bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3548: Oncolytic adenovirus Ad5dlE1b replication efficiency is dependent on p53 mutation type in cancer cells
Authors: Abdalla Moemen , Abbas Basma M. , Haj-Ahmad Yousef 
Published: August 2015

Abstract
Adenoviruses are the most popular viral DNA vectors in the development of gene therapies and oncolytic therapy. Oncolytic adenoviruses are genetically modified to provide a means of tumor-selectivity by conditionally replicating in tumor cells and substantially killing them via their viral lytic cycle. The p53 molecule is a tumor suppressor protein that regulates the genomic integrity of the cell by controlling apoptosis and cell cycle events. Upon viral infection, normal cell (p53 intact cell) responds through the activation of apoptosis by the p53 dependent pathway. The adenovirus E1B 55kDa protein inactivates p53 and prevents apoptosis leading to progressive viral lytic cycle. Although demonstrating a moderate successes rate in some cancers, Ad deleted E1B 55kDa has not been approved as a standard therapy for all cancer types. Several studies have revealed that E1B deleted Ad replication was independent of p53 status in the cell, as the virus replicated better in some p53 deficient cancers more than others. However, this relationship has not been investigated deeply on the molecular level. However, this relationship has not been investigated deeply on the molecular level. Therefore, the objective of this study is to understand the correlation between p53 status, levels, and functional activity, and oncolytic Ad5dl E1B 55kDa replication efficiency at the molecular level. We evaluated the effect of p53's functional status on the replication efficiency of oncolytic Ad5dl E1B 55kDa. Multiple mutant p53 were engineered and viral growth was evaluated with each mutant form in H1299 cells. P53-R175H mutant successfully rescued viral growth and its transcriptome analysis showed partial loss of wild type activity as well as gain of new function by allowing the virus to grow and to exert its mechanism of selectivity. The mechanism entailed deregulating the expression of specific cellular genes in the p53 pathway, cell cycle and apoptosis, to promote its production leading to efficient oncolytic effect. These results confirmed that onclytic Ad5dl E1B 55kDa sensitivity is mutation type-specific. Therefore, before it is applied clinically as cancer therapy for p53 deficient tumors, the type of p53 mutation must be determined and also more screening for the effect of other mutations should be done for successful rescuing and efficient antitumor effect.
Citation Format: Moemen Abdalla, Basma M. Abbas, Yousef Haj-Ahmad. Oncolytic adenovirus Ad5dlE1b replication efficiency is dependent on p53 mutation type in cancer cells. [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 3548. doi:10.1158/1538-7445.AM2015-3548
Abstract 3551: A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma
Authors: Wang Fengfei , Remke Marc , Bhat Kruttika , Wong Eric , Zhou Shuang , Ramaswamy Vijay , Dubuc Adrian , Fonkem Ekokobe , Salem Saeed , Zhang Hongbing , Hsieh Tze-chen , O'Rourke Stephen , Wu Lizi , Li David , Hawkins Cynthia , Kohane Isaac , Wu Joseph , Wu Min , Taylor Michael , Wu Erxi 
Published: August 2015

Abstract
Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRβ and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRβ-driven signaling cascade and a potential therapeutic target.
Citation Format: Fengfei Wang, Marc Remke, Kruttika Bhat, Eric Wong, Shuang Zhou, Vijay Ramaswamy, Adrian Dubuc, Ekokobe Fonkem, Saeed Salem, Hongbing Zhang, Tze-chen Hsieh, Stephen O'Rourke, Lizi Wu, David Li, Cynthia Hawkins, Isaac Kohane, Joseph Wu, Min Wu, Michael Taylor, Erxi Wu. A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma. [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 3551. doi:10.1158/1538-7445.AM2015-3551
Abstract 3553: xCT is a new cancer stem cell immunotherapeutic target for breast cancer
Authors: Macagno Marco , Lanzardo Stefania , Conti Laura , Ruiu Roberto , Calogero Raffaele A. , Cavallo Federica 
Published: August 2015

