bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A134: MiR-875-5p impairs prostate cancer metastasis by remodeling tumor secretome and enhances tumor radiation response via EGFR suppression
Authors: Fenderico Nicola , Cominetti Denis , El Bezawy Rihan , Tortoreto Monica , Dugo Matteo , Valdagni Riccardo , Gandellini Paolo , Zaffaroni Nadia 
Published: May 2016

Abstract
Acquisition of mesenchymal features by carcinoma cells through the epithelial-mesenchymal transition (EMT) is responsible for the initiation and sustainment of the metastatic cascade, as well as the establishment of a chemo- and radio-resistant phenotype. In prostate cancer (PCa), metastatic disease remains incurable despite the approval of several new drugs for clinical use in recent years. In addition, emergence of resistance to radiotherapy, which is one of the mostly used therapeutic options for PCa, still represents a clinical challenge. In the study, we reported for the first time on the possible therapeutic utility of miR-875-5p, a microRNA the role of which in human cancer has not been so far investigated. By exploiting the correlation with E-cadherin levels in a series of PCa clinical specimens, we identified miR-875-5p as a novel microRNA able to impair metastasis in PCa experimental models by repressing EMT and remodeling tumor secretome, mainly reducing cytokine secretion. Indeed, the sole intratumoral administration of the culture media obtained from PCa cells ectopically overexpressing miR-875-5p showed antitumor (max tumor volume inhibition: 49%, P&lt;0.01) and antimetastatic (significant reduction of spontaneous dissemination to the lung) effects in SCID mice subcutaneously xenotransplanted with PCa cells. We additionally found that the reversion of EMT operated by miR-875-5p depends at least in part on the repression of epidermal growth factor receptor (EGFR), a direct target of the microRNA as confirmed in a luciferase assay, and consequent reduction of interleukin-8 secretion. Consistent with the known role of EGFR in determining response to ionizing radiation, we found that miR-875-5p overexpression increased the radiosensitivity of PCa cells, in terms of reduced clonogenic cell survival and decreased DNA damage repair, as assessed by γH2AX foci and DNA comet tail in individual cells. Overall, our data support the clinical interest in developing a novel therapeutic approach for PCa based on miR-875-5p reconstitution to counteract tumor dissemination and increase response to radiotherapy.
Citation Format: Nicola Fenderico, Denis Cominetti, Rihan El Bezawy, Monica Tortoreto, Matteo Dugo, Riccardo Valdagni, Paolo Gandellini, Nadia Zaffaroni. MiR-875-5p impairs prostate cancer metastasis by remodeling tumor secretome and enhances tumor radiation response via EGFR suppression. [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 A134.
Abstract A171: Targeting tumor metabolism by novel EGFR inhibitor in head and neck cancer
Authors: Kuo Ching-Chuan , Hsieh Hsing-Pang , Kung Hsing-Jien 
Published: May 2016

Abstract
Cellular metabolism is substantially altered during tumor progression, and associated with poor prognosis and therapeutic resistance of human cancers. Therefore, the metabolic rewiring of cancer cells has been viewed as a promising source for novel drug targets, and being actively pursued in the development of selective antineoplastic agents. EGFR targeted agents currently approved or under investigation for head and neck squamous cell carcinoma (HNSCC) include EGFR monoclonal antibodies or EGFR tyrosine kinase inhibitors (EGFR-TKI). However, HNSCC patients failing to these agents treatment, due to the development of acquired tumor resistance, will have a compromised survival. We have identified a novel EGFR-TKI, BPR3K007S0. Based on the EC50 in enzyme-based assay of wild-type EGFR & EGFR mutant L858R protein, BPR3K007S0 is more effective than that of clinical used EGFR-TKI gefitinib (Iressa). We further evaluated the drug effects on EGFR phosphorylation in HNSCC cells, and found that BPR3K007S0 inhibited phosphorylation of EGFR in a time-dependent manner. Further study demonstrated that BPR3K007S0 decreased HNSCC cell proliferation and colony formation by causing G1-phase arrest, which was strongly associated with a marked decrease of the