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Source: Molecular Cancer Therapeutics
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Total 96 results found since Jan 2013.
Genome and Immune Profiling of Inflammatory Breast Cancer
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted next-generation sequencing (NGS) and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biologic pathways, including ac...
Source: Molecular Cancer Therapeutics - July 4, 2016 Category: Cancer & Oncology Authors: Hamm, C. A., Moran, D., Rao, K., Trusk, P. B., Pry, K., Sausen, M., Jones, S., Velculescu, V. E., Cristofanilli, M., Bacus, S. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Radiosensitization of Medulloblastoma by Inhibition of MRK
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule in...
Source: Molecular Cancer Therapeutics - August 2, 2016 Category: Cancer & Oncology Authors: Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., Ruggieri, R. Tags: Small Molecule Therapeutics Source Type: research
HDACi and Celecoxib Induce Apoptosis in Bladder Cancer
The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Toriyama, S., Horinaka, M., Yasuda, S., Taniguchi, T., Aono, Y., Takamura, T., Morioka, Y., Miki, T., Ukimura, O., Sakai, T. Tags: Small Molecule Therapeutics Source Type: research
Vitamin D Inhibits Intratumoral Drug Metabolism
Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D–regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer ce...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Sun, M., Zhang, Q., Yang, X., Qian, S. Y., Guo, B. Tags: Small Molecule Therapeutics Source Type: research
{beta}-Catenin Targeting DsiRNAs
In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Signif...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., Siddiquee, Z., Craig, K., Lai, C., Dudek, H., Monga, S. P., Wang, W., Brown, B. D., Abrams, M. T. Tags: Large Molecule Therapeutics Source Type: research
A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells
The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Toriyama, S., Horinaka, M., Yasuda, S., Taniguchi, T., Aono, Y., Takamura, T., Morioka, Y., Miki, T., Ukimura, O., Sakai, T. Tags: Small Molecule Therapeutics Source Type: research
Vitamin D Enhances the Efficacy of Irinotecan through miR-627-Mediated Inhibition of Intratumoral Drug Metabolism
Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D–regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer ce...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Sun, M., Zhang, Q., Yang, X., Qian, S. Y., Guo, B. Tags: Small Molecule Therapeutics Source Type: research
Direct Pharmacological Inhibition of {beta}-Catenin by RNA Interference in Tumors of Diverse Origin
In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Signif...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., Siddiquee, Z., Craig, K., Lai, C., Dudek, H., Monga, S. P., Wang, W., Brown, B. D., Abrams, M. T. Tags: Large Molecule Therapeutics Source Type: research
Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule in...
Source: Molecular Cancer Therapeutics - August 2, 2016 Category: Cancer & Oncology Authors: Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., Ruggieri, R. Tags: Small Molecule Therapeutics Source Type: research
Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer
Oncogenic BRAFV600E mutations activate MAPK signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer. In BRAFV600E-mutant colorectal cancers, treatment failure may be related to BRAFV600E-mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using colorectal cancer cell lines isogenic for BRAF. BRAFV600E-induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1Thr163) and stabilize MCL-1. ...
Source: Molecular Cancer Therapeutics - November 30, 2016 Category: Cancer & Oncology Authors: Kawakami, H., Huang, S., Pal, K., Dutta, S. K., Mukhopadhyay, D., Sinicrope, F. A. Tags: Cancer Biology and Signal Transduction 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
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
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
