bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C189: Defective S phase cell cycle checkpoint: A potential culprit and target in melanoma
Authors: Oo Zay Y. , Daignault Sheena , Chen James , Gabrielli Brian 
Published: May 2016

Abstract
The S phase cell cycle checkpoint is critical for maintaining genomic integrity. This checkpoint is triggered in response to DNA damage and replication stresses to control cell cycle progression, halting DNA replication and allowing the time to repair to maintain genomic integrity. If this checkpoint is defective, cells lose their ability to ensure the fidelity of replication and repair any damage, resulting in replicative stress and genomic instability which will subsequently increase the risk of cancer. We have discovered that a large proportion of melanoma cell lines lose the ability to halt replication when challenged with high dose hydroxyurea-induced replicative stress, despite normal cell cycle checkpoint signalling. We found that failure in the crosstalk between ATR-CHK1 checkpoint signalling and the cell cycle mechanism in destabilization of CDC25A. Although CHK1-dependent phosphorylation of CDC25A which triggers its degradation was detected, the S phase checkpoint defective melanoma cell lines fail to destabilize CDC25A, maintaining normal activation of CDK2/Cyclin E. The melanoma cells with this S phase checkpoint defect are also hyper-sensitive to killing by CHK1 inhibitor. We have previously shown that melanoma with high levels of replicative stress are very sensitive to CHK1 inhibitors. I will report our studies investigating whether CHK1 inhibitor sensitivity is a direct outcome of the replicative stress arising from the S phase checkpoint defect, or whether the loss of the ATR-CHK1-CDC25A dependent S phase checkpoint signalling mechanism is directly responsible for the hyper-sensitivity to CHK1 inhibitors.
Citation Format: Zay Y. Oo, Sheena Daignault, James Chen, Brian Gabrielli. Defective S phase cell cycle checkpoint: A potential culprit and target in melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C189.
Abstract C193: Combining ibrutinib with Chk1 inhibitors as a new therapeutic strategy for mantle cell lymphoma
Authors: Restelli Valentina , Vagni Micaela , Lupi Monica , Bertoni Francesco , Damia Giovanna , Carrassa Laura 
Published: May 2016

Abstract
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by an initial high response to first line treatment, followed by a continuous relapse, resulting in a discouraging long term outcome. Recently a novel potent inhibitor of BTK, ibrutinib, was found to induce impressive response in B-cell malignancies and has been approved for therapy of refractory mantle cell lymphoma. BTK (bruton's tyrosine kinase) is required for B cell receptor signaling (BCR) and is essential for B cell development, differentiation, signaling and survival. Despite its unprecedented clinical activity, acquired resistance to ibrutinib also develops, pushing the evaluation of new drug combinations. We have recently shown that Chk1 inhibitors (PF-00477736) not only are very effective as single agents in MCL but are strongly synergistic with Wee1 inhibitors. We tested ibrutinib in combination with PF-00477736 in different MCL cell lines (JVM2, JEKO-1, MAVER-1, GRANTA-519, REC1), finding that the combination is synergistic in all these cell lines, with Combination Index values, evaluated at the IC50 doses, ranging from 0.5 to 0.7. The combination was also very active in a JEKO-1 cell line made resistant to PF-00477736. The synergistic effect of the combination was also observed using another Chk1 inhibitor (AZD-7762). Western Blot Analysis revealed that the combined treatment at concentrations of ibrutinib and PF-00477736 not toxic as single agents, neutralized the increase in phosphor-ERK observed after PF-00477736 treatment, and led to a substantial decrease in the active phosphorylated form of BTK in Y223. Cell cycle analysis and apoptosis are undergoing to try to dissect the cytotoxic mechanisms induced by the combination along with studies aiming at elucidating the molecular mechanisms at the basis of this combination. These data would suggest that ibrutinib in combination with Chk1 inhibitors could be a new and effective therapeutic strategy to test in clinical setting in MCL.
Citation Format: Valentina Restelli, Micaela Vagni, Monica Lupi, Francesco Bertoni, Giovanna Damia, Laura Carrassa. Combining ibrutinib with Chk1 inhibitors as a new therapeutic strategy for mantle cell lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C193.
Abstract C194: Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in cancer
Authors: Rzymski Tomasz , Dreas Agnieszka , Wincza Ewelina , Fabritius Charles-Henry , Kulesza Urszula , Kucwaj- Brysz Katarzyna , Milik Mariusz , Gołas Aniela , Windak Renata , Żyłkiewicz Eliza , Wróbel Anna , Sułkowski Maciej , Brzózka Krzysztof 
Published: May 2016

