bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 674: Early integrated stress response induction of ATF4 is required for the anticancer effects of the dual Akt/ERK inhibitor and TRAIL pathway inducer ONC201/TIC10
Authors: Kline Christina Leah , van den Heuvel Pieter , Allen Joshua E. , Dicker David T. , El-Deiry Wafik S. 
Published: August 2015

Abstract
ONC201/TIC10 is a first-in-class small molecule inducer of the tumor necrosis apoptosis-inducing ligand (TRAIL) pathway, inhibiting both Akt and ERK and consequently activating FOXO3a. Here we present a hitherto unrecognized and early mechanism that contributes to ONC201/TIC10's cytotoxic effects. ONC201/TIC10 activates the integrated stress response, thereby engaging the ATF4 pathway and consequently inducing expression of the pro-apoptotic proteins CHOP and DR5. Cells that are resistant to ONC201/TIC10 do not exhibit ATF4 pathway activation. Knocking down ATF4 and CHOP partially abrogates ONC201/TIC10's cytotoxicity and ONC201/TIC10-induced DR5 upregulation. We also report here that ONC201/TIC10 does not only cause apoptosis but also inhibits cell cycle progression, potentially explaining its broad-spectrum cytotoxicity against 22 out of the 23 tumor cell lines tested. ONC201/TIC10-induced cell cycle arrest was associated with downregulation of Cyclin D1 expression. ONC201/TIC10 induces CHOP and DR5 in cells regardless of whether cells are susceptible to ONC201/TIC10-induced apoptosis. Levels of the X-linked inhibitor of apoptosis (XIAP) influence whether a cell succumbs to proliferation inhibition or apoptosis in response to ONC201/TIC10. Our findings show that ONC201/TIC10 upregulates the TRAIL pathway not only by inhibiting Akt and ERK, and activating FOXO3a but also by engaging the ATF4/CHOP/DR5 pathway that leads to complementary and potent tumor cell killing. Our findings also suggest that CHOP expression may serve as a pharmacodynamic marker for ONC201/TIC10 activity.
Citation Format: Christina Leah Kline, Pieter van den Heuvel, Joshua E. Allen, David T. Dicker, Wafik S. El-Deiry. Early integrated stress response induction of ATF4 is required for the anticancer effects of the dual Akt/ERK inhibitor and TRAIL pathway inducer ONC201/TIC10. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 674. doi:10.1158/1538-7445.AM2015-674
Abstract 677: Possible role of nimbolide in prevention and therapy of prostate cancer
Authors: Zhang Jingwen , Shanmugam Muthu K. , Deivasigamani Amudha , Kumar Alan P. , Hui Kam M. , Sethi Gautam 
Published: August 2015

Abstract
Prostate cancer is one of the most commonly diagnosed cancers worldwide. Current therapies for metastatic prostate cancer are only marginally effective, and hence novel treatment modalities are urgently needed. Considerable evidence suggests that chronic inflammation plays a pivotal role in the development and progression of prostate cancer. Thus agents that can suppress these inflammatory mediators could form the basis of novel therapy for prostate cancer patients. In our study, we focused on analyzing the potential anticancer effects of nimbolide, a terpenoid lactone derived from Azadirachta indica (Neem tree) against prostate cancer. Data from the in vitro studies indicated that nimbolide could inhibit cell proliferation, induce apoptosis and suppress cellular invasion and migration. Interestingly, nimbolide also abrogated the activation of pro-inflammatory STAT3 transcription factor, and this effect was found to be mediated via an increased production of reactive oxygen species (ROS), whereas depletion of ROS attenuated p-STAT3 inhibitory effects of the drug. The in vivo efficacy of nimbolide was also analyzed in transgenic adenocarcinoma of mouse prostate (TRAMP) model, in which this triterpenoid significantly suppressed the tumor progression and growth without exhibiting any significant adverse effects. Overall our findings indicate that nimbolide exhibits significant anticancer effects in prostate cancer, and these effects may be mediated at least in part through the modulation of STAT3 signaling pathway.
Citation Format: Jingwen Zhang, Muthu K. Shanmugam, Amudha Deivasigamani, Alan P. Kumar, Kam M. Hui, Gautam Sethi. Possible role of nimbolide in prevention and therapy of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 677. doi:10.1158/1538-7445.AM2015-677
Abstract 679: CF102 induces apoptosis of hepatocellular carcinoma
Authors: Cohen Shira , Barer Faina , Stemmer Salomon M. , Fishman Pnina 
Published: August 2015

