statistical analysis to derive ROC curves.
Results: Urine samples from 258 men scheduled for a PNB were tested. Triaged gene lists previously shown to be important in prostate cancer were compiled and univariately assessed with respect to discrimination of PNB results. A series of single and multiple gene expression profiles representing anywhere from 1 to 3 gene signatures relative to a reference gene were identified. Multivariate models including several gene signatures with a ROC AUC performance &gt; 0.7 were found. Interestingly, a 3 gene signature composed of PCA3, ERG and KLK3 provided a very good performance with an AUC of 0.76 (N = 122).
Conclusions: Prostate cancer cells release exosomes / microvesicles that can be isolated from a random urine sample. The exosomal RNA is stable and can be efficiently isolated and used for tumor profiling even without a prior DRE. This urine exosome platform presents a robust model for a quick and simple test that can assist in the initial biopsy decision process.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B34.
Citation Format: Johan Skog, Mikkel Noerholm, Stefan Bentink, Charlotte Romain, Jillian Fishbeck, Ian Sinclair, Anna Scott, Romy Mueller, Tina Koestler, Susan Belzer. Development of a urine microvesicle/exosome RNA biomarker panel to identify prostate cancer. [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 B34.
Abstract B36: Expression of growth and cell proliferation factors in gastric carcinomas: The association with poor overall survival on patients with intestinal type.
Authors: Begnami Maria D. , Pinto Clovis AL , Nonogaki Sueli , Soares Fernando , Lima Luiz GCA 
Published: August 2014

Abstract
Background: Gastric carcinomas (GC) express a variety of growth factors and cell proliferation acting in the mechanisms of tumor invasion and spread. The expression of angiogenic factors such as vascular endothelial growth factor (VEGF) has been demonstrated in diffuse type GC, whereas expression of growth factors is associated with intestinal-type carcinomas. Objective: To study the immunohistochemical expression of proteins associated with growth factors and cell proliferation in GC. Methods: We studied 400 GC, arranged in duplicates in 2 blocks of tissue microarray (TMA). Immunohistochemistry was performed using antibodies: c-MET (Novocastra), TGFbetaI (Santa Cruz), TGFbetaII (Santa Cruz), c-erbB-2 (Dako) and VEGF (Santa Cruz). Cases were considered positive for TGFbetaI, TGFbetaII and VEGF when cytoplasmic staining was observed in more than 10% of tumor cells. Positive cases for c-met and c-erbB-2 were detected when strong staining on the membrane cells was observed in more than 10% of neoplastic cells. Results: Expression of TGFbetaI, TGFbetaII and VEGF were detected in 314/385 (81%), 370/382 (96%) and 333/366 (90%) of GC. 333/376 (88%) cases were positive for c-met and 54/385 (14%) for c-erbB-2. Intestinal type carcinomas were more often positive for TGFbetaII (p = 0.01), VEGF (p = 0.001), c-met (p = 0.01), and c-erbB-2 (p = 0.001). According to univariate statistical analyzes expressions of TGFbeta II, c-met and c-erbB-2 were independent factors associated with overall survival of patients with GC. Conclusions: The proteins associated with growth factors and cell proliferations are differentially expressed in intestinal type of GC. Our findings pointed them out as biological factors associated with worse prognosis and important therapeutic targets.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B36.
Citation Format: Maria D. Begnami, Clovis AL Pinto, Sueli Nonogaki, Fernando Soares, Luiz GCA Lima. Expression of growth and cell proliferation factors in gastric carcinomas: The association with poor overall survival on patients with intestinal type. [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 B36.
Abstract B44: Assessing factors predictive of response to ADCs for companion diagnostic strategies.
