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Source: Molecular Cancer Therapeutics

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Total 96 results found since Jan 2013.

GCS Inhibition in HNC
This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. The effect of genetic or pharmacologic GCS inhibition (using GCS siRNA/shRNA or d,l-threo-PPMP, respectively) on cisplatin sensitivity was assessed in several human HNC cells and acquired cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, ceramide production, and in preclinical tumor xenograft mouse models. GCS and P-gp expression were significantly associated with cisplatin resistance in several HNC cell lines (P = 0.007). Both were significantly ...
Source: Molecular Cancer Therapeutics - August 5, 2015 Category: Cancer & Oncology Authors: Roh, J.-L., Kim, E. H., Park, J. Y., Kim, J. W. Tags: Cancer Biology and Signal Transduction Source Type: research

Abstract B26: PI3K class I and mTOR regulate distinct steps in Met dependent tumorigenesis
The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. Although several Met inhibitors are in clinical trials, resistance may occur as experienced in the clinic with other RTKs. Thus, a need for alternative / complementary therapy may be required to target Met driven tumors efficiently.The aim of this study was to investigate whether PI3K plays a role in Met oncogenic activity, in view of designing appropriate therapy.The study was performed on two cell models suitable to study Met driven NIH3T3 cells expre...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Hervieu, A., Kermorgant, S. Tags: PI3K-mTOR Activation in Human Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B27: Superoxide anion O2.-mediated activation of mTORC2 by estrogen receptor in breast cancer cells: Role of acetylation dependent inhibition of MnSOD
Conclusion: Our finding unravel a new role of MnSOD as important control switch through which ER might affect its downstream non genomic signaling cascades in a redox dependent manner particularly potentiation of mTOR signaling complex 2. We present data in support of MnSOD being responsible for previously reported ER dependent superoxide anion O2.- potentiation in breast cancer cells following E2 exposure. We showed that MnSOD interacts with ER alpha which in turn is associated with its diminished SIRT 3 dependent deacetylation, leading to its inhibition and superoxide anion O2.- build up and consequent activation of mTOR...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Lone, M. U. d., Kanchan, R. K., Tripathi, C., Baghel, K. S., Tiwari, B., Bhadauria, S. Tags: PI3K-mTOR Activation in Human Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A30: A genome-wide siRNA screen in mammalian cells for regulators of S6 phosphorylation
To identify the cellular components that participate in the regulation of mTOR complex 1 (mTORC1), the amino acid-dependent, rapamycin-inhibitable complex, we carried out a genome-wide RNAi depletion screen. We employed a rabbit monoclonal antibody specific for RPS6 [Ser235P/Ser236P] and high content microscopy to quantify rpS6 phosphorylation in the pancreatic ductal adenocarcinoma cancer cell line (PDAC) MiaPaCa-2. Applying a stringent selection, we retrieved over 600 genes wherein at least two RNAi gave significant reduction in S6 phosphorylation. This cohort is significantly enriched in genes whose depletion affects th...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Papageorgiou, A., Tamayo, P., Mesirov, J., Avruch, J., Rapley, J. Tags: PI3K-mTOR Activation in Human Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A36: Combined inhibition of PI3K isoforms and mTOR kinase is critical for cancer stem cell inhibition by VS-5584
We report here that VS-5584 is up to 30-fold more potent at inhibiting the proliferation and survival of CSCs than non-CSCs in breast cancer cell lines using multiple orthogonal CSC assays. Moreover, VS-5584 preferentially induced apoptosis in Aldefluor-positive CSCs relative to Aldefluor-negative non-CSCs as measured by Annexin V and Caspase 3/7 assays. In contrast, paclitaxel induced more apoptosis in non-CSCs than CSCs cells. VS-5584 also preferentially diminished CSCs in human breast and small cell lung cancer xenograft models in vivo, as evidenced by marked reduction of tumor-initiating capacity in an in vivo limiting...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Kolev, V. N., Wright, Q. G., Weaver, D. T., Padval, M. V., Pachter, J. A., Xu, Q. Tags: Preclinical and Clinical Studies in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research