Abstract
Background: The A3 Gi protein adenosine receptor (A3AR) is highly expressed in tumor compared to normal cells. A3AR agonists were shown to inhibit the growth of various tumor cell types via down-regulation of the Wnt and NF-κB signaling pathways. CF102 is a highly selective agonist of the A3AR, shown to have an anti-tumor effect in liver cancer in in vivo models. CF102 induced apoptosis via up-regulation of caspase-3 and the mitochondrial proteins Bax and Bad, demonstrating cell death in the tumor cells.
In this study we explored the molecular mechanism involved with the effect of CF102 on human hepatocellular carcinoma cells.
Methods: CF102 was added to a medium culture of Hep3b for 48 hours. CF102 effect was observed using Lactate dehydrogenase (LDH), MTT and H3 Thymidine proliferation assays. Cell mRNA and protein were extracted and were analyzed for different signaling pathways.
Results: CF102 inhibits the proliferation of Hep3b cells and showed an apoptotic activity in MTT assay. A cytotoxicity effect of CF102 was observed when high levels of LDH were measured in the culture medium of CF102 treated cells compared to the control. Moreover, cyclin D1 expression levels were down-regulated and caspase-3 levels were up-regulated upon CF102 treatment. Both mRNA and protein expression levels of A3AR were down-regulated by CF102 with a subsequent decrease in all members of the JAK-STAT signaling pathway including pSTAT-1, p-JAK-2 and p-AKT along with up-regulation of SOCS-1 and SOCS-3.
Conclusions: CF102 showed an anti-cancer activity via down-regulation of the A3AR and the JAK-STAT signaling pathway. CF102 induces cytotoxicity effect resulting in apoptosis of Hep3b cells, indicating that this drug may be considered as an anti-cancer drug for the treatment of human hepatocellular carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: Shira Cohen, Faina Barer, Salomon M. Stemmer, Pnina Fishman. CF102 induces apoptosis of hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2015-679
Abstract 687: Compound screen identifies PIM kinases as therapeutic targets for melanoma
Authors: Vultur Adina M. , Shannan Batool , Chen Quan , Watters Andrea , Mollin Stefan , Meggers Eric , Krepler Clemens , Perego Michela , Li Ling , Gimotty Phyllis A. , Xu Xiaowei , Herlyn Meenhard 
Published: August 2015

Abstract
Current treatments against malignant melanoma, including the use of small molecule inhibitors, are displaying encouraging results in the clinic. However, tumor resistance develops even for patients who initially respond favorably. To identify novel drug targets and compounds with anti-melanoma activity, we screened a panel of genetically distinct human-derived metastatic melanoma cell lines against structurally diverse organometallic kinase inhibitors. We observed a compound that preferentially inhibits melanoma cell proliferation compared to normal primary fibroblasts and melanocytes in adherent and three-dimensional (3D) cultures. We further showed that this compound (SM200) is pro-apoptotic and anti-invasive in 3D melanoma cell cultures. A kinome screen to identify the targets responsible for the anti-melanoma effects of SM200 revealed PIM kinases to be highly inhibited. PIM1 knockdown studies to validate this target in human metastatic melanoma indicate that PIM1 contributes to melanoma growth in 3D culture and in a xenograft model. We then evaluated the clinically available PIM kinase inhibitor SGI-1776 in our melanoma models and observed reduced cell proliferation in 2D, 3D, and in vivo melanoma models (as seen for SM200) suggesting an important role for PIM kinases in melanoma pathobiology. Taken together, our findings suggest that PIM kinases are valid targets for melanoma and PIM kinase inhibitors could enhance the effects of current therapies in the clinic.
Citation Format: Adina M. Vultur, Batool Shannan, Quan Chen, Andrea Watters, Stefan Mollin, Eric Meggers, Clemens Krepler, Michela Perego, Ling Li, Phyllis A. Gimotty, Xiaowei Xu, Meenhard Herlyn. Compound screen identifies PIM kinases as therapeutic targets for melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 687. doi:10.1158/1538-7445.AM2015-687
Abstract 688: Activating JAK1-S703I mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma patient-derived xenograft tumor models
Authors: Yang Shuqun , Luo Chonglin , Gu Qingyang , Xu Qiang , Sun Hongye , Qian Ziliang , Tan Yexiong , Wu Hao , Qin Yuxin , Shen Yuhong , Xu Xiaowei , Chen Shu-Hui , Chan Chi-Chung , Wang Hongyang , Mao Mao , Fang Douglas D. 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer worldwide. However, current therapeutic approaches for this epidemic disease are limited and its 5-year survival rate has not been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited point mutations in JAK1 (Janus Kinase) gene, which were confirmed by Sanger sequencing. To explore the transforming capability, these mutations were then introduced into 293T and Ba/F3 cells by transient transfection and retroviral infection, respectively. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore, a modest sensitivity to the treatment of a JAK1/2 inhibitor, Ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly inhibited. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo. JAK-STAT pathway might represent a new therapeutic opportunity for HCC. Monotherapy using a more potent inhibitor and combinatory therapy may be further explored in JAK1S703I mutant PDX model.
Citation Format: Shuqun Yang, Chonglin Luo, Qingyang Gu, Qiang Xu, Hongye Sun, Ziliang Qian, Yexiong Tan, Hao Wu, Yuxin Qin, Yuhong Shen, Xiaowei Xu, Shu-Hui Chen, Chi-Chung Chan, Hongyang Wang, Mao Mao, Douglas D. Fang. Activating JAK1-S703I mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma patient-derived xenograft tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 688. doi:10.1158/1538-7445.AM2015-688
Abstract 69: Identification of rare and novel alleles in FFPE tumor samples using laser capture microdissection (LCM) and Ampliseq™ sequencing technologies
Authors: Jackson Stephen , Choppa Paul , Kulvar Kulvinda , Schmidt Kristin 
Published: August 2015