Abstract
The several unsuccessful treatments in metastatic cancers might miss cancer stem cells (CSC), a sub-population of cells with a critical role in cancer. By contrast, a vaccine-elicited immune response against CSC might be particularly effective. The identification of oncoantigens (OA) expressed by CSC may provide new targets for effective anticancer vaccines.
To this purpose, the transcription profile of the ErbB2+ TUBO mammary cancer cell line was compared with that of TUBO cells grown under specific conditions to generate CSC-enriched mammospheres.
Integrating the data obtained with meta-analyses of seven independent human breast tumor data sets we identified new CSC mammary OA that were validated both in vitro and in vivo.
Among the identified OA, we focused on xCT, a channel that supports glutathione synthesis regulating the intracellular redox balance. We observed that xCT expression increases in TUBO and 4T1 derived mammospheres; its silencing, obtained with specific siRNA, or incubating mammospheres with its inhibitor sulfasalazine (2), significantly reduces TUBO cells ability to generate mammospheres. In vivo xCT inhibition impaired CSC ability to generate lung metastases derived both from an intravenous injection of TUBO-derived mammospheres and from subcutaneous 4T1 tumors; furthermore, this effect was improved when combined with the cytotoxic drug doxorubicin. Moreover, the anti xCT vaccination of mice bearing mammosphere-derived tumors both from TUBO and 4T1 cells reduced the speed of tumor growth.
In conclusion, this study provides a genomic characterization of mammary CSC and identifies fresh target for new and potentially effective anticancer vaccines, thus providing a new tool for the design of combined therapeutic approaches that efficaciously target both CSC and more differentiated cells in breast cancers, leading to both cancer treatment and prevention of metastases and recurrence.
BIBLIOGRAPHY
1. Nagano O et al., Oncogene 2013.
2. Chen RS et al., Oncogene 2009.
Citation Format: Marco Macagno, Stefania Lanzardo, Laura Conti, Roberto Ruiu, Raffaele A. Calogero, Federica Cavallo. xCT is a new cancer stem cell immunotherapeutic target for breast 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 3553. doi:10.1158/1538-7445.AM2015-3553
Abstract 3555: Akt kinase-interacting protein1 as a potential therapeutics target in CREB1 signaling in malignant pleural mesothelioma
Authors: Yamada Tadaaki , Amann Joseph M. , Shilo Konstantin , Fujita Naoya , Yano Seiji , Carbone David P. 
Published: August 2015

Abstract
Background:
Diffuse malignant mesothelioma (DMM) is an aggressive tumor arising from the mesothelial cells of serosal membranes. As conventional treatment regimens are commonly unsuccessful in changing its outcome, novel effective therapeutic strategies based on the molecular mechanisms of disease are needed to improve the prognosis of DMM. Akt kinase-interacting protein1 (Aki1), known as a scaffold protein of PI3K/PDK1/Akt that determines receptor signal selectivity for EGFR, has been suggested as a therapeutic target in lung cancer. The aim of this study was to evaluate Aki1 as a potential therapeutic target for treatment of DMM.
Methods:
DMM cell lines (211H, H290, H2052, H2373, H2452, Y-meso8A, and Y-meso14) and immortalized human mesothelial cells (Met-5A) were employed for evaluation of effects of treatment with Aki1 or CREB1 siRNAs on cell viability by MTT assay, cell cycle by FACS analysis, cell signaling by WB, and CREB transcriptional activity. The efficacy of Aki1 siRNA against growth of 211H cells was investigated in an orthotropic implantation model using SCID mice. We further examined Aki1 and p-CREB1 expression in DMM tumors from 35 patients utilizing tissue microarray and resection specimens.
Results:
Cell based assay showed that silencing of Aki1 inhibited cell viability and caused cell arrest of mesothelioma cell lines but not immortalized mesothelial cells (Met-5A). Importantly, we identified that the efficacy of Aki1 is regulated by CREB1 signaling which is involved in cell viability, cell cycle, and transcriptional activity. Application of Aki1 siRNA significantly inhibited growth of 211H cell line within pleural cavity compared with that of control siRNA in an orthotropic implantation model (p = 0.006). Aki1 and phosphorylated CREB1 were frequently expressed in DMM patients (65/68 and 30/35 cases, respectively). Furthermore, the expression of Aki1 correlated with phosphorylation of CREB1 (Spearman rank correlations = 0.521; p = 0.002).
Conclusions:
Our data suggest that Aki1/CREB axis may regulate the survival signaling, and may therefore be a potent target for DMM patients.
Citation Format: Tadaaki Yamada, Joseph M. Amann, Konstantin Shilo, Naoya Fujita, Seiji Yano, David P. Carbone. Akt kinase-interacting protein1 as a potential therapeutics target in CREB1 signaling in malignant pleural mesothelioma. [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 3555. doi:10.1158/1538-7445.AM2015-3555
Abstract 3558: uPAR mediated endothelial targeting by oncolytic measles virus
Authors: Toro Bejarano Marcela M. , Jing Yuqi , Kovacs Krisztina , Merchan Jaime 
Published: August 2015