Authors: Krueger Joseph S. , Lange Holger , Potts Steve , Young David 
Published: August 2014

Abstract
One premise of antibody-drug conjugates (ADC) is that the bound mAb-antigen complex on the cell surface will internalize and be metabolized by lysosomal proteases to release the free drug. Thus, the efficacy of an ADC is dependent not only on the presence of cell surface antigens, but also in-tact delivery of the conjugated drug, and an active pathway of receptor-mediated endocytosis. On a cellular level, the biological mechanisms behind receptor internalization and turnover have not been elucidated for novel therapeutic targets. On a tissue level, vascularization and hypoxic profile will affect delivery of the antibody into the tissue. Varying expression of the antibody target within the tissue (antigen density) will also affect the uptake of the ADC. Furthermore, the extracellular stability of the ADC may be affected by the activity of the various proteases in the tumor microenvironment (TME), outside of the lysozome. These concepts are critical for efficacy, and thus are especially important for companion diagnostic approaches (CDx) meant to predict response to ADCs. Thus, a predictive assay which would account not only for the degree of cell surface expression of the target, but also receptor internalization and potential effects of tumor microenvironment is required. To answer this need, Flagship Biosciences has invented several proprietary approaches for measuring critical properties of the therapeutic target on the cell surface or inside the cell, as well as properties of the TME which could be used to understand and predict efficacy to an ADC using FFPE biopsies. These quantitative pathology approaches are based on image analysis approaches which been designed specifically for ADC CDx programs to answer these critical questions: 1) Defining cell surface target expression independent of cytoplasmic expression; 2)Estimating receptor flux (turnover, internalization) based on staining profile; 3) Assessing critical factors in the TME which may affect delivery of the in-tact drug to the intracellular target; 4) Assaying vascular properties which may affect delivery of the drug; and 5)Heterogeneity of the target within a tumor. We are able to provide these as discrete evaluations or multiplex these evaluations for an integrative answer which can be derived from a typical clinical biopsy. Incorporation of these novel tools will enable ADC developers to create efficacy and patient stratification paradigms which incorporate the critical biological endpoints unique to ADCs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B44.
Citation Format: Joseph S. Krueger, Holger Lange, Steve Potts, David Young. Assessing factors predictive of response to ADCs for companion diagnostic strategies. [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 B44.
Abstract B49: Prox1 Transcription factor promotes colorectal cancer growth by expanding the Lgr5-positive stem cell pool.
Authors: Wiener Zoltan , Högström Jenny , Hyvönen Ville , Holopainen Tanja , Band Arja , Kallio Pauliina , Dufva Olli , Haglund Caj , Kruuna Olli , Ben-Neriah Yinon 
Published: August 2014

Abstract
The Wnt pathway that is central in the development of colorectal cancer (CRC) plays a critical role also in the maintenance of the normal gut. Inhibition of this pathway could thus lead to serious side-effects in CRC patients. We have previously shown that the Prox1 transcription factor is expressed only in a few cells of normal intestinal crypts, yet it contributes to CRC progression via an unknown mechanism. In this study, we show that Prox1 deletion in the WT intestinal epithelium has no obvious phenotypic consequence and that Prox1 regulates the number of Lgr5+ CRC stem cells via establishing a proper niche for them. Upon Apc deletion, Prox1 expression is rapidly induced in both the Lgr5+ CRC stem cells and Lgr5- non-stem. Prox1 deletion in 3D organoid cultures derived from mouse intestinal adenomas or human CRC cells leads to a decrease in lumen formation and crypt-like "outpocketings” that are enriched in Lgr5+ CRC stem cells. This results in a decreased number of Lgr5+ stem cells and a shift from the CRC stem cell-like phenotype to a progenitor-like phenotype, which consequently leads to decreased tumor cell growth. Interestingly, we show that silencing of the Prox1-suppressed Wnt-target Annexin A1 (Anxa1) mimics the effects of Prox1, including the establishment of a niche for Lgr5+ CRC stem cells. Anxa1 silencing in human and mouse CRC organoids results in an enhanced formation of outpocketings, an elevated number of Lgr5+ CRC stem cells and increased tumor growth in xenotransplantation assays. We propose a model where the deletion of the Apc gene induces both Anxa1 and Prox1 expression in the intestinal epithelium. Prox1 silencing elevates the expression of Anxa1, which inhibits the formation of crypt-like outpocketings and the Lgr5+ CRC stem cell niche, consequently leading to reduced tumor growth. Based on this study Prox1 is the first molecule which regulates the number of CRC stem cells without affecting the homeostasis of the adult WT intestine and it provides an attractive therapeutic target for drug development in CRC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B49.