Abstract
Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases are activated by RAS and MAPK signaling pathways, and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype. Recently first dual MNK1/MNK2 inhibitors have entered clinical trials as a combinational therapy with docetaxel in NSCLC.
SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range and high selectivity confirmed in kinome panels. Analysis of SEL201 cellular activity indicated potent inhibition of eIF4e Ser209 in vitro in cancer cells and in vivo after oral administration in xenograft tumors. Repressed phosphorylation of eIF4e resulted in impaired translation of several proteins involved in metastasis and activation of immune cells. High potency, selectivity and favorable ADME/PK profile indicates that SEL201 inhibitors would be useful tools in probing molecular consequences of eIF4e Ser209 inhibition in cancer cells. SEL201 in vitro and in vivo activities on viability and metastasis will be presented in cellular and in vivo models of solid tumors and hematological malignancies. SEL201 series is further developed as a cancer therapy with a good therapeutic window.
Citation Format: Tomasz Rzymski, Agnieszka Dreas, Ewelina Wincza, Charles-Henry Fabritius, Urszula Kulesza, Katarzyna Kucwaj- Brysz, Mariusz Milik, Aniela Gołas, Renata Windak, Eliza Żyłkiewicz, Anna Wróbel, Maciej Sułkowski, Krzysztof Brzózka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C194.
Abstract C20: Reversal of mesenchymal phenotype of triple-negative breast cancer and glioblastoma cells and its therapeutic implication
Authors: Yoshikawa Kiyotsugu , Sakai Hiroaki , Shimazaki Masahiro , Okada Nobuhiro , Matsumoto Yoshiaki , Reinherz Ellis , Toi Masakazu 
Published: May 2016

Abstract
Mesenchymal transition is common to many aggressive cancers including breast, glioblastoma (GBM), lung and pancreatic cancers characterized by chemo/radiotherapy-resistance and cancer stem cell-like property. Claudin-low msenchymal subtype in triple-negative breast cancer (TNBC) is a major problem due to the lack of molecularly-targeting drugs. So far, we have identified an shRNA (shP1) which can induce mesenchymal to epithelial transition (MET) in shRNA library screening using positive selection reporter system in MDA-MB-231 mesenchymal TNBC cell line. Here, we have analyzed the effect of shP1 on morphology, transcription and cell proliferation in various mesenchymal cancer cell lines derived from breast, glioblastoma (GBM), lung and pancreatic cancers.
The shP1 increased E-cadherin promoter-driven GFP in a wide range of mesenchymal cancers including brain, breast, pancreatic, lung origin. Drastic morphology change introduced by shP1 was observed both in 2D and 3D cultures (matrigel, collagen), reducing their invasive and branching morphogenesis, especially in U251 GBM and MDA-MB-231 TNBC cell lines. The shP1-introduced cells are more sensitive to EGFR-inhibition and paclitaxel in TNBC cell line, reminiscent of reversal of therapy-resistant phenotype. Gene expression analysis reveals alteration of pathways related to cell adhesion, ERRB signal pathway, apoptosis and cytokines signaling. Of note, shP1-introduced U251 cells increased gene expression characteristic of proneural subtype, indicating shP1 reverted the subtype from mesenchymal to proneural. These results suggest that although U251 and MDA-MB-231 cell lines are of different tissue origins, their mesenchymal property can be reverted by the same program targeted by single shRNA.
These results provide a rationale of MET as therapeutic for a wide range of cancers with mesenchymal property.
Citation Format: Kiyotsugu Yoshikawa, Hiroaki Sakai, Masahiro Shimazaki, Nobuhiro Okada, Yoshiaki Matsumoto, Ellis Reinherz, Masakazu Toi. Reversal of mesenchymal phenotype of triple-negative breast cancer and glioblastoma cells and its therapeutic implication. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C20.
Abstract C35: Low-dose imatinib mesylate suppressed PDGF-BB mediated motility and invasion of gastric cancer cells
Authors: Kim Hong Jun , Lee Suk Young , Oh Sang Cheul , Kim Jun Suk , Kim Jung Lim , Kim Bo Ram , Na Yoo Jin 
Published: May 2016

