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Source: Molecular Cancer Therapeutics
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Total 96 results found since Jan 2013.
Abstract B15: In vivo analysis of repeated siRNA silencing on protein expression levels
This study focused on determining the possibility of resistance development against siRNA treatment as a result of repeated exposure to siRNA in vivo. Our preliminary experiments in vitro revealed an unaffected siRNA cellular internalization and reproducible silencing efficiency of selected targets. The expression level of other mediators involved in breast cancer cell survival and proliferation (notably survivin, JUN, JAK2, NFkB and STAT3) were, however, altered in siRNA treated cells. In vivo experiments in a xenograft model demonstrated a similar silencing efficiency at the mRNA level after each repeated dose, with litt...
Source: Molecular Cancer Therapeutics - December 6, 2015 Category: Cancer & Oncology Authors: Aliabadi, H. M., Mahdipoor, P., Uludag, H. Tags: Other Combination Therapies: Poster Presentations - Proffered Abstracts 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
Abstract B166: A RNA helicase siRNA screen to identify potential therapeutic targets in castration-resistant prostate cancer
Castration-resistant prostate cancers (CRPC) are resistant to androgen-deprivation therapies commonly used to treat carcinoma of the prostate, resulting in death from this disease. CRPC can remain AR-driven through upregulation of the expression of wild-type, mutated or alternatively spliced constitutively active AR. Targeting both full-length AR and AR splice variants may overcome endocrine resistance. Since RNA helicases play crucial roles in various aspects of RNA metabolism including transcription, pre-mRNA splicing, translation, RNA export and RNA decay, we evaluated potentially druggable RNA helicases implicated in t...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Wang, H., de Billy, E., de Bono, J., Workman, P. Tags: Target Identification and Validation: Poster Presentations - Proffered Abstracts 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
Abstract A30: A genome-wide siRNA screen in mammalian cells for regulators of S6 phosphorylation
To identify the cellular components that participate in the regulation of mTOR complex 1 (mTORC1), the amino acid-dependent, rapamycin-inhibitable complex, we carried out a genome-wide RNAi depletion screen. We employed a rabbit monoclonal antibody specific for RPS6 [Ser235P/Ser236P] and high content microscopy to quantify rpS6 phosphorylation in the pancreatic ductal adenocarcinoma cancer cell line (PDAC) MiaPaCa-2. Applying a stringent selection, we retrieved over 600 genes wherein at least two RNAi gave significant reduction in S6 phosphorylation. This cohort is significantly enriched in genes whose depletion affects th...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Papageorgiou, A., Tamayo, P., Mesirov, J., Avruch, J., Rapley, J. Tags: PI3K-mTOR Activation in Human Cancer: Poster Presentations - Proffered Abstracts Source Type: research
Abstract C81: Identification of novel synergistic targets for rational drug combinations with PI3 kinase inhibitors using siRNA synthetic lethality screening against GBM
In this study, we performed a synthetic lethality screen to identify genes or pathways whose inactivation, in combination with the PI3K inhibitors PX-866 and NVPBEZ-235, might result in a lethal phenotype in glioblastoma multiforme (GBM) cells. We screened GBM cells (U87, U251, and T98G) with a large-scale, short hairpin RNA library (GeneNet), which contains 43 800 small interfering RNA sequences targeting 8500 well-characterized human genes. To decrease off-target effects, we selected overlapping genes among the 3 cell lines that synergized with PX- 866 to induce cell death. To facilitate the identification of potential t...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kim, Y.-W. Tags: Drug Resistance and Modifiers: Poster Presentations - Proffered Abstracts 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
Targeting MLL5{beta} for Cervical Cancer Therapy
In this report, we investigated the potential of RNAi-mediated silencing of MLL5β through the use of MLL5β-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5β silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model. This corresponded with the enhanced antitumor effects of MLL5β-siRNA compared with E6- or E7-siRNA single treatments. Significant reduction in tumor size after MLLβ-siRNA treatment in the HeLa xenograft tumor model further emphasized the importanc...
