Filtered By:
Source: Molecular Cancer Therapeutics
Cancer: Colorectal Cancer
This page shows you your search results in order of date.
Order by Relevance | Date
Total 18 results found since Jan 2013.
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 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
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
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
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
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
HSP90 Inhibition Kills Mutant KRAS Colon Cancer Cells
Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolis...
Source: Molecular Cancer Therapeutics - March 6, 2016 Category: Cancer & Oncology Authors: Wang, C. Y., Guo, S. T., Wang, J. Y., Liu, F., Zhang, Y. Y., Yari, H., Yan, X. G., Jin, L., Zhang, X. D., Jiang, C. C. Tags: Cancer Biology and Signal Transduction 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 B68: Screening for the compound that induces cell death selectively in {beta}-catenin mutant tumor cells
The Wnt signal transduction pathway plays a central role for the cell proliferation, differentiation and apoptosis. β-catenin, a component of Wnt pathway, translocates to nucleus and forms an active complex with TCF4, leading to activate cell growth signaling, and this activity is tightly regulated by the "destruction complex" consisting of Axin, APC, GSK3β and CK1α. However, when β-catenin is actively mutated, this cell growth signaling would be hyperactive and drive oncogenesis. As β-catenin is mutated in up to 10% of all sporadic colon carcinomas resulting from point mutations or in-frame delet...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Shikata, Y., Kiga, M., Tashiro, E., Imoto, M. Tags: Drug Screening: 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