level of cyclin E and cdk2 with concomitant induction of p21 and p27. Notably, BPR3K007S0 showed much potent effect toward cell growth in vitro and in vivo than that of gefitinib in HNSCC cells, implicating that the anticancer effect of BPR3K007S0 is not limited to EGFR inhibition. More importantly, we found that BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes. Among them, the levels of c-Myc and hexokinase 2 were significantly decreased in a time-dependent manner by treatment with BPR3K007S0. Gene manipulation study demonstrated that knockdown of c-Myc leads to a decreased level of hexokinase 2. In this system, silence of EGFR did not affect c-Myc expression, suggesting that c-Myc may not be the EGFR downstream target in used HNSCC cells. Taken together, these results revealed that BPR3K007S0 has added benefits by targeting of EGFR and cancer metabolism, and are likely to be superior to gefitinib in HNSCC models. Thus, development of multi-kinase and metabolic inhibitors holds promises for overcoming treatment resistance of HNSCC. (Grant support: DOH102-TD-M-111-102001)
Citation Format: Ching-Chuan Kuo, Hsing-Pang Hsieh, Hsing-Jien Kung. Targeting tumor metabolism by novel EGFR inhibitor in head and neck 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 A171.
Abstract A176: RET inhibition: Development of novel compounds and a personalized medicine strategy in lung adenocarcinoma
Authors: Watson Mandy , Small Helen , Chapman Phil , Hopkins Gemma , Begum Habiba , Waddell Ian D. , Ashton Garry , Abbey Caron , Harris Jade , Ayub Mahmood , Mohan Sumitra , Rothwell Dominic , Brady Ged , Dive Caroline , Jordan Allan , Ogilvie Donald 
Published: May 2016

Abstract
Background:RET is a receptor tyrosine kinase (RTK) and forms part of a macromolecular receptor complex containing dimerised RET receptor, two co-receptors and a bound ligand. Signalling networks downstream of RET play an important role in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activating mutations in RET (e.g. C634W and M918T) are known drivers in medullary thyroid carcinomas (MTC). More recently, oncogenic RET fusions (e.g. CCDC6-RET and KIF5B-RET) have been identified in 1-2% of lung adenocarcinoma patients. We are currently developing novel, selective inhibitors of RET, and at the same time, investigating a number of biomarker approaches for the stratification of RET fusion-positive lung cancer patients who might benefit from such therapy.
Methods: We have undertaken collaborative studies using established techniques including immunohistochemistry (IHC) and FISH (DNA break apart and RNA). In addition, we have investigated hybrid capture DNA sequencing of both biopsy material and circulating tumour DNA in the blood. Here we, compare and contrast the benefits of each biomarker assay evaluated and consider how these approaches could be translated for use in Phase I clinical trials at The Christie.
Conclusion: Our data supports the successful implementation of predictive biomarkers to identify patients who might benefit from treatment with selective RET inhibitors.
Acknowledgements:This work was funded by Cancer Research UK (Grant numbers C480/A1141 and C5759/A17098).
Citation Format: Mandy Watson, Helen Small, Phil Chapman, Gemma Hopkins, Habiba Begum, Ian D. Waddell, Garry Ashton, Caron Abbey, Jade Harris, Mahmood Ayub, Sumitra Mohan, Dominic Rothwell, Ged Brady, Caroline Dive, Allan Jordan, Donald Ogilvie. RET inhibition: Development of novel compounds and a personalized medicine strategy in lung adenocarcinoma. [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 A176.
Abstract A182: Targeting the topoisomerase I enzyme in cancer cells with acquired resistance to SN-38
Authors: Stenvang Jan , Jensen Niels Frank , Jandu Haatisha , Knudsen Steen , Agama Keli , Jensen Thomas , Hansen Anker , Jensen Peter Buhl , Pommier Yves , Cushman Mark , Brünner Nils 
Published: May 2016

Abstract
De novo or acquired resistance to anti-cancer drugs represents a major obstacle to successful treatment of cancer patients. In order to improve future cancer drug development we have established the DEN-50R cell line panel which when fully developed will consist of isogenic pairs of drug sensitive and resistant human cancer cell lines representing the 5 most common cancer types.