Abstract
Background: The urokinase receptor (uPAR) is over-expressed in tumor cells as well as in tumor endothelium and plays a critical role in tumor neovascularization. We have recently rescued an oncolytic measles virus fully retargeted against human uPAR (MV-h-uPA). The aim of this study was to further characterize the endothelial targeting capabilities of MV-h-uPA over MV-GFP.
Methods: In vitro cytotoxicity assays were performed in unstimulated and stimulated HUVEC, and the effects of both viruses were analyzed. The effects of MV-GFP and MV-h-uPA on actively forming vs. established capillaries was investigated using the matrigel tube formation assay. Endothelial to tumor transfer of MV-uPA or MV-GFP was investigated in breast, colon cnd kidney cancer cell lines expressing RFP by overlaying infected HUVEC on tumor cell monolayers. The mechanisms/kinetics of viral transfer from HUVEC to tumor cells was characterized. Microvessel density of tumors treated with MV-h-uPA was quantitated by immunohistochemistry using an antibody against CD31.
Results: MV-h-uPA and MV-GFP induced cytotoxicity at 24, 48 and 72 hours in stimulated HUVECs. MV-h-uPA replicated more efficiently in growth factor stimulated, compared to resting HUVECs. Interestingly, MV-h-uPA, but not MV-GFP successfully infected actively forming (angiogenic) HUVEC capillaries, as assessed by mean fluorescence quantification of GFP expression of infected capillaries. On the other hand, the non-targeted MV-GFP predominantly infected already established HUVEC capillaries (infected 24 hours after tubes were formed), an effect not observed with MV-h-uPA. Importantly, MV-h-uPA did not induce vascular disrupting effects in HUVEC capillaries. MV-h-uPA was successfully transferred from infected endothelial cells to tumor cells. This effect was mediated by heterofusion, as chemical inhibition of virus induced fusion at different time points during co-culture completely blocked EC to TC transfer. Heterofusion occurred as early as 4 hours after endothelial cell overlay into tumor cell cultures. EC to TC viral transfer resulted in significant tumor cell cytotoxicity.
Conclusion: The above results demonstrate the improved ability of uPAR retargeted oncolytic measles virus to infect, replicate and successfully infect angiogenic endothelial cells, as well as successful EC to TC transfer in vitro, resulting in tumor cell cytotoxicity. Vascular targeting by oncolytic MVs may result in improved tumor cell delivery in vivo, and enhanced antitumor effects.
Citation Format: Marcela M. Toro Bejarano, Yuqi Jing, Krisztina Kovacs, Jaime Merchan. uPAR mediated endothelial targeting by oncolytic measles virus. [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 3558. doi:10.1158/1538-7445.AM2015-3558
Abstract 3562: Protein palmitoylation in breast cancer: DHHC5 palmitoyltransferase as a potential therapeutic target
Authors: Tian Hui , Qi Xiaoxia , Huffman Kenneth , Minna John , Hofmann Sandra L. 
Published: August 2015

