bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 768: MCL1 and glycolysis synergistically induce prednisolone resistance, which can be therapeutically reversed
Authors: Ariës Ingrid M. , van den Dungen Rosanna , Pieters Rob , Boer Monique L. Den 
Published: August 2012

Abstract
Although cure rates for acute lymphoblastic leukemia (ALL) have greatly improved, contemporary treatment is still ineffective in 20% of patients. Unsuccessful treatment can be mainly ascribed to resistance towards antileukemic drugs. In particular prednisolone is highly associated with poor prognosis. Overcoming drug resistance is therefore necessary to increase current survival rates. Microarray analysis of precursor B-ALL patients revealed MCL1 as an important gene involved in prednisolone resistance (Holleman, N Engl J Med 2004). We demonstrated sensitization towards prednisolone after lentiviral silencing of MCL1 in prednisolone resistant leukemic cell lines (Stam, Blood 2009). These results point to MCL1 as an interesting candidate for targeted therapy. We also discovered that cells upregulate their glucose consumption level to protect from prednisolone induced apoptosis. 2-Deoxyglucose (2DG), an inhibitor of glycolysis, sensitized for prednisolone in leukemic cell lines and patients’ cells (Hulleman, Blood 2009). We here provide evidence for an inter-connection between MCL1, glycolysis and prednisolone resistance. A clear increase in glucose consumption was observed after targeting MCL1 in leukemic cells by both lentiviral silencing and mRNA antagonists. This suggests that cells upregulate glycolysis to prevent apoptosis induced upon MCL1 knockdown. Indeed, co-exposure to 2DG substantially decreased the proliferation rate of MCL1-silenced cells, and most importantly, synergized with silencing of MCL1 in reversing resistance to prednisolone. Altogether these data provide evidence for concomitant causes of resistance and indicate that MCL1 silencing and glycolysis inhibition can serve as potent ways to reverse resistance to prednisolone in acute leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 768. doi:1538-7445.AM2012-768
Abstract 777: GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance
Authors: Sodani Kamlesh S. , Tiwari Amit K. , Singh Satyakam , Patel Atish , Xiao Zhijie , Chen Junjiang , Sun Yueli , Talele Tanaji T. , Chen Zhe-Sheng 
Published: August 2012

Abstract
The overexpression of ATP-binding cassette (ABC) transporters often lead to the development of multidrug resistance (MDR), resulting in chemotherapy failure. Previously, we reported that lapatinib (GW572016), a human epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinase inhibitor (TKI), modulates ABC subfamily B member 1 (ABCB1)- and ABC subfamily G member 2 (ABCG2)-mediated MDR in cancer cells. In the present study, we conducted experiments to determine if GW583340 and GW2974; structural analogues of lapatinib; could reverse ABCB1- and ABCG2-mediated MDR. Our results showed that both GW583340 and GW2974 significantly sensitized MDR cells overexpressing ABCB1 to their anticancer substrates as well as ABCG2 overexpressing cells to its substrates. Subsequently, both GW583340 and GW2974 significantly increased intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells. Similarly, both GW583340 and GW2974 significantly increased accumulation of [3H]-mitoxantrone in ABCG2 overexpressing cells. In addition, GW583340 and GW2974 significantly inhibited ABCG2-mediated transport of methotrexate in ABCG2 overexpressing membrane vesicles. Moreover, there was no significant change in the expression levels of ABCB1 and ABCG2 in the cell lines exposed to 5 μM of either GW583340 or GW2974 for 3 days. In addition, docking model predicted the binding conformation of GW583340 and GW2974 within the large cavity of the transmembrane region of homology modeled human ABCB1. We conclude that GW583340 and GW2974, at clinically achievable concentrations reverse ABCB1- and ABCG2-mediated MDR by directly blocking the drug efflux function of these transporters. These findings may be useful in developing cancer combinational therapy with EGFR TKIs in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 777. doi:1538-7445.AM2012-777
Abstract 78: BRCA1/2 mutation analysis in 43 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation
Authors: Stordal Britta , Timms Kirsten , Renaud Mickaël , Thery Julien , Farelly Angela , Williams Deborah , Potter Jennifer , Tran Thanh , Korpanty Greg , Cremona Mattia , Carey Mark , Li Jie , Li Yang , Aslan Ozlem , O'Leary John J. , Mills Gordon B. , Hennessy Bryan T. 
Published: August 2012

Abstract
Introduction: Germline mutations in DNA repair genes BRCA1/