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Source: Molecular Cancer Therapeutics
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Total 96 results found since Jan 2013.
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
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
MCL-1 Is a Key Determinant of Breast Cancer Cell Survival
Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and ...
Source: Molecular Cancer Therapeutics - August 5, 2015 Category: Cancer & Oncology Authors: Xiao, Y., Nimmer, P., Sheppard, G. S., Bruncko, M., Hessler, P., Lu, X., Roberts-Rapp, L., Pappano, W. N., Elmore, S. W., Souers, A. J., Leverson, J. D., Phillips, D. C. Tags: Small Molecule Therapeutics Source Type: research
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 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
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 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
STAT1 and Cisplatin/Cetuximab in HNSCC
Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGF receptor (EGFR) inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at s...
Source: Molecular Cancer Therapeutics - September 2, 2015 Category: Cancer & Oncology Authors: Schmitt, N. C., Trivedi, S., Ferris, R. L. Tags: Cancer Biology and Signal Transduction Source Type: research
Ingenol Mebutate's Mechanism in Keratinocytes
In conclusion, we have shown that ingenol mebutate–induced cell death is mediated through the PKC/MEK/ERK pathway, and we have functionally linked the downstream induction of IL1R2 and IL13RA2 expression to the reduced viability of ingenol mebutate–treated cells. Mol Cancer Ther; 14(9); 2132–42. ©2015 AACR.
Source: Molecular Cancer Therapeutics - September 2, 2015 Category: Cancer & Oncology Authors: Freiberger, S. N., Cheng, P. F., Iotzova-Weiss, G., Neu, J., Liu, Q., Dziunycz, P., Zibert, J. R., Dummer, R., Skak, K., Levesque, M. P., Hofbauer, G. F. L. Tags: Cancer Biology and Signal Transduction Source Type: research
ABCB1 Inhibition Overcomes Resistance to MET Inhibitors
In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752–resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosph...
Source: Molecular Cancer Therapeutics - November 3, 2015 Category: Cancer & Oncology Authors: Sugano, T., Seike, M., Noro, R., Soeno, C., Chiba, M., Zou, F., Nakamichi, S., Nishijima, N., Matsumoto, M., Miyanaga, A., Kubota, K., Gemma, A. Tags: Small Molecule Therapeutics Source Type: research
Abstract A25: Molecular characterization of cyclin-dependent kinase 1 pathway in newly established epithelial ovarian cancer cell lines
Conclusions: These results suggest that elevated expression of Cdk1/cyclinB1 is important to EOC development and progression, providing new insight into the biology of EOC.Citation Format: Hanbyoul Cho, Assel Sabrgaliyeva, Woo Kyeom Yang, Sol Kim, Ha-Yeon Shin, Eun Ju Lee, Jae-hoon Kim. Molecular characterization of cyclin-dependent kinase 1 pathway in newly established epithelial ovarian cancer cell lines. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 ...
Source: Molecular Cancer Therapeutics - December 6, 2015 Category: Cancer & Oncology Authors: Cho, H., Sabrgaliyeva, A., Yang, W. K., Kim, S., Shin, H.-Y., Lee, E. J., Kim, J.-h. Tags: Biomarkers / Novel Imaging to Assess Response: Poster Presentations - Proffered Abstracts Source Type: research
