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Source: Molecular Cancer Therapeutics
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Total 96 results found since Jan 2013.
Abstract A03: Several rational combination kinase inhibitor treatments identified by synthetic lethality screens are efficacious in intracranial triple negative breast cancer models
Conclusions: Synthetic lethality screens identified multiple rational combination therapies based on PI3K and/or MEK inhibition in TNBC cells, particularly PI3K+MEK, MEK+PDGFR, and PI3K+AURKA. Combined use of brain-penetrant, clinically available inhibitors against these targets showed promising efficacy in intracranial TNBC mouse models. Rational combinations of brain-penetrant kinase inhibitors are promising strategies for a patient population with few options. In vivo studies assessing the efficacy of other identified combinations, as well as more extensive characterization of potential resistance mechanisms, in intracr...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Swearingen, A. E. D. V., Sambade, M. J., Siegel, M. B., Sud, S., Bevill, S. M., Golitz, B. T., Bash, R. E., Santos, C. M., Darr, D. B., Parker, J. S., Miller, C. R., Johnson, G. L., Anders, C. K. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B04: RAD51 expression as a biomarker of homologous recombination deficiency in ovarian cancer
RAD51 is a critical component of the homologous recombination pathway, forming a nucleoprotein filament that enables strand exchange and templated error-free DNA repair. The tumor suppressors BRCA1 and BRCA2 interact with RAD51 to control its activity on DNA. Defects in homologous recombination in tumors are clinically relevant, with evidence of synthetic lethality of such cancers to poly ADP ribose polymerase (PARP) inhibitors.Mutations in RAD51 are uncommon in cancer, but aberrant over-expression of RAD51 has been reported as a mechanism to overcome a recombination defect in in-vitro models. However there are no large sc...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Hoppe, M. M., Tan, D. S., Lim, D. G., Karnezis, A., Huntsman, D., Steel, J., Liu, X., Paul, J., Lewsley, L.-A., Siddiqui, N., Brown, R., Jeyasekharan, A. D. Tags: New Technology and Bioinformatics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA14: Understanding the complex biology of KRAS mutant cancers using genetic screens
Apart from identifying synthetic lethal genes, genetic screens have the potential to reveal much about the basic biology of cell lines. We utilize two techniques, one analytical and one experimental, to demonstrate how genetic screens can also reveal which pathways are on in cell lines and what are the phenotypic consequences of pathway perturbation. First, we apply a clustering analysis of genome-scale CRISPR screening data to map out active pathways in cancer cell lines and to discover novel members of signaling transduction pathways and protein complexes. Secondly, we performed a combinatorial siRNA screen that knocks o...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: L, T. Tags: New Technology and Bioinformatics: Oral Presentations - Invited Abstracts Source Type: research
Abstract A15: Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status
In conclusion, we demonstrated that dual CDK + PARP inhibition is synthetic lethal in both BRCA wild-type and mutant TNBC cell lines and is dependent upon down regulation of c-myc. This study supports c-myc as predictor of response to PARP inhibitor therapy and may also serve as a biomarker of response to Dinaciclib + PARPi therapy in high MYC expressing tumors.Citation Format: Jason PW Carey, Smruthi Vjayaraghavan, Kelly Hunt, Khandan Keyomarsi. Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status [abstract]. In: Proceedings of the AACR Precision Medicine Series: ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Carey, J. P., Vjayaraghavan, S., Hunt, K., Keyomarsi, K. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR15: Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma
The objective of this study was to identify chemical compounds that are synthetically lethal with VHL deficiency in CC-RCC. An annotated chemical library, the library of pharmacologically active compounds (LOPAC), was screened in parallel on VHL-deficient RCC4 cells and RCC4VHL cells with re-introduced VHL. The ROCK inhibitor, Y-27632, was identified and validated for selective targeting of VHL-deficient CC-RCC in multiple genetic backgrounds by clonogenic assays. Downregulation of ROCK1 by small interfering RNA (siRNA) selectively reduced the colony forming ability of VHL-deficient CC-RCC, thus mimicking the effect of Y-2...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Thompson, J. M., Nguyen, Q. H., Singh, M., Pavesic, M. W., Nesterenko, I., Nelson, L. J., Liao, A., Razorenova, O. V. Tags: Chemical Biology: Oral Presentations - Proffered Abstracts 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
Abstract A31: Targeting APC loss using synthetic lethality in Colorectal Cancer
Conclusions: We have identified seven genes as potential therapeutic targets and a number of FDA-approved compounds, which could potentially be new selective therapies for 80% of CRC patients. Currently we are validating these findings and investigating the mechanism of synthetic lethality with APC mutation. To further validate our findings we are also exploring whether these results extend to other CRC cell lines with different mutational backgrounds, this will help us access how many patients may benefit from our novel therapeutic targets.Acknowledgments: We would like to thank Bowel and Cancer Research and The Rosetree ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Shailes, H., Bridge, G., Foxler, D., Sharp, T. V., Silver, A., Martin, S. A. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2
This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo. Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Weiswald, L.-B., Hasan, M. R., Wong, J. C. T., Pasiliao, C. C., Rahman, M., Ren, J., Yin, Y., Gusscott, S., Vacher, S., Weng, A. P., Kennecke, H. F., Bieche, I., Schaeffer, D. F., Yapp, D. T., Tai, I. T. Tags: Cancer Biology and Signal Transduction Source Type: research
Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)
To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N = 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic param...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Wagner, M. J., Mitra, R., McArthur, M. J., Baze, W., Barnhart, K., Wu, S. Y., Rodriguez-Aguayo, C., Zhang, X., Coleman, R. L., Lopez-Berestein, G., Sood, A. K. Tags: Large Molecule Therapeutics 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
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
In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance
This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced v...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Anisuzzaman, A. S. M., Haque, A., Wang, D., Rahman, M. A., Zhang, C., Chen, Z., Chen, Z. G., Shin, D. M., Amin, A. R. M. R. Tags: Cancer Biology and Signal Transduction Source Type: research
Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform
Metastatic breast cancer is developed in about 20% to 30% of newly diagnosed patients with early-stage breast cancer despite treatments. Herein, we report a novel nanoparticle platform with intrinsic antimetastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple-negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor-initiating cells in a kinome-wide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducib...
Source: Molecular Cancer Therapeutics - April 2, 2017 Category: Cancer & Oncology Authors: Morry, J., Ngamcherdtrakul, W., Gu, S., Reda, M., Castro, D. J., Sangvanich, T., Gray, J. W., Yantasee, W. Tags: Models and Technologies Source Type: research
Dimethyl Fumarate Controls the NRF2/DJ-1 Axis in Cancer Cells: Therapeutic Applications
The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in noncancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (<25 μmol/L), DMF has a cytoprotective role through activation of the NRF2 antioxidant pathway. At higher concentrations, however (>25 μmol/L), DMF caused oxidative s...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Saidu, N. E. B., Noe, G., Cerles, O., Cabel, L., Kavian-Tessler, N., Chouzenoux, S., Bahuaud, M., Chereau, C., Nicco, C., Leroy, K., Borghese, B., Goldwasser, F., Batteux, F., Alexandre, J. Tags: Cancer Biology and Signal Transduction Source Type: research
The FA/BRCA Pathway Identified as the Major Predictor of Cisplatin Response in Head and Neck Cancer by Functional Genomics
Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that influence the response to cisplatin in HNS...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Martens-de Kemp, S. R., Brink, A., van der Meulen, I. H., de Menezes, R. X., te Beest, D. E., Leemans, C. R., van Beusechem, V. W., Braakhuis, B. J. M., Brakenhoff, R. H. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