Cosilencing PKM-2 and MDR-1 in Ovarian Cancer
In this study, siRNA duplexes against pyruvate kinase M2 and multidrug resistance gene-1 were encapsulated in hyaluronic acid–based self-assembling nanoparticles. The particles were characterized for morphology, size, charge, encapsulation efficiency, and transfection efficiency. In vivo studies included biodistribution assessment, gene knockdown confirmation, therapeutic efficacy, and safety analysis. The benefit of active targeting of cancer cells was confirmed by modifying the particles' surface with a peptide targeted to epidermal growth factor receptor, which is overexpressed on the membranes of the SKOV-3 cance...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Talekar, M., Ouyang, Q., Goldberg, M. S., Amiji, M. M. Tags: Small Molecule Therapeutics Source Type: research

Significance of PTBP1 in Colorectal Cancer
Polypyrimidine tract–binding protein (PTBP1) is an RNA-binding protein with various molecular functions related to RNA metabolism and a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs. Here, we have investigated the role of PTBP1 in colorectal cancer. PTBP1 expression levels were significantly overexpressed in cancerous tissues compared with corresponding normal mucosal tissues. We also observed that PTBP1 expression levels, c-MYC expression levels, and PKM2:PKM1 ratio were positively correlated in colorectal cancer specimens. Moreover, PTBP1 expre...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Takahashi, H., Nishimura, J., Kagawa, Y., Kano, Y., Takahashi, Y., Wu, X., Hiraki, M., Hamabe, A., Konno, M., Haraguchi, N., Takemasa, I., Mizushima, T., Ishii, M., Mimori, K., Ishii, H., Doki, Y., Mori, M., Yamamoto, H. Tags: Cancer Biology and Signal Transduction Source Type: research

Abstract PR01: Inhibitory role of phosphatidylinositol-3,4-bisphosphate in triple-negative breast cancers
Triple-negative breast cancer (lacking expression of estrogen receptor, progesterone receptor and amplification of HER2/Neu) remains one of the most aggressive subtypes, affects the youngest patients and yet still lacks an effective targeted therapy. Novel insights into the molecular mechanisms that drive these cancers are imperative to guide development and application of such targeted therapies. Data from The Cancer Genome Atlas and other sources have suggested that phospho-Akt (pAkt) levels are significantly higher in triple-negative tumors compared to either hormone receptor positive tumors (express estrogen and/or pro...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Reed, D. E., Shokat, K. M. Tags: Molecular Regulation of the PI3K-mTOR Network: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B04: NPM1: A new downstream effector of PI3K-AKT-mTOR pathway in prostate cancer?
Nucleophosmin NPM1 is a molecular chaperone involved in many aspect of cellular physiology, eg. ribosomal biogenesis and cell cycle regulation. NPM1 is overexpressed in numerous types of solid tumors, including prostate cancer but the underlying molecular mechanisms are largely unknown. Using both cell lines and transgenic mouse models, we show that NPM1 expression is significantly increased in cells where the PI3K-AKT-mTOR pathway is activated through PTEN deletion. This overexpression is reversed when cells are treated with the pharmacological inhibitor of mTOR rapamycin. In accordance, transfection of small interfering ...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Boudra, R., Loubeau, G., Lours-Calet, C., Dejoussineau, C., Morel, L., Beaudoin, C. Tags: Downstream Effectors Underlying Cancer Progression: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B05: PI3K/mTOR pathway-dependent regulation of oxygen metabolism via pyruvate dehydrogenase (PDH)-E1alpha phosphorylation
The PI3K/mTOR pathway plays a central role in coupling metabolic processes to the cellular proliferative state. In the current study we show that pharmacological inhibition of this pathway leads to a decrease in hypoxia within SQ20B human head and neck cancer xenografts. The mechanism underlying the effect appears in part to be due to reduced tumor cell oxygen consumption induced by the drug. Pharmacologic inhibitors of the PI3K/mTOR pathway or genetic inhibition of Akt/PI3K decreased the oxygen consumption rate (OCR) in transformed cell lines in vitro by 30-40%. Pharmacologic inhibition of this pathway increased phosphory...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Cerniglia, G., Dey, S., Gallagher-Colombo, S. M., Daurio, N., Tuttle, S., Busch, T. M., Lin, A., Esipova, T. V., Vinogradov, S., Koumenis, C., Maity, A. Tags: Downstream Effectors Underlying Cancer Progression: Poster Presentations - Proffered Abstracts Source Type: research