Abstract
Purpose
Imatinib mesylate is a powerful tyrosine kinase inhibitor that specifically targets BCR-ABL, KIT, and PDGFR kinases and is used in treatment of chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST), and other cancers. Although imatinib has not yet been used in gastric cancer, we verified that high-dose imatinib leads gastric cancer cell lines to apoptosis via down regulation of Akt phosphorylation in previous study. This study was undertaken to evaluate the in vitro effect of low-dose imatinib in inhibition of invasion and migration of gastric cancer cells and to define molecular mechanism underlying these effects.
Methods
This study was to determine the expression of PDGFR molecules in gastric cancer cells (four human gastric cancer cell lines; AGS, MKN28, MKN45, and SNU638) by semi-quantitative polimerase chain reaction (PCR). The effects of low-dose imatinib (≤20uM.ml) on cell viability were examined using MTT assay. The effects of imatinib and PDGF-BB on cell motility and cell invasion were studied using wound healing assay and matrigel invasion assay respectively.
Results
The results showed expression of PDGFR in all four gastric cancer cells. We measured the sensitivity of gastric cancer cell line (AGS, MKN28, MKN45, SNU638) to imatinib using MTT assay. Cell viability of low-dose imatinib treated cell was not decreased. However, cell migration and invasion was decreased with low-dose imatinib. When PDGF-BB was added, cell motility and invasion were activated. However, when both PDGF-BB and imatinib were added, that activation was not shown.
Conclusion
In conclusion, low-dose imatinib mesylate inhibits PDGF-BB mediated cell migration and invasion not decreasing cell viability. The results suggest that imatinib mesylate may be useful in the treatment of gastric cancer.
Citation Format: Hong Jun Kim, Suk Young Lee, Sang Cheul Oh, Jun Suk Kim, Jung Lim Kim, Bo Ram Kim, Yoo Jin Na. Low-dose imatinib mesylate suppressed PDGF-BB mediated motility and invasion of gastric cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C35.
Abstract C51: Chemosensitisation to cisplatin by STAT3 inhibitors is mediated through the inhibition of DNA interstrand crosslink unhooking
Authors: Valentine Helen , Dixon Emily , Hartley John A. , Kiakos Konstantinos 
Published: May 2016

Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in many cancer cell lines, leading to survival, proliferation, angiogenesis and metastasis. The inhibition of STAT3 by natural or synthetic compounds has been shown to sensitise cancer cell lines to the chemotherapy agent cisplatin, however the molecular mechanisms contributing to this chemosensitisation have not yet been fully elucidated. Therefore we investigated the effect of STAT3 inhibition on cisplatin-induced DNA damage and key DNA repair factors.
STAT3 inhibitors stattic and curcumin were investigated in combination with cisplatin using the Suphorhodamine B cell growth inhibition assay in the DU145 prostate cancer and A549 non-small cell lung cancer cell lines. Combination treatments result in a significant (P&lt;0.0001) reduction in cisplatin GI50 values. These combinations were synergistic as determined by combination index value analysis using the software Calcusyn, confirming that inhibition of STAT3 enhances the cytotoxic effect of cisplatin. Using a modification of the alkaline comet assay we observed that STAT3 inhibitors significantly prevent the unhooking step of repair of cisplatin induced interstrand crosslinks (ICLs). Treatment with cisplatin alone induces formation of ICLs which peak at 9 hours and unhook by 24 hours post cisplatin exposure in both cell lines. Pre-treating cells with 12μM stattic or 48μM curcumin followed by cisplatin results in an equivalent peak formation of ICLs at 9 hours, however 24 and 48 hours post cisplatin no unhooking is observed. Therefore both STAT3 inhibitors used in this study block the unhooking stage of ICL repair. Using RT-PCR and immunoblotting we show that treatment with STAT3 inhibitors dose-dependently down-regulates EME1, BRCA1 and FANCD2 mRNA and protein levels. These three DNA repair proteins have been shown to be involved in the early stages of ICL repair and therefore down-regulation of these genes may be responsible for the impairment of ICL unhooking seen with STAT3 inhibition.
As the effects observed here have been replicated with two STAT3 inhibitors of differing chemical structure, this suggests that STAT3 is directly involved in the regulation of cisplatin-induced ICL repair through modulation of key ICL repair genes. We propose this as a contributing mechanism to the synergy reported between STAT3 inhibitors and cisplatin. The data presented here will inform the design of future drug combination strategies.
Citation Format: Helen Valentine, Emily Dixon, John A. Hartley, Konstantinos Kiakos. Chemosensitisation to cisplatin by STAT3 inhibitors is mediated through the inhibition of DNA interstrand crosslink unhooking. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C51.
Abstract C78: ATM/G6PD-dependent metabolic pathways promote mitochondrial redox homeostasis and resistance to FLT3 inhibition in acute myeloid leukemia
Authors: Gregory Mark A. , D'Alessandro Angelo , Alvarez-Calderon Francesca , Kim Jihye , Nemkov Travis , Tan Aik Choon , Hansen Kirk C. , DeGregori James 
Published: May 2016