Source: Molecular Cancer Therapeutics - November 3, 2014 Category: Cancer & Oncology Authors: Nin, D. S., Yew, C. W., Tay, S. K., Deng, L.-W. Tags: Small Molecule Therapeutics Source Type: research
Multifunctional Micelles for the Reversal of Drug Resistance
Ovarian cancer is a dreadful disease estimated to be the second most common gynecologic malignancy worldwide. Its current therapy, based on cytoreductive surgery followed by the combination of platinum and taxanes, is frequently complicated by the onset of multidrug resistance (MDR). The discovery that survivin, a small antiapoptotic protein, is involved in chemoresistance provided a new prospect to overcome MDR in cancer, because siRNA could be used to inhibit the expression of survivin in cancer cells. With this in mind, we have developed self-assembly polymeric micelles (PM) able to efficiently co-load an anti–sur...
Source: Molecular Cancer Therapeutics - April 9, 2015 Category: Cancer & Oncology Authors: Salzano, G., Navarro, G., Trivedi, M. S., De Rosa, G., Torchilin, V. P. Tags: Models and Technologies Source Type: research
Targeting c-MYC in Ovarian Cancer
The purpose of this study was to investigate the molecular and therapeutic effects of siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer. Statistical analysis of patient's data extracted from The Cancer Genome Atlas (TCGA) portal showed that the disease-free (DFS) and the overall (OS) survival were decreased in ovarian cancer patients with high c-MYC mRNA levels. Furthermore, analysis of a panel of ovarian cancer cell lines showed that c-MYC protein levels were higher in cisplatin-resistant cells when compared with their cisplatin-sensitive counterparts. In vitro cell viability, growth, cell-cycle progres...
Source: Molecular Cancer Therapeutics - October 5, 2015 Category: Cancer & Oncology Authors: Reyes-Gonzalez, J. M., Armaiz-Pena, G. N., Mangala, L. S., Valiyeva, F., Ivan, C., Pradeep, S., Echevarria-Vargas, I. M., Rivera-Reyes, A., Sood, A. K., Vivas-Mejia, P. E. Tags: Small Molecule Therapeutics Source Type: research
EpCAM Aptamer-siRNAs for Targeted Breast Cancer Treatment
Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (TIC, also known as cancer stem cells). Here, we show that aptamer–siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knock down gene expression in EpCAM+ cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and m...
Source: Molecular Cancer Therapeutics - October 5, 2015 Category: Cancer & Oncology Authors: Gilboa-Geffen, A., Hamar, P., Le, M. T. N., Wheeler, L. A., Trifonova, R., Petrocca, F., Wittrup, A., Lieberman, J. Tags: Large Molecule Therapeutics Source Type: research
Abstract A07: Knockdown laminin-511 expression blocked endlthelial cell function in vitro and angiogenesis in vivo knockout skin model
In conclusion, our data suggested a possible involvement of laminin-511 in integrin alphaV and beta3-dependent angiogenesis and blood vessel maturation. Our works revealed the important roles of laminin-511 in endothelial cell activities, which proved its significance for angiogenesis.Citation Format: Jie Li, Tengjiao Cui. Knockdown laminin-511 expression blocked endlthelial cell function in vitro and angiogenesis in vivo knockout skin model. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA...
Source: Molecular Cancer Therapeutics - December 6, 2015 Category: Cancer & Oncology Authors: Li, J., Cui, T. Tags: Antiangiogenic Therapy: Poster Presentations - Proffered Abstracts 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 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 PR01: Inhibitory role of phosphatidylinositol-3,4-bisphosphate in triple-negative breast cancers
Triple-negative breast cancer (lacking expression of estrogen receptor, progesterone receptor and amplification of HER2/Neu) remains one of the most aggressive subtypes, affects the youngest patients and yet still lacks an effective targeted therapy. Novel insights into the molecular mechanisms that drive these cancers are imperative to guide development and application of such targeted therapies. Data from The Cancer Genome Atlas and other sources have suggested that phospho-Akt (pAkt) levels are significantly higher in triple-negative tumors compared to either hormone receptor positive tumors (express estrogen and/or pro...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Reed, D. E., Shokat, K. M. Tags: Molecular Regulation of the PI3K-mTOR Network: Oral Presentations - Proffered Abstracts Source Type: research
