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Source: Molecular Cancer Therapeutics

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Total 96 results found since Jan 2013.

Abstract B50: Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation
ConclusionOur results implicate the actin cytoskeleton in the induction of YAP/TAZ-dependent resistance to vemurafenib, and inhibition of actin remodeling might be a promising synthetic lethal strategy to suppress resistance in BRAF inhibitor therapies.Citation Format: Min Hwan Kim, Joon Kim. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. [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 B50.
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kim, M. H., Kim, J. Tags: Drug Resistance and Modifiers: Poster Presentations - Proffered Abstracts Source Type: research

CDK4/6 Inhibitor Reduces Human Liposarcoma Growth
In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts. We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma (RB) phosphorylation and dramatically decreased liposarcoma cell growth. Cell-cycle analysis demonstrated arrest at G0–G1. siRNA-mediated knockdown of RB rescued the inhibitory effects of LEE011, demonstrating that LEE011 decreased proliferation through RB. Oral administration of LEE011 to mice bearing human liposarcoma xenograft...
Source: Molecular Cancer Therapeutics - September 2, 2014 Category: Cancer & Oncology Authors: Zhang, Y.-X., Sicinska, E., Czaplinski, J. T., Remillard, S. P., Moss, S., Wang, Y., Brain, C., Loo, A., Snyder, E. L., Demetri, G. D., Kim, S., Kung, A. L., Wagner, A. J. Tags: Small Molecule Therapeutics Source Type: research

TMPRSS2-ERG Fusion Inhibits NHEJ DNA Repair
We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer cells expressing the TMPRSS2–ERG gene fusion protein. Here, we show that TMPRSS2–ERG blocks nonhomologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2–ERG and PC3 cells that stably express it, displayed H2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2–ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2–ERG's ability to inhibit DNA-PKcs function, as i...
Source: Molecular Cancer Therapeutics - August 5, 2015 Category: Cancer & Oncology Authors: Chatterjee, P., Choudhary, G. S., Alswillah, T., Xiong, X., Heston, W. D., Magi-Galluzzi, C., Zhang, J., Klein, E. A., Almasan, A. Tags: Cancer Biology and Signal Transduction Source Type: research

Systemic PSMA-Targeted IR Sensitization
Radiation therapy is a highly effective tool for treating all stages of prostate cancer, from curative approaches in localized disease to palliative care and enhanced survival for patients with distant bone metastases. The therapeutic index of these approaches may be enhanced with targeted radiation-sensitizing agents. Aptamers are promising nucleic acid delivery agents for short interfering RNAs (siRNA) and short hairpin RNAs (shRNA). We have previously developed a radiation-sensitizing RNA aptamer–shRNA chimera that selectively delivers DNA-PK targeting shRNAs to prostate-specific membrane antigen (PSMA) positive c...
Source: Molecular Cancer Therapeutics - December 6, 2015 Category: Cancer & Oncology Authors: Ni, X., Zhang, Y., Zennami, K., Castanares, M., Mukherjee, A., Raval, R. R., Zhou, H., DeWeese, T. L., Lupold, S. E. Tags: Large Molecule Therapeutics Source Type: research

A Top1 Inhibitor Selectively Toxic for Certain NSCLC Cells
SW044248, identified through a screen for chemicals that are selectively toxic for non–small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently from camptothecin and camp...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Zubovych, I. O., Sethi, A., Kulkarni, A., Tagal, V., Roth, M. G. Tags: Small Molecule Therapeutics Source Type: research

Abstract C1: Harnessing the pro-inflammatory tumor microenvironment of castrate-resistant prostate cancer to promote apoptosis
ConclusionProstate cancer cell lines are inherently resistant to SMAC mimetic therapy even in the presence of TNFα or TRAIL. However, dual targeting of FLIP and IAPs sensitises CRPC cell lines to microenvironment-derived TNFα. Combined targeting of IAPs and FLIP, or single targeting of FLIP, may be an effective means of treating pro-inflammatory prostate cancer.Citation Format: Christopher McCann, Nyree Crawford, David Waugh, Daniel Longley. Harnessing the pro-inflammatory tumor microenvironment of castrate-resistant prostate cancer to promote apoptosis. [abstract]. In: Proceedings of the AACR-NCI-EORTC Interna...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: McCann, C., Crawford, N., Waugh, D., Longley, D. Tags: Apoptosis, Necrosis, and Autophagy: Poster Presentations - Proffered Abstracts Source Type: research