Abstract
Acute myeloid leukemia (AML) is the most common adult acute leukemia and accounts for approximately 20% of childhood leukemias. Although frontline treatment of AML with cytotoxic chemotherapy is capable of achieving high remission rates, 75-80% of patients will either not respond to or will relapse after initial therapy, and most patients will die of their disease. More effective and better-tolerated therapies for AML are required. Activating mutations in fms-like tyrosine kinase 3 (FLT3) are the most frequently observed genetic defect in AML and drive leukemic cell growth and survival. FLT3 tyrosine kinase inhibitors have shown impressive anti-leukemic activity in clinical trials, however, sustained remissions using these inhibitors as monotherapy have not been achieved. In order to identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a large-scale RNA interference-based screen. The screen identified several genes involved in metabolic regulation, including ataxia telangiectasia mutated (ATM), as being synthetic lethal with FLT3 inhibition in FLT3 mutated AML. Genetic or pharmacological inactivation of ATM or its downstream effector glucose-6-phosphate dehydrogenase (G6PD) sensitized AML cells to FLT3 inhibition through enhancing apoptosis. Whole metabolome profiling revealed that FLT3 inhibition causes severe and widespread metabolic deficiencies, including depletion of the antioxidant factor glutathione. Inactivation of either ATM or G6PD exacerbated glutathione depletion upon FLT3 inhibition. Subsequent analyses revealed that FLT3 inhibition elicits severe mitochondrial oxidative stress that is causative in apoptosis and accentuated by ATM or G6PD inhibition. The use of a drug that promotes the production of mitochondrial reactive oxygen species (ROS) in combination with a FLT3 inhibitor augmented elimination of AML cells both in vitro and in vivo. Our data support the hypothesis that FLT3 mutated AML cells are highly dependent on FLT3 activity to maintain glutathione levels and sufficient mitochondrial antioxidant capacity to sustain cell survival. Moreover, these data support the novel strategy of employing mitochondrial ROS inducing agents as adjuvant to FLT3 inhibitor therapy to more effectively treat FLT3 mutated AML.
Citation Format: Mark A. Gregory, Angelo D'Alessandro, Francesca Alvarez-Calderon, Jihye Kim, Travis Nemkov, Aik Choon Tan, Kirk C. Hansen, James DeGregori. ATM/G6PD-dependent metabolic pathways promote mitochondrial redox homeostasis and resistance to FLT3 inhibition in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C78.
Abstract CN05-03: Personalized cancer diagnostics and therapeutics based on the computational modeling of signal transduction networks
Authors: Kolch Walter , Fey Dirk , Halasz Melinda , Rauch Nora , Munoz Amaya Garcia , Pilkington Ruth , Kholodenko Boris N. , Croucher David R. , Kennedy Sean P. , Hastings Jordan F. , Westermann Frank , Dreidax Daniel , Fischer Matthias , Duffy David , Krstic Aleksandar , Schwarzl Thomas 
Published: May 2016

Abstract
Signalling pathways exert finely tuned control over cell fate decisions that ultimately determine the behaviour of cancer cells. It could therefore be expected that the dynamics of key pathway activation may contain prognostically relevant information over and above that which is contained in the static nature of traditional biomarkers. To investigate this hypothesis we have characterised the network architecture regulating JNK stress signalling in neuroblastoma cells and applied an experimentally calibrated and validated computational model of this network to extract prognostic information from neuroblastoma patient-specific simulations of JNK activation. Survival analysis based upon the dynamics of these simulations revealed that an inability to initiate switch-like JNK signalling in silico was significantly associated with poor overall survival for both MYCN amplified and non-amplified neuroblastoma patients. Furthermore, our analysis demonstrated that in order to extract prognostic information from a signalling pathway, deciphering the extant network structure is a vital consideration in model development. We also show that network based analysis can lead to the discovery of new therapeutic targets.
Citation Format: Walter Kolch, Dirk Fey, Melinda Halasz, Nora Rauch, Amaya Garcia Munoz, Ruth Pilkington, Boris N. Kholodenko, David R. Croucher, Sean P. Kennedy, Jordan F. Hastings, Frank Westermann, Daniel Dreidax, Matthias Fischer, David Duffy, Aleksandar Krstic, Thomas Schwarzl. Personalized cancer diagnostics and therapeutics based on the computational modeling of signal transduction networks. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN05-03.
Abstract CN06-04: Combination strategies
Authors: Bono Johann S. De 
Published: May 2016

Abstract
Targeting the endocrine axis remains a mainstay of the treatment of many breast and most prostate cancers. Recent studies indicate that these tumors commonly remain nuclear steroid hormone receptor driven once endocrine resistance ensues. Multiple novel, rationally designed, agents are in development that are showing promise in the treatment of these diseases including drugs targeting p110beta, AKT, TORC1/2, as well as drugs targeting PARP, bromodomain proteins BRD2-4 and heat shock proteins including HSP90 and HSP27. Furthermore novel agents targeting the amino terminus of the androgen receptor and degrading these receptors are being evaluated. This presentation will describe challenges and solutions to their successful drug combination development.
Citation Format: Johann S. De Bono. Combination strategies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN06-04.