Abstract
Protein S-palmitoylation is a widespread and dynamic post-translational modification that regulates protein-membrane interactions, protein-protein interactions, and protein stability. S-palmitoylation is catalyzed by members of a family of 23 palmitoyl acyl transferases, termed the DHHC family due to the presence of a common catalytic motif. The role of protein palmitoylation in cancer is largely unexplored.
In our previous study, we have shown that DHHC5 palmitoyltransferase supports the growth of non-small cell lung cancer. To further investigate the role of DHHC5 in cancer, we expanded our study to include breast cancer cell lines. Stable knockdowns of DHHC5 were undertaken in 8 breast cancer cell lines (including 4 “triple-negative” breast cancer lines) as well as in two normal human mammary epithelial cell lines (HMECs) using lentiviral shRNAs. The protein levels of DHHC5 were analyzed by immunoblotting, which all showed efficient knockdown. Cell proliferation and anchorage-dependent/ independent colony formation assays indicated that DHHC5 knockdown led to cell growth arrest and decreased cell clonogenicity in most of the tested breast cancer cell lines in vitro, but not in the HMECs. BT-549, SkBr3 and T-47D cell lines were particularly dependent on DHHC5 expression, and rescue experiments involving ectopic plasmid-driven DHHC5 and its catalytic mutant DHHS expression are in progress. In vivo tumor formation assays will be carried out by injecting MCF-7 and T-47D control cells and DHHC5 stable knockdown cells as well as rescued cells subcutaneously into NOD/SCID mice. Tumor xenograft formation will be measured.
As DHHC5 function is needed for optimal breast cancer cell growth, it will be important to identify physiologically relevant substrates in order to develop inhibitors of DHHC5 function. Future plans include microarray and protein kinase array analysis to identify possible signaling pathways in which DHHC5 may be involved, as well as palmitoyl-protein profiling of control and knockdown DHHC5 cell lines by mass spectrometry.
Citation Format: Hui Tian, Xiaoxia Qi, Kenneth Huffman, John Minna, Sandra L. Hofmann. Protein palmitoylation in breast cancer: DHHC5 palmitoyltransferase as a potential therapeutic 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 3562. doi:10.1158/1538-7445.AM2015-3562
Abstract 3588: Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer
Authors: Lazzari Luca , Arena Sabrina , Bellosillo Beatriz , Siravegna Giulia , Martínez Alejandro , Cañadas Israel , Ferruz Noelia , Russo Mariangela , Misale Sandra , González Iria , Iglesias Mar , Gavilan Elena , Corti Giorgio , Hobor Sebastijan , Crisafulli Giovanni , Salido Marta , Sánchez Juan , Dalmases Alba , Bellmunt Joaquim , De Fabritiis Gianni , Rovira Ana , Di Nicolantonio Federica , Albanell Joan , Bardelli Alberto , Montagut Clara 
Published: August 2015

Abstract
Colorectal cancer (CRC) patients who respond to the anti-EGFR antibody cetuximab often develop resistance within several months of initiating therapy. To design new lines of treatment the molecular landscape of resistant tumors must be ascertained. We investigated the role of mutations in the EGFR signalling axis on the acquisition of resistance to cetuximab in patients and cellular models.
Mutational profiling was performed on both biopsies collected from 37 CRC patients who became refractory to cetuximab and on a collection of cetuximab-resistant derivatives obtained from CRC cells sensitive to EGFR blockade.
The genetic profile of tumor specimens obtained after cetuximab treatment revealed the emergence of a complex pattern of mutations in EGFR, KRAS, NRAS, BRAF and PIK3CA genes, including two novel EGFR ectodomain mutations. Mutational profiling of cetuximab resistant cells recapitulated the molecular landscape observed in clinical samples and revealed three additional EGFR ectodomain alleles.
Structural modelling showed that these mutations are located in the cetuximab-binding region, except for one mutant. Functionally, EGFR ectodomain mutations prevent binding to cetuximab but a subset is permissive for interaction with panitumumab.
In conclusion, we reported that colorectal tumors evade EGFR blockade by constitutive activation of downstream signalling effectors and through mutations affecting receptor-antibody binding. Both mechanisms of resistance may occur concomitantly. Our data have implications for designing additional lines of therapy for CRC patients who relapse upon treatment with anti-EGFR antibodies.
Citation Format: Luca Lazzari, Sabrina Arena, Beatriz Bellosillo, Giulia Siravegna, Alejandro Martínez, Israel Cañadas, Noelia Ferruz, Mariangela Russo, Sandra Misale, Iria González, Mar Iglesias, Elena Gavilan, Giorgio Corti, Sebastijan Hobor, Giovanni Crisafulli, Marta Salido, Juan Sánchez, Alba Dalmases, Joaquim Bellmunt, Gianni De Fabritiis, Ana Rovira, Federica Di Nicolantonio, Joan Albanell, Alberto Bardelli, Clara Montagut. Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal 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 3588. doi:10.1158/1538-7445.AM2015-3588
Abstract 359: STAT3-axis activated snail expression and promoted drug resistance in pediatric brain tumor
Authors: Chi-Chang Tsai 
Published: August 2015

Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment select not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulation which occurred simultaneously with higher expression of Snail, an activator of epithelial-mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly invasion and recurrence. Therefore, the STAT3/Snail could be a target for ATRT treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Tsai Chi-Chang. STAT3-axis activated snail expression and promoted drug resistance in pediatric brain tumor. [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 359. doi:10.1158/1538-7445.AM2015-359