These findings demonstrate that PPARγ agonists can have differential effects on RPE survival in response to oxidative stress. Oxidative stress leads to deregulation of a large set of genes in ARPE-19 cells. A specific subset of these genes can be selectively modulated by troglitazone and represent potential novel targets for cytoprotective therapies.
Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.
The dual-specificity tyrosine phosphorylated and regulated kinase Mirk/DYRK1B belongs to an evolutionary conserved family of kinases involved in the control of growth and development. DYRK1B has low level of expression in most normal cell types but is amplified or over-expressed in a number of human cancers. DYRK1B regulates the exit of cancer cells from quiescence through regulating cyclin D turnover and p27kip1 stabilization, thus participating as substantial actor in the control of cancer cell cycle progression. Diaxonhit has developed a novel class of DYRK inhibitors with potent in vitro efficacy. Among them, EHT 5372 reduces tumor growth in a PANC-1 xenograft model and reduces ascites spheroids to single cells and induces their apoptosis. Three-dimensional (3D) multicellular spheroids are symmetrical cellular aggregates that model an in vitro system of intermediate complexity between monolayer cultures and tumors in vivo. Here, we have conducted genome-wide analysis of transcriptional changes between normal (monolayer, 2D) and 3D culture conditions of pancreatic PANC-1 cells using Diaxonhit's GWSATM platform to identify tumor-relevant genes and pathways. The PANC-1 multicellular spheroid model was first characterized based on phenotypical and functional properties and we then analyzed the pharmacological response of spheroids to EHT 5372 and other DYRK inhibitors treatment. A strong up-regulation of DYRK1B was evidenced and confirmed at the protein level. Stemness-related markers were investigated and some were also found much higher in the spheroids than within the monolayer cultures and further increased in a culture time-dependent manner. Stem-like cancer cells may be the cause of therapy-resistance and relapse in patients and sphere forming ability is one of properties of this quiescent cancer-initiating cells. As DYRK1B contributes to G0 arrest to maintain the viability of quiescent cancer cells, pharmacological DYRK inhibition would reduce the capacity of cells to enter into quiescence and sensitize cancer cells to conventional chemotherapeutic agents or radiation. Molecular and physiological consequences of inhibiting DYRK1B with EHT 5372 are now being investigated along with genes expression changes in stemness-related markers and in biological pathways involved in tumor cell growth regulation. A molecular characterization of pancreatic cancer cell spheroids is currently undertaken to determine the utility of the 3D assay as a surrogate tool enriched in cancer stem cells. Spheroids also enable the study of quiescence, chemoresistance and metastasis. DYRK1B inhibitors screening in 3D models is a powerful approach that can help focus on compounds active on these crucial mechanisms of cancer cell biology. The most active compounds identified in this program are likely good candidates for in vivo xenograft studies. Citation Format: Anne-Sophie CASAGRANDE, Florence BACHELOT, Emeline THROO, Florence MAHE, Bertrand LEBLOND, Thierry BESSON, Matthew PANDO, Laurent DESIRE. 3D multicellular pancreatic cancer spheroids as drug screening tool for pharmacological evaluation of EHT 5372 and other Mirk/DYRK1B inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2620. doi:10.1158/1538-7445.AM2014-2620
Alternative splicing of pre-mRNA, a key post-transcriptional mechanism allowing for the production of distinct proteins from a single gene, affects over 90% of human genes. Splicing plays a major role in gene regulation in normal tissues as well as in disease. In cancer, alternative splicing permits the generation of protein isoforms having different biological activities. Thus, splicing alterations participate in the diversity and phenotypic plasticity of tumor cells. The identification of such molecular changes represent promising avenues for cancer diagnosis and therapy.Lung cancer is the leading cause of cancer mortality. Over 80% of lung cancers are non-small cell lung carcinomas (NSCLC). Adenocarcinoamas (AC) and Squamous Cell Carcinomas (SCC) are the two most common subtypes of NSCLC and account for more than 60% of lung cancer cases. Despite being categorized together in NSCLC due to similar microscopic appearance of their tumour cells and similar treatment options in the clinic, AC and SCC are heterogeneous in many clinical aspects, these include distinct oncogenic mutations and divergent therapeutic responses, thus heightening the emphasis on accurate NSCLC subtyping.Here, we describe two approaches to seek transcriptome changes that discriminate between SCC and AC subtypes. To do so, we profiled SCC and AC biopsies together with their adjacent normal tissues on Exonhit's Genome Wide SpliceArray™, a new generation of microarray that extends transcriptomic profiling to the monitoring of alternative splicing, thereby increasing the discriminatory power of the analyses. Through this discovery platform, disease status, progression, and drug response can be monitored. First, we developed transcriptomic signatures using combinations of exon body, exon-intron junction, evidenced and discovery probes and performed principal component analyses at various q values and fold change thresholds. Using a t-test on the first principal component, we compared their respective efficacy to discriminate between SCC and AC subtypes. The data that will be discussed highlight the importance of discovery and junction probes in the signatures. Second, an epitope identification approach was conducted. We focused on splicing events that generate potential novel amino acid sequences. Events up-regulated were selected based on combination of statistical analysis of probe sets deregulations, protein knowledge and pathway analyses. The events were used to identify novel cell surface epitopes which may be suitable for antibody development. These findings should be validated with larger sample numbers but indicate that alternative RNA splicing offers a currently underexploited source of biological information for cancer research. Platforms dedicated to splicing can be useful to allow identification of biomarkers and novel targets, as well as guidance in the selection and follow-up of patients for therapy. Citation Format: Laurent Désiré, Anne-Sophie Casagrande, Florence Mahé, Emeline Throo, Matthew P. Pando. An alternative splicing study approach to discriminate between NSCLC subtypes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4147. doi:10.1158/1538-7445.AM2013-4147
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