Based on the DEN-50R we have tested a number of novel anti-cancer drugs in this panel of cell lines. One class of drugs that includes the indenoisoquinolines LMP400 and LMP776, which have topoisomerase 1 inhibitory activity and recently passed phase 1 clinical studies, showed very interesting features in the cell line studies.
When tested in SN-38 (the active metabolite of irinotecan) -sensitive and -resistant isogenic colorectal cancer cell lines and breast cancer cell lines, LMP400 showed significant dose related cytotoxicity independent of the state of SN-38-resistance (Table). As these resistant cell lines have significant up-regulation of either the BCRP and/or mdr-1 protein, it can be concluded that the indenoisoquinoline LMP400 can target topoisomerase 1 enzyme without being a substrate for these drug efflux pumps.
We are now planning to initiate two clinical phase II studies (Simon's two stage design) with LMP400; one in irinotecan-failed metastatic colorectal cancer patients and one in late stage metastatic breast cancer patients. Patients for these studies will be preselected based on an LMP400-responsiveness profile we generated by gene expression data where associations between gene expression profiles and growth inhibition were compared in a panel of cell lines exposed to LMP400. A second step included filtering the identified gene expression profile against mRNA expression from a collection of 3200 human tumors. Only genes being differentially expressed in the clinical tumor material were retained in the model.
Sensitivity to LMP776 and LMP400 of human colorectal and breast cancer cell lines with acquired resistance to SN-38
Cell lineCross-resistantSensitiveHCT116-SN-38*LMP400; LMP776HT29-SN-38LMP776LMP400LoVo-SN-38LMP776LMP400MDA-MB-231- SN-38LMP776LMP400MCF-7- SN-38LMP776; LMP400* HCT-116-SN38 resistant cells have gained a mutation in the binding site of SN38 and LMP400 during acquisition of SN-38 resistance.
Citation Format: Jan Stenvang, Niels Frank Jensen, Haatisha Jandu, Steen Knudsen, Keli Agama, Thomas Jensen, Anker Hansen, Peter Buhl Jensen, Yves Pommier, Mark Cushman, Nils Brünner. Targeting the topoisomerase I enzyme in cancer cells with acquired resistance to SN-38. [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 A182.
Abstract CN07-01: Using CTCs to improve outcomes in SCLC: Single cell profiling, ex vivo cultures, and mouse models
Authors: Dive Caroline 
Published: May 2016

Abstract
There is increasing agreement that minimally invasive biomarkers to monitor patients receiving targeted therapies have significant potential to facilitate personalized medicine. The rarity and heterogeneity of CTCs make them a technically demanding source of biomarkers but one that holds great promise as the technical challenges are met. Marker independent technology platforms are in development which will better assess CTC subpopulations, but none so far have been fully validated for clinical trial use and treatment decision-making. CTC enumeration with CellSearch (EpCam and cytokeratin positive CTCs) has prognostic significance in many epithelial tumors, and in diseases with prevalent CTCs such as small cell lung cancer (SCLC) the dynamic range of CTC number allows pharmacodynamic evaluation. Biomarkers based on multiplex protein analysis and FISH are also evaluable in CTCs if sufficient can be detected. Examples of CTC based biomarkers in clinical trials will be presented.