Abstract
Tumors are becoming recognized as genetically heterogeneous masses of cells with different clonal histories. Identifying the mutations present in these heterogeneous masses can lead to important insights into the future behavior of the tumor and possible intervention mechanisms. However, the rarity of pathogenic mutations in small subsets of cells can make identification of such alleles difficult. In this study, we demonstrate a complete workflow that facilitates the identification of rare and novel alleles from FFPE tumor sections. We collected small regions with different cellular morphologies from lung tumor samples using laser capture microdissection, extracted both DNA and RNA from these regions, and characterized mutations present and transcript abundances by using Ampliseq™ targeted sequencing. We show that LCM facilitates the detection of alleles that are not detectable in macrodissected tissue scrapes. We also show that different regions of a tumor have very different patterns of alleles detectable and have a great deal of genetic diversity. Finally, we show that RNA expression patterns are also clearly different in the different regions. Interestingly, dissected regions with similar gross tissue morphologies display differences in alleles present and RNA expression patterns. These results suggest the best way to analyze mutations present in a tumor is to microdissect different subregions of the tumor, and using Ampliseq™ panels to identify the alleles present in those subregions.
Citation Format: Stephen Jackson, Paul Choppa, Kulvinda Kulvar, Kristin Schmidt. Identification of rare and novel alleles in FFPE tumor samples using laser capture microdissection (LCM) and Ampliseq™ sequencing technologies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 69. doi:10.1158/1538-7445.AM2015-69
Abstract 695: Synergistic antitumor effects of polo like kinase inhibitor volasertib in combination with ionizing radiation in glioblastoma
Authors: Dong Jianwen , Nguyen Nghi , Ezhilarasan Ravesanker , Wu Shaofang , Piao Yuji , Park Soon Young , Tiao Ningyi , Stephan Clifford , Sulman Erik P. , de Groot John F. 
Published: August 2015

Abstract
Despite the availability of hundreds of drugs, there is little data on the efficacy of these agents in the extremely heterogeneous populations of tumor cells observed in glioblastoma. In this study, a high-throughput compound-screening (HTS) assay was used to identify drug sensitivities of a panel of 15 glioblastoma stem cell (GSC) lines, which are representative of the classic the cancer genome atlas (TCGA) molecular subtypes, to 21 compounds in Published Protein Kinase Inhibitor Set (PKSI). This HTS screen identified sensitivity of GSCs to inhibition of polo like kinase-1 (PLK-1), a key regulator of mitosis. Given that PLK-1 is often overexpressed in a broad spectrum of cancers, and with highest expression levels being correlated with poor prognosis in several cancer types as well, we further verified the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent or in combination with ionizing radiation in GSCs. Efficacy of volasertib was analyzed by Cell-Titer Glo 5 days after treatment. Morphological and molecular changes were approached by immunoblotting and flow cytometry after volasertib treatment, and in combination with ionizing radiation at 2 Gy. In vitro studies showed that volasertib inhibited cell viability with an IC50 ranging from 44.3nM to 4.36μM. Volasertib induced G2/M arrest accompanied by high levels of PLK-1, Aurora B and phosphor-histone 3 and prominent cleaved poly ADP ribose polymerase (PARP) in a dose- and time-dependent manner. Colony formation assay demonstrated that volasertib and ionizing radiation had synergistic effects on colony formation inhibition, suggesting that GSCs arrested in M phase by volasertib are more sensitive to ironizing radiation. The promising in vitro results of volasertib in GSCs led to further investigate the drug efficacy in intracranial xenograft models by volasertib alone, and in combination with radiation. Taken together, our results reinforce the potential therapeutic candidate of volasertib as a single agent and in combination with ionizing radiation in glioblastoma.
Citation Format: Jianwen Dong, Nghi Nguyen, Ravesanker Ezhilarasan, Shaofang Wu, Yuji Piao, Soon Young Park, Ningyi Tiao, Clifford Stephan, Erik P. Sulman, John F. de Groot. Synergistic antitumor effects of polo like kinase inhibitor volasertib in combination with ionizing radiation in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 695. doi:10.1158/1538-7445.AM2015-695
Abstract 697: c-MET as a potential target in ovarian clear-cell carcinoma
Authors: Lee Jeong-Won , Kim Byoung-Gie , Bae Duk-Soo , Lee Yoo Young 
Published: August 2015

