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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 C138: Targeting macropinocytosis in pancreatic cancer
In this study, we investigated the effects of knockdown of these three genes on the macropinocytic activity of pancreatic cancer cells. The goal of this study is to assess whether PAK1, ARF6, or SNX5 may serve as potential targets for the suppression of macropinocytosis in pancreatic cancer, which would hamper the cells' uptake of nutrients thus starving the cancer cells and hindering tumor growth. We carried out this study using MIA PaCa-2 pancreatic cancer cells, which are known to exhibit relatively high levels of macropinocytosis. Treatment of cells with siRNA sequences specific to the three genes resulted in a signifi...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Hunt, J., Ng, S., Whatcott, C., Von Hoff, D. D., Han, H. Tags: New Molecular Targets: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A155: Small molecule metabolic inhibitors, compound A and the derivatives specifically inhibit the cell growth of Ewing's sarcoma cells harbor EWS-FLI1 in vitro and in vivo
Conclusions: Compound A and its derivatives may be a therapeutic agent with potent antitumor activity for Ewing's sarcoma patients.Citation Format: Hiromichi Kosaka, Yasuo Watanabe, Michihiro Maemoto, Masamori Sugawara, Miwa Watanabe, Yoko Ono, Yoshisuke Nakasato, Masahiro Matsubara, Ryuichiro Nakai. Small molecule metabolic inhibitors, compound A and the derivatives specifically inhibit the cell growth of Ewing's sarcoma cells harbor EWS-FLI1 in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (P...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kosaka, H., Watanabe, Y., Maemoto, M., Sugawara, M., Watanabe, M., Ono, Y., Nakasato, Y., Matsubara, M., Nakai, R. Tags: Therapeutic Agents: Other: Poster Presentations - Proffered Abstracts Source Type: research

Abstract C156: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts (PFs)/stellate cells (PSCs), immune/inflammatory cells and other cell types. This unique tumor microenvironment is increasingly recognized as a key mediator of PDAC progression and drug resistance. Targeting the tumor stroma may thus be a therapeutic approach for PDAC. Pancreatic cancer-associated fibroblasts (CAFs), myofibroblast-like cells that produce extracellular matrix proteins, are responsible for the desmoplasia in PDAC. PSCs and PFs are the key progenitors of CAFs. Blocking the activity of...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Zhou, S., Chang, S., McCann, T., French, R., Lowy, A. M., Insel, P. A. Tags: Target Identification and Validation: 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

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

Dual PI3K/mTOR Inhibitors Enhance ERK Activation via mTORC2
The PI3K/AKT/mTOR pathway, which is aberrantly stimulated in many cancer cells, has emerged as a target for therapy. However, mTORC1/S6K also mediates negative feedback loops that attenuate upstream signaling. Suppression of these feedback loops opposes the growth-suppressive effects of mTOR inhibitors and leads to drug resistance. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser240/244), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at T...
Source: Molecular Cancer Therapeutics - April 9, 2015 Category: Cancer & Oncology Authors: Soares, H. P., Ming, M., Mellon, M., Young, S. H., Han, L., Sinnet-Smith, J., Rozengurt, E. Tags: Cancer Biology and Signal Transduction Source Type: research