Developments in single CTC isolation and genomic profiling are increasingly reported by allowing insight to the biology of invasive tumor cells, including cellular co-expression of cancer specific mutations. I will present our progress in DNA profiling of single SCLC CTCs, and how this approach may inform on inter- and intratumor heterogeneity, and via serial sampling, on mechanisms of drug resistance. Most recently, we developed lung cancer patient CTC derived mouse models (termed CDX). SCLC CDX models faithfully recapitulate patient drug responses and will be useful to test novel therapeutics. CDX are generated at patient presentation and for those patients who first respond and then relapse with drug resistant disease, the relapse blood sample can be used to generate a paired CDX. Alongside single CTC profiling, the CDX approach will allow a comprehensive analysis of acquired drug resistance to chemotherapy, the discovery of new drug targets and testing of targeted therapies and drug combinations. I will also describe recent research exploring vasculogenic mimicry (VM) in SCLC, whereby tumor cells adopt endothelial characteristics and form vessels to increase nutrient and oxygen delivery to tumor independent of host vasculature. SCLC VM may explain the prevalence of CTCs and the early dissemination of this dismal disease and VM pathways may provide novel therapeutic targets.
Finally, I will present a case report on a NSCLC patient whose blood sample contained no CellSearch CTCs yet generated a CDX model. CTC filtration of this patients blood revealed a high proportion of mesenchymal CTCs consistent with Epithelial to Mesenchymal Transition (EMT).
Citation Format: Caroline Dive. Using CTCs to improve outcomes in SCLC: Single cell profiling, ex vivo cultures, and mouse models. [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 CN07-01.
Abstract CN07-04: Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Authors: Tirosh Itay , Izar Benjamin , Prakadan Sanjay M. , Wadsworth Marc H. , Treacy Daniel , Trombetta John J. , Lu Diana , Rotem Asaf , Lian Christine , Murphy George , Cohen Ofir , Allen Eli van , Bertagnolli Monica , Genshaft Alex , Hughes Travis K. , Ziegler Carly G. K. , Kazer Samuel W. , Gaillard Aleth , Kolb Kellie E. , Valbuena1 Judit , Yoon Charles , Rozenblatt-Rosen Orit , Shalek Alex K. , Regev Aviv , Garraway Levi 
Published: May 2016

Abstract
A single tumor is composed of malignant cells in diverse genetic and epigenetic states, and this diversity presents a significant barrier for targeted therapies. Furthermore, diverse non-malignant cells, such as immune, fibroblasts and endothelial cells shape the tumor microenvironment and are emerging as important drug targets. However, the diversity of cellular states among malignant and non-malignant cells within any tumor remains poorly understood. To begin to address these challenges we applied single-cell RNA-seq to profile &gt;3,000 single cells isolated from 16 fresh human melanomas, and characterized distinct cell types and cell states. We found that malignant cells within the same tumor display transcriptional heterogeneity associated with multiple biological processes. In particular, subpopulations of cells in treatment-naïve tumors expressed a transcriptional program associated with resistance to RAF/MEK inhibition, and these were enriched in post-relapsed samples. Among several non-malignant cell types that were identified we focused on tumor-infiltrating T-cells and identified multiple profiles of exhaustion which differed among patients and could be linked to prior immunotherapies. Finally, we used our single cell–derived profiles of cell types within melanoma to deconvolve publicly available bulk tumor profiles and infer interactions between cells in the tumor microenvironment. This work demonstrates the capacity of single cell transcriptomics to offer new insights with implications for both targeted and immune therapies and will be broadly applicable to other tumor types.
Citation Format: Itay Tirosh, Benjamin Izar, Sanjay M. Prakadan, Marc H. Wadsworth II, Daniel Treacy, John J. Trombetta, Diana Lu, Asaf Rotem, Christine Lian, George Murphy, Ofir Cohen, Eli van Allen, Monica Bertagnolli, Alex Genshaft, Travis K. Hughes, Carly G. K. Ziegler, Samuel W. Kazer, Aleth Gaillard, Kellie E. Kolb, Judit Valbuena1, Charles Yoon, Orit Rozenblatt-Rosen, Alex K. Shalek, Aviv Regev and Levi Garraway. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. [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 CN07-04.