Abstract C138: Targeting macropinocytosis in pancreatic cancer
In this study, we investigated the effects of knockdown of these three genes on the macropinocytic activity of pancreatic cancer cells. The goal of this study is to assess whether PAK1, ARF6, or SNX5 may serve as potential targets for the suppression of macropinocytosis in pancreatic cancer, which would hamper the cells' uptake of nutrients thus starving the cancer cells and hindering tumor growth. We carried out this study using MIA PaCa-2 pancreatic cancer cells, which are known to exhibit relatively high levels of macropinocytosis. Treatment of cells with siRNA sequences specific to the three genes resulted in a signifi...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Hunt, J., Ng, S., Whatcott, C., Von Hoff, D. D., Han, H. Tags: New Molecular Targets: Poster Presentations - Proffered Abstracts Source Type: research

Cyclin-Dependent Kinase 11 and Ovarian Cancer
Ovarian cancer is currently the most lethal gynecologic malignancy with limited treatment options. Improved targeted therapies are needed to combat ovarian cancer. Here, we report the identification of cyclin-dependent kinase 11 (CDK11) as a mediator of tumor cell growth and proliferation in ovarian cancer cells. Although CDK11 has not been implicated previously in this disease, we have found that its expression is upregulated in human ovarian cancer tissues and associated with malignant progression. Metastatic and recurrent tumors have significantly higher CDK11 expression when compared with the matched, original primary ...
Source: Molecular Cancer Therapeutics - July 4, 2016 Category: Cancer & Oncology Authors: Liu, X., Gao, Y., Shen, J., Yang, W., Choy, E., Mankin, H., Hornicek, F. J., Duan, Z. Tags: Cancer Biology and Signal Transduction Source Type: research

HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer
Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 minutes at 43&de...
Source: Molecular Cancer Therapeutics - May 2, 2017 Category: Cancer & Oncology Authors: Court, K. A., Hatakeyama, H., Wu, S. Y., Lingegowda, M. S., Rodriguez-Aguayo, C., Lopez-Berestein, G., Ju-Seog, L., Rinaldi, C., Juan, E. J., Sood, A. K., Torres-Lugo, M. Tags: Models and Technologies Source Type: research

Abstract A25: Synthetic lethal CRISPR-Cas9 screen imply an oncogenic role for FBXW7 mutations in colon cancer
Mutations in tumour suppressors and un-druggable oncogenes dominate the landscape of cancer driver genes. Only a minority of colon cancers have mutations in druggable cancer drivers, such as PIK3CA. Conversely, mutations in tumour suppressors such as APC and TP53 are frequent, as are mutations in the notoriously difficult to drug KRAS target. There is an urgent need for new therapeutics to target tumours driven by these mutations: immune checkpoint approaches are likely to only prove effective in the fraction of patients whose tumours bear high mutation loads, which is colon cancer may be restricted to the minority of mism...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Moore, J. D., Hudson, C., Russell, P., Tiwana, G., Walter, D., Wiggins, C. M., Yarker, J. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research

ADAM9 in Gastric Cancer
Advanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockd...
Source: Molecular Cancer Therapeutics - December 4, 2014 Category: Cancer & Oncology Authors: Kim, J. M., Jeung, H.-C., Rha, S. Y., Yu, E. J., Kim, T. S., Shin, Y. K., Zhang, X., Park, K. H., Park, S. W., Chung, H. C., Powis, G. Tags: Cancer Biology and Signal Transduction Source Type: research

Inhibition of Neuroblastoma Development by Targeting Midkine
Midkine (MDK) is a member of a new family of neurotrophic factors considered as rate-limiting growth and angiogenic factors implicated in the onset, invasion, and metastatic process of neuronal tumors, including neuroblastoma. We showed that all neuroblastoma cell lines highly expressed MDK, indicating that it is a critical player in tumor development, which may henceforth represent an attractive therapeutic target. We showed that the knockdown of MDK expression by siRNA led to a marked and significant decrease in neuroblastoma (IGR-N91 and SH-SY5Y) cell proliferation in vitro. Using a new strategy, we then evaluated the a...
Source: Molecular Cancer Therapeutics - January 13, 2015 Category: Cancer & Oncology Authors: Dianat, N., Le Viet, B., Gobbo, E., Auger, N., Bieche, I., Bennaceur-Griscelli, A., Griscelli, F. Tags: Cancer Biology and Signal Transduction Source Type: research

Predictive Biomarkers for IGF-1R/IR Inhibitor BMS-754807 in Colorectal Cancer
Insulin-like growth factor receptor 1 (IGF-1R)–targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAFV600E or KRASG13D mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF we...
Source: Molecular Cancer Therapeutics - February 9, 2015 Category: Cancer & Oncology Authors: Huang, F., Chang, H., Greer, A., Hillerman, S., Reeves, K. A., Hurlburt, W., Cogswell, J., Patel, D., Qi, Z., Fairchild, C., Ryseck, R.-P., Wong, T. W., Finckenstein, F. G., Jackson, J., Carboni, J. M. Tags: Companion Diagnostics and Cancer Biomarkers 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

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