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Source: Molecular Cancer Therapeutics
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Total 96 results found since Jan 2013.
Inhibition of Class I HDACs in Urothelial Carcinoma
Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assa...
Source: Molecular Cancer Therapeutics - February 7, 2016 Category: Cancer & Oncology Authors: Pinkerneil, M., Hoffmann, M. J., Deenen, R., Köhrer, K., Arent, T., Schulz, W. A., Niegisch, G. Tags: Cancer Biology and Signal Transduction Source Type: research
Abstract LB-C22: Acquired resistance to the cMET inhibitor savolitinib in lung cancer models through EGFR/mTOR/MYC deregulation and adoption of PIM signaling
Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression in multiple cancer types, including non-small cell lung cancer (NSCLC), where the cMET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here, we explore the therapeutic potential of the potent and selective cMET inhibitor savolitinib (volitinib, AZD6094, HMPL-504) in NSCLC and begin to elucidate mechanisms of acquired savolitinib resistance in preclini...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Henry, R. E., Barry, E. R., Ladd, B., Markovets, A., Beran, G. J., Ren, Y., Zhou, F., Castriotta, L., Adam, A., Qing, W., Su, W., Clark, E., D'Cruz, C. M., Schuller, A. Tags: Drug Resistance and Modifiers: Poster Presentations - Proffered Abstracts Source Type: research
Abstract C25: Targeting cancer stem cells using ALDH-dependent 5-nitrofuran pro-drugs
We hypothesise that cancer stem cells with high aldehyde dehydrogenase (ALDHhigh) activity present a new therapeutic target and will be selectively sensitive to 5-nitrofuran pro-drugs.Cancers are heterogeneous and contain subpopulations of ALDHhigh cells with tumour initiating potential. ALDH enzymes metabolize toxic aldehydes, and are highly expressed in somatic and cancer stem cells (CSCs), although their function in stem cells is not fully understood. In a small molecule screen coupled with target ID, we recently discovered that clinically active 5-nitrofurans (5-NFNs) are substrates of ALDH2 (Zhou et al., 2012). 5-NFNs...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Crispin, R., Spockeli, N., Brunton, V., Carragher, N., Gourley, C., Houston, D., Unciti-Broceta, A., Patton, E. E. Tags: Cancer Stem Cells: Poster Presentations - Proffered Abstracts Source Type: research
Abstract C26: Development of selective MELK kinase inhibitors for breast cancer treatment
In this study, we are reporting development of a series of selective MELK kinase inhibitors. Synthesized compounds exert excellent selectivity and potency in MELK inhibition in a low nanomolar range. Therapeutic effect of the compounds was investigated in the panel of breast cancer cell lines with different genetic background as well as with different MELK kinase levels; it was shown that for some cell lines compounds induced cell death with nanomolar ED50 values. The compound's effect on the proliferation and in the colony formation assay was also investigated. Taken altogether, the presented data supports our rationale o...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kowalczyk, P., Węgrzyn, P., Prokopowicz, M., Knop, M., Mazur, K., Dziedzic, K., Gluza, K., Knop, M., Dziedzic, K., Mazur, K., Radzimierski, A., Commandeur, C., Zawadzka, M., Bloudoff, K., Vaillancourt, F., Larsen, N., Wang, J., Reynolds, D., Ito, D Tags: Cancer Stem Cells: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A28: NFATC3-PLA2G15 fusion transcript identified by RNA-sequencing promotes tumor progression in colorectal cancer cells
In order to identify novel fusion transcripts in colorectal cancer, we carried out paired-end RNA sequencing in 28 human colorectal cancer cell lines. Fusion transcript candidates were identified using ChimeraScan and FusionMap tools. We obtained 1380 candidates having 4 or more read counts and spanning reads. Among the candidates, we selected 27 candidates for validation which harbors genes related to the Wnt signaling pathway or kinases according to KEGG or DAVID. After the targeted gene filtering step, validation using RT-PCR with fusion specific primers finally resulted in 2 intra- and 1 inter-fusion transcripts. Intra...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Jang, J., Kim, H., Lee, S., Lee, D., Lim, Y., Han, S., Kim, T. Tags: Biomarkers: Poster Presentations - Proffered Abstracts Source Type: research
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
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
pAT2R Gene Therapy Inhibits Lung Cancer via IV/IT Injection
Transfection efficiency and toxicity concerns remain a challenge for gene therapy. Cell-penetrating peptides (CPP) have been broadly investigated to improve the transfection of genetic material (e.g., pDNA and siRNA). Here, a synthetic CPP (polylysine, K9 peptide) was complexed with angiotensin II type 2 receptor (AT2R) plasmid DNA (pAT2R) and complexes were condensed using calcium chloride. The resulting complexes were small (~150 nm) and showed high levels of gene expression in vitro and in vivo. This simple nonviral formulation approach showed negligible cytotoxicity in four different human cell lines (cervix, breast, k...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Alhakamy, N. A., Ishiguro, S., Uppalapati, D., Berkland, C. J., Tamura, M. Tags: Models and Technologies Source Type: research
Abstract C59: Role of MTH1 (NUTD1) in cancer cell survival