Citation Format: Zoltan Wiener, Jenny Högström, Ville Hyvönen, Tanja Holopainen, Arja Band, Pauliina Kallio, Olli Dufva, Caj Haglund, Olli Kruuna, Yinon Ben-Neriah. Prox1 Transcription factor promotes colorectal cancer growth by expanding the Lgr5-positive stem cell pool. [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 B49.
Abstract C111: In vitro characterization of TAS-121, a novel, highly potent, and mutant-specific EGFR-TKI.
Authors: Ito Kimihiro , Miyadera Kazutaka , Aoyagi Yoshimi , Kato Masanori , Yonekura Kazuhiko , Iwasawa Yoshikazu , Utsugi Teruhiro 
Published: August 2014

Abstract
Background: The active mutation of epidermal growth factor receptor (EGFR), L858R or deletion in exon19, are present in patients with NSCLC and responsive to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib. Over time, most tumors develop resistance to these EGFR inhibitors by the acquiring of drug-resistant mutations including gatekeeper T790M mutation (more than 50% cases). Severe skin rash and diarrhea caused by wild-type EGFR (wtEGFR) inhibition limit EGFR TKI treatment. Therefore targeting mutant EGFR (mtEGFR) but not wtEGFR represents an attractive therapeutic strategy.
In this report, we identify a small molecule EGFR inhibitor, TAS-121, that targets mtEGFR but not wtEGFR and its biological characterization in vitro.
Methods: In vitro enzyme inhibition activity of TAS-121 for EGFR and its mutants was determined by using purified EGFRs and peptide substrates. Cellular phosphorylation of EGFR was assayed by immunoblot analysis. For growth inhibition assay, cells were treated with TAS-121 for 3 days, and living cells were determined by using CellTiter GloTM which measures cellular ATP. Apoptosis assay was conducted by using Caspase-GloTM and Cell Counting Kit.
Results: TAS-121 was found to be a more potent mutant selective EGFR-TKI based on bioavailability characteristics compared to our proto-type compound, TAS-2913.
TAS-121 inhibits kinase activity of EGFR mutants harboring T790M in a sub-nano molar range and much more potently than that of wtEGFR. TAS-121 inhibits auto-phosphorylation of EGFR and intercellular signaling pathways in NCI-H1975 (EGFR T790M / L858R) and HCC827 (EGFR del E746-A750). In a cell proliferation assay, TAS-121 also suppresses growth of NCI-H1975 and HCC827 more potently than that of a normal cell which grows in an EGF-dependent manner. Therefore, the wtEGFR / mtEGFR inhibition ratio of TAS-121 appears to be higher than those of other EGFR TKIs. Furthermore, TAS-121 induces apoptosis in NCI-H1975 but erlotinib could not.
Conclusion: These results suggest that TAS-121, a potent mutant-selective EGFR inhibitor, may represent a new therapeutic strategy in the treatment of NSCLC resistant to currently available EGFR/TKIs. Further pre-clinical evaluations and development are ongoing.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C111.
Citation Format: Kimihiro Ito, Kazutaka Miyadera, Yoshimi Aoyagi, Masanori Kato, Kazuhiko Yonekura, Yoshikazu Iwasawa, Teruhiro Utsugi. In vitro characterization of TAS-121, a novel, highly potent, and mutant-specific EGFR-TKI. [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 C111.
Abstract C132: Targeting heat shock factor 1 improves the antitumor efficiency of hyperthermia.