MEK/Aurora Kinase Inhibition in Melanoma
Resistance to BRAF inhibitors is a major clinical problem. Here, we evaluate BI-847325, an ATP-competitive inhibitor of MEK and Aurora kinases, in treatment-naïve and drug-resistant BRAF-mutant melanoma models. BI-847325 potently inhibited growth and survival of melanoma cell lines that were both BRAF inhibitor naïve and resistant in 2D culture, 3D cell culture conditions, and in colony formation assays. Western blot studies showed BI-847325 to reduce expression of phospho-ERK and phospho-histone 3 in multiple models of vemurafenib resistance. Mechanistically, BI-847325 decreased the expression of MEK and Mcl-1 w...
Source: Molecular Cancer Therapeutics - June 4, 2015 Category: Cancer & Oncology Authors: Phadke, M. S., Sini, P., Smalley, K. S. M. Tags: Cancer Biology and Signal Transduction Source Type: research

Targeting MASTL and FOXM1 for Radiosensitization
In this study, we identified many genes that could potentially be exploited for targeted radiosensitization using a genome-wide siRNA screen in non–small cell lung cancer (NSCLC) cells. The screen identified 433 siRNAs that potentially sensitize lung cancer cells to radiation. Validation experiments showed that knockdown of expression of Forkhead box M1 (FOXM1) or microtubule-associated serine/threonine kinase-like (MASTL) indeed causes radiosensitization in a panel of NSCLC cells. Strikingly, this effect was not observed in primary human fibroblasts, suggesting that the observed radiosensitization is specific for ca...
Source: Molecular Cancer Therapeutics - June 4, 2015 Category: Cancer & Oncology Authors: Nagel, R., Stigter-van Walsum, M., Buijze, M., van den Berg, J., van der Meulen, I. H., Hodzic, J., Piersma, S. R., Pham, T. V., Jimenez, C. R., van Beusechem, V. W., Brakenhoff, R. H. Tags: Cancer Biology and Signal Transduction Source Type: research

Druggable Vulnerabilities in E-Cadherin-Deficient Cells
The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein–coupled receptor (GPCR) signaling protei...
Source: Molecular Cancer Therapeutics - May 5, 2015 Category: Cancer & Oncology Authors: Telford, B. J., Chen, A., Beetham, H., Frick, J., Brew, T. P., Gould, C. M., Single, A., Godwin, T., Simpson, K. J., Guilford, P. Tags: Cancer Biology and Signal Transduction Source Type: research

Dual PI3K/mTOR Inhibitors Enhance ERK Activation via mTORC2
The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser240/244), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at T...
Source: Molecular Cancer Therapeutics - April 9, 2015 Category: Cancer & Oncology Authors: Soares, H. P., Ming, M., Mellon, M., Young, S. H., Han, L., Sinnet-Smith, J., Rozengurt, E. Tags: Cancer Biology and Signal Transduction Source Type: research

Multifunctional Micelles for the Reversal of Drug Resistance
Ovarian cancer is a dreadful disease estimated to be the second most common gynecologic malignancy worldwide. Its current therapy, based on cytoreductive surgery followed by the combination of platinum and taxanes, is frequently complicated by the onset of multidrug resistance (MDR). The discovery that survivin, a small antiapoptotic protein, is involved in chemoresistance provided a new prospect to overcome MDR in cancer, because siRNA could be used to inhibit the expression of survivin in cancer cells. With this in mind, we have developed self-assembly polymeric micelles (PM) able to efficiently co-load an anti–sur...
Source: Molecular Cancer Therapeutics - April 9, 2015 Category: Cancer & Oncology Authors: Salzano, G., Navarro, G., Trivedi, M. S., De Rosa, G., Torchilin, V. P. Tags: Models and Technologies Source Type: research