Abstract
Purpose: Recent reports revealed that c-MET activation is associated with epithelial ovarian carcinoma (EOC) and is association with poor prognosis. In this study, we investigated the effects of therapeutic targeting for c-MET in ovarian clear cell carcinoma (OCCC).
Experimental Design: Expression levels of c-MET in the epithelial ovarian carcinomas and normal ovarian tissues were evaluated using real-time PCR. To test c-MET inhibitors in CCC cell lines, we performed in vitro experiments including MTT and apoptosis assay. We performed Western blots to evaluate the c-MET expression and down-stream pathway. In addition, we performed in vivo therapy experiments in orthotopic ovarian cancer mice model (RMG1) and patient-derived tumor xenograft (PDX) models of CCC to confirm these effects.
Results: The c-MET expression was significantly increased in CCCs compared with serous carcinomas and normal ovarian tissues (P &lt; 0.05). CCC cells treated with c-MET inhibitors (SU11274 or crizotinib) demonstrated significantly decreased cell viability and increased apoptosis. Western blot assay showed that the protein expressions for c-MET signaling pathway were decreased by c-MET inhibitor. Moreover, tumor weight was significant decreased in both in vivo RMG1 and PDX models receiving SU11274 treatment compared with control (P &lt; 0.05).
Conclusion: These results show that c-MET inhibitor has the significant anti-tumor effects in ovarian CCC, and suggested that c-MET could have the potential agent in the therapy for this cancer.
Citation Format: Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae, Yoo Young Lee. c-MET as a potential target in ovarian clear-cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 697. doi:10.1158/1538-7445.AM2015-697
Abstract 698: CPI-based Crizotinib systemic study on discovery of phenotypic off-target
Authors: Sun Jiazhi , Yang Lun , Li Minghua , Zhang Shimin , Heller Ian E. , Samuelson Johnathan , Cindric Steven , Mishra Kunal , Mohamed Eslam , Cheng Feng , Sneed Kevin B. , He Lin , Zhou Shu-Feng 
Published: August 2015

Abstract
Crizotinib, a first ever ALK/MET multi-targeted receptor tyrosine kinase inhibitor for the treatment of ALK-rearranged NSCLC patients. We hypothesize that crizotinib acts on other molecular targets in addition to tyrosine kinases ALK/MET and may play critical role given that there is a complex network of kinases that work together to regulate a number of important cellular processes and different disease signature. Approaching with a comprehensive docking method with our established chemical-protein interactome (CPI) and crizotinib, we have discovered 301 PDB-deposited proteins corresponding to 353 ligand binding pockets among a total of 1,780 PDB-deposited human protein entries. Systemic pharmacology approach also applied including validation the molecular target(s) of TKIs in vitro. Especially multiple human cellular models (including NSCLC and melanoma) and signaling study, luc-reporter, autophagy/apoptosis, proteomics study and NGS analysis applied. Interestingly, crizotinib besides had a high CPI binding score (ZZ_score) of -2.2778 against tyrosine kinase Lck, also had -1.4672, -1.1242, -0.7033 and -1.5384 against MAPK3, S6K, GSK-3β and HDAC 7A, respectively, which indicated crizotinib had potential broad range interaction with both TK and ser/thr kinases. Our data have showed that the crizotinib induced autophagy by activated LC3 in vitro and inhibited oncogenic Akt/mTOR signaling in human multiple melanoma cells resulting in G2/M cell cycle arrest. Furthermore, crizotinib increased p21Waf1/cip1 and Foxo3A expression and tumor suppressor miR-146a in human melanoma cells. Taken together, crizotinib induces miR-146a, autophagy and p21waf1/cip1 may potentially treat other type of human cancer by concurrently targeting tyrosine kinase, Akt/mTOR/Foxo axis and nuclear receptor, shedding a light for future both anti-cancer and anti-metabolic disorder drug discovery and development. This is the first CPI-based systemic study on leading discovery of crizotinib off-target phenotypic importance. These findings suggest that non-tyrosine kinase target of crizotinib may play critical role(s) for drug repositioning may represent a new and effective approach to expanding the application of existing drugs.
Citation Format: Jiazhi Sun, Lun Yang, Minghua Li, Shimin Zhang, Ian E. Heller, Johnathan Samuelson, Steven Cindric, Kunal Mishra, Eslam Mohamed, Feng Cheng, Kevin B. Sneed, Lin He, Shu-Feng Zhou. CPI-based Crizotinib systemic study on discovery of phenotypic off-target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 698. doi:10.1158/1538-7445.AM2015-698