Authors: Scherz-Shouval Ruth , Bagley Alexander F. , Whitesell Luke , Bhatia Sangeeta N. , Lindquist Susan 
Published: August 2014

Abstract
The heat-shock response is a powerful transcriptional program which acts genome-wide, not only to restore normal protein folding through the induction of heat shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1]. HSF1 exerts its role by activating a unique transcriptional program in the cancer cells [2]. Indeed, increased HSF1 levels, as well as activation of its transcriptional signature, are associated with reduced survival in breast, lung and colon cancer patients [3].
Cancer cells are exquisitely dependent on HSF1 for survival. Exposure to additional stress, such as heat, further increases their dependency on HSF1. Recently we described how translation is linked to HSF1 activation using a derivative of the natural compound rocaglamide [4]. We found that this drug-like inhibitor of translation-initiation inhibits HSF1 and leads to tumor regression in hematopoietic malignancies. Here we combine this compound, or genetic inhibition of HSF1 expression, with focal heat therapy delivered via gold nano rods. We find that inhibiting HSF1 in solid tumors increases the efficiency of hyperthermia as an anticancer treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C132.
Citation Format: Ruth Scherz-Shouval, Alexander F. Bagley, Luke Whitesell, Sangeeta N. Bhatia, Susan Lindquist. Targeting heat shock factor 1 improves the antitumor efficiency of hyperthermia. [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 C132.
Abstract C138: Loss of NF1 in melanoma cell lines is associated with active Ras and dependence on MEK even in the absence of BRAF or NRAS mutation.
Authors: Nissan Moriah H. , Pratilas Christine , Jones Alexis , Won Helen , Kong Li , Yao Zhan , Merghoub Taha , Ribas Antoni , Chapman Paul , Yaeger Rona , Taylor Barry , Shultz Nikolaus , Berger Michael F. , Rosen Neal , Solit David B. 
Published: August 2014

Abstract
Though two-thirds of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the roughly 30% of melanoma tumors wild-type for BRAF and NRAS remain largely uncharacterized. The selective RAF inhibitors vemurafenib and dabrafenib inhibit MAPK pathway activity only in BRAF mutant cells, thus their clinical utility is restricted to patients with BRAF mutant tumors. MEK inhibitors, which have broader antitumor activity and have shown promising activity in NRAS mutant melanoma, may be effective in a broader range of MAPK pathway-dependent tumors. We performed a functional and genomic analysis of melanoma cell lines wild-type for BRAF and NRAS to determine whether occult mutations in RAS signaling were present. Elevated RAS-GTP was common in BRAF/NRAS wild-type melanoma cell lines, a subset of which exhibited total loss of NF1 protein expression. The proliferation of NF1-null melanoma cells was dependent upon MEK, though the cellular potency of several allosteric MEK inhibitors that are currently in clinical testing (PD0325901, AZD6244, MEK162 and trametinib) varied widely in NF1-null melanoma cells. The greatest antitumor activity was noted with trametinib, a MEK inhibitor that also blocks RAF mediated phosphorylation of MEK. Notably, alterations in NF1 also co-occurred with RAS and BRAF mutations in both cell lines and human melanomas. In the setting of BRAF co-mutation, loss of NF1 abrogated upstream negative feedback on RAS activation resulting in constitutive expression of RAS-GTP and resistance to RAF but not MEK inhibition. In summary, NF1 loss is a common event in cutaneous melanoma that is associated with RAS activation, MEK dependence and RAF inhibitor resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C138.
Citation Format: Moriah H. Nissan, Christine Pratilas, Alexis Jones, Helen Won, Li Kong, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul Chapman, Rona Yaeger, Barry Taylor, Nikolaus Shultz, Michael F. Berger, Neal Rosen, David B. Solit. Loss of NF1 in melanoma cell lines is associated with active Ras and dependence on MEK even in the absence of BRAF or NRAS mutation. [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 C138.