Abstract PR01: Structural mechanism of sequence-specific 5-methylcytosine (5mC) recognition by AP-1 transcription factors
Authors: Hong Samuel , Cheng Xiaodong 
Published: May 2016

Abstract
DNA methylation is generally known to inhibit transcription factor binding. However, this notion has been challenged with identifications of several transcription factors that preferentially activate methylated promoters in specific sequences. AP-1 transcription factor (c-Jun/c-Fos heterodimer), a master regulator of a wide range of cancer-related genes, has been shown to bind a novel consensus sequence (5'-TGACTCG-3') in CpG methylation-dependent manner. In the fluorescence polarization-based DNA binding assay, both c-Jun/c-Fos heterodimer and c-Jun/c-Jun homodimer preferentially bind DNA containing the methylated consensus sequence compared to DNA with unmethylated sequence. Using a homodimer of c-Jun/c-Jun basic leucine zipper (bZIP) DNA binding domain, we have solved the X-ray structure of AP-1 in complex with an oligonucleotide containing the methylated consensus sequence. The structure reveals that a common motif conserved among bZIP proteins is involved in the specific recognition of methylated CpG by one monomer and TpG by the other monomer. Like 5mC, thymine (5-methyluracil) contains a methyl group at C5 position, and the similarity imposed by the methyl C5 preserves key structural features of DNA sequence recognized by AP-1. Our in vitro finding resonates with previous studies of AP-1-like transcription factors that preferentially bind methylated response elements. In light of such evidence, our characterization of AP-1 as a sequence-specific 5mCpG and TpG reader suggests a novel way in which DNA methylation may function to activate transcription in a methylation-dependent manner.
Citation Format: Samuel Hong, Xiaodong Cheng. Structural mechanism of sequence-specific 5-methylcytosine (5mC) recognition by AP-1 transcription factors. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR01.
Abstract A36: Nuclear NUAK1 function on cancer cell survival, independently of LKB1 and p53
Authors: Palma Mario , Peña Daniela , Venturelli Katherine , Castro Ariel F. 
Published: May 2016

Abstract
Cancer cells evade cell death during tumor progression under metabolic stress. However, molecular mechanisms involved in cellular adaptation to this stress are still poorly understood. NUAK1, a serine threonine kinase of the AMPK catalytic subunit family, has been involved in tumor cell survival, but its regulation and function under metabolic stress remain unclear. For this study, we have used mouse embryo fibroblasts (MEFs) and cancer cells to better understand the role of NUAK1 in cell survival. We found that NUAK1 mRNA and protein levels increase in response to metabolic stress, suggesting a transcriptional regulation of NUAK1 expression. In addition, we found that NUAK1 is expressed almost exclusively in the nucleus of MEFs and several cancer cell lines. Because of the nuclear localization of NUAK1 and previous studies showing that NUAK1 regulates p53 transcription factor, we investigated whether p53 is necessary for NUAK1´s effect on cell survival. By using p53ER/ER MEFs that can be reversibly and rapidly switched between p53 wild-type and knockout states, we demonstrated that NUAK1 can promote cell survival in a p53-independent cellular context. Furthermore, NUAK1 was involved in cell survival of p53-null H1299 lung cancer and p53-null HCT116 colorectal cancer cells under metabolic stress. In parallel to the increase of NUAK1 expression, we found that NUAK1 is phosphorylated. LKB1 kinase is known to phosphorylate NUAK1, increasing NUAK1 kinase activity. However, shRNA-mediated depletion of LKB1 or mutation of the NUAK1 residue phosphorylated by LKB1 did not affect NUAK1 function on cell survival. By bioinformatics analysis of NUAK1 protein sequence, we found several sites predicted to be phosphorylated by JNK and p38. Future studies will determine whether JNK or p38 is involved in NUAK1 phosphorylation, and also evaluate whether NUAK1 nuclear localization is directly related with tumor progression in a p53-independent manner. Overall, our results showed that NUAK1 is transcriptional and post-translational regulated in response to metabolic stress, and that the effect of NUAK1 on cell survival is independently of LKB1 and p53.
Funded by FONDECYT 1120923
Citation Format: Mario Palma, Daniela Peña, Katherine Venturelli, Ariel F. Castro. Nuclear NUAK1 function on cancer cell survival, independently of LKB1 and p53. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A36.