Human mutT homolog MTH1 (also known as NUDT1) is a purine nucleoside triphosphatase which hydrolyses oxidised nucleotides (8-oxo-dGTP and 2-OH-dATP) into mono-phosphate forms to prevent these damaged bases from being incorporated into DNA. Recent studies have suggested a key role of MTH1 in the survival of cancer cells. It was hypothesized that in cancer cells with high levels of reactive oxygen species (ROS), small molecule inhibition or loss of MTH1 would lead to accumulation of oxidised nucleotides in DNA, increased genome instability and loss of cell viability. In order to validate MTH1 as a potential cancer therapeuti...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Alwan, H., Eckersley, K., Goodwin, L., Lau, A., Jones, D., Kettle, J., Nissink, W. M., Read, J., Scott, J. S., Taylor, B. J. M., Walker, G. E., Foote, K. M. Tags: DNA Repair and Modulation: Poster Presentations - Proffered Abstracts 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 A62: PARP-1 regulates NF-{kappa}B-mediated IL-8 expression in HER2 positive breast cancer
Conclusions:Trastuzumab resistant HER2+ breast cancer cells remain sensitive to PARP inhibition. Further, PARP-1 regulates the expression of IL-8, an NF-B regulated gene. These results suggest that inhibition of the interaction between PARP-1 and the NF-B signaling pathway may be a potential mechanism behind the sensitivity to PARPi in HER2+ trastuzumab resistant breast cancer cells.Citation Format: Monicka E. Wielgos, Rajani Rajbhandari, Susan Nozell, C. Kent Osborne, Rachel Schiff, Eddy S. Yang. PARP-1 regulates NF-B-mediated IL-8 expression in HER2 positive breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORT...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Wielgos, M. E., Rajbhandari, R., Nozell, S., Osborne, C. K., Schiff, R., Yang, E. S. Tags: EGFR / Her2: Poster Presentations - Proffered Abstracts Source Type: research
Abstract LB-B02: Acquisition of stem cell-like properties accompanying with Src family kinase/Focal adhesion kinase activation contributes to acquired resistance to afatinib in lung cancer cells
Conclusions] Together, our present study presents that increase of cancer stem like cells and SFK/FAK activation could be a mechanism responsible for acquired resistance to afatinib. We would further discuss the association of ALDH1 expression and SFK/FAK activation with afatinib resistance in lung cancer.Citation Format: Yuichi Murakami, Kahori Sonoda, Koichi Azuma, Kosuke Watari, Michihiko Kuwano, Mayumi Ono. Acquisition of stem cell-like properties accompanying with Src family kinase/Focal adhesion kinase activation contributes to acquired resistance to afatinib in lung cancer cells. [abstract]. In: Proceedings of the A...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Murakami, Y., Sonoda, K., Azuma, K., Watari, K., Kuwano, M., Ono, M. Tags: Drug Resistance and Modifiers: Poster Presentations - Proffered Abstracts Source Type: research
Abstract C5: FLIP protein-protein interaction inhibitors enhance sensitivity of colorectal cancer cells to chemotherapy and TRAIL
ConclusionWe have developed inhibitors of FLIP that decrease its recruitment to the TRAIL-R2 DISC and increase TRAIL-induced caspase activation and apoptosis. Moreover, these inhibitors synergise with 5-Fluorouracil, oxaliplatin and SN38, suggesting that this novel class of agents has therapeutic potential in CRC when used in conjunction with standard-of-care chemotherapeutic agents.AcknowledgementsThis work was supported by a Seeding Drug Discovery award from the Wellcome Trust (reference: 099470).Citation Format: Jennifer P. Fox, Joanna Majkut, Catherine Higgins, Zsuzsanna Nemeth, Adnan Malik, Christopher J. Scott, Peter...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Fox, J. P., Majkut, J., Higgins, C., Nemeth, Z., Malik, A., Scott, C. J., Blurton, P., Boffey, R. J., Perrior, T. R., Harrison, T., Longley, D. B. Tags: Apoptosis, Necrosis, and Autophagy: Poster Presentations - Proffered Abstracts Source Type: research
Abstract LB-A12: New target for cancer metabolism : Steroid Sulfatase
In conclusion, STS and the major product DHEA may regulate aerobic glycolysis via HIF1α induction and c-Myc related PKM2 alternative splicing.Citation Format: sangyun shin, Yeo-Jung Kwon, Dong-Jin Ye, Hyoung-Seok Baek, Young-Jin Chun. New target for cancer metabolism : Steroid Sulfatase. [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 LB-A12.
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: shin, s., Kwon, Y.-J., Ye, D.-J., Baek, H.-S., Chun, Y.-J. Tags: Signal Transduction Modulators: Poster Presentations - Proffered Abstracts Source Type: research
Abstract LB-A13: Cellular characterization of the selective inhibition of UBA5 by organometallic, adenosine-based inhibitors
Cells that undergo higher protein turnover, such as pancreatic secretory cells and cancerous cells, have the propensity to undergo endoplasmic reticulum (ER) stress. If left uncorrected, ER stress can result in the initiation of apoptosis. To avoid these fates, cells have developed support systems to counteract the apoptotic effects of ER stress, such as conjugation of certain stress-associated proteins with the ubiquitin-fold modifier 1 (UFM1) ubiquitin-like protein. Our research has recently focused on the discovery and in vitro validation of the first selective inhibitor of the UFM1 pathway, 5C-Z, which selectively targ...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: da Silva, S. R., Geletu, M., Javed, F., Paiva, S.-L., Lewis, A. M., Li, H., Gunning, P. T. Tags: Target Identification and Validation: Poster Presentations - Proffered Abstracts Source Type: research
