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Source: Molecular Cancer Therapeutics
Cancer: Lung Cancer
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Total 12 results found since Jan 2013.
Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398
Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines. We identified cancer cell lines that have activating mutations in FGFR1, 2, or 3 and treated them chronically wi...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Datta, J., Damodaran, S., Parks, H., Ocrainiciuc, C., Miya, J., Yu, L., Gardner, E. P., Samorodnitsky, E., Wing, M. R., Bhatt, D., Hays, J., Reeser, J. W., Roychowdhury, S. Tags: Small Molecule Therapeutics 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 B119: Blocking metabolic stress response with genetic knockdown and selective ligands of sigma-1 receptor in cancer cells
In this study we examined whether Sig1R sustains proliferation, survival and tumorigenic properties of human cancer cells. Knockdown of Sig1R using small interfering RNA (siRNA) in human prostate and lung cancer cell lines had profound effect on proliferation, clonogenic capability and tumor-sphere formation, indicating reversal of the tumorigenic and stem-like phenotype in absence of Sig1R. Next, in the attempt to discover pharmacological agents that could phenocopy the effects of the genetic knockdown in cancer cells we tested a series of structurally diverse Sig1R ligands selected for high affinity and selectivity for t...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Civenni, G., De Monte, C., Sereni, F., Allegrini, S., Bosotti, R., Laurini, E., Wunsch, B., Pricl, S., Carbone, G. M., Catapano, C. V. Tags: New Molecular Targets: 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
Abstract C145: Targeted radiosensitization of non-small cell lung cancer (NSCLC) through ADAM17 inhibition
Conclusions: These findings implicate that radiotherapy significantly activates ADAM17 in non–small cell lung cancer (NSCLC) cells, which results in shedding of multiple survival factors, growth factor pathway activation and contributes to treatment resistance. We provide a sound rationale for repositioning ADAM17 inhibitors as short-term adjuvants to improve the radiotherapy outcome of NSCLC.Citation Format: Ashish Sharma, Sabine Bender, Oliver Riesterer, Angela Broggini-Tenzer, Martin Pruschy. Targeted radiosensitization of non-small cell lung cancer (NSCLC) through ADAM17 inhibition. [abstract]. In: Proceedings of...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Sharma, A., Bender, S., Riesterer, O., Broggini-Tenzer, A., Pruschy, M. Tags: Radiotherapeutics: Poster Presentations - Proffered Abstracts 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 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 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
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 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
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
In Vivo KRAS Silencing with siRNA
This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional "undruggable" targets. Mol Cancer Ther; 13(12); 2876–85. ©2014 AACR.
Source: Molecular Cancer Therapeutics - December 4, 2014 Category: Cancer & Oncology Authors: Pecot, C. V., Wu, S. Y., Bellister, S., Filant, J., Rupaimoole, R., Hisamatsu, T., Bhattacharya, R., Maharaj, A., Azam, S., Rodriguez-Aguayo, C., Nagaraja, A. S., Morelli, M. P., Gharpure, K. M., Waugh, T. A., Gonzalez-Villasana, V., Zand, B., Dalton, H. Tags: Small Molecule Therapeutics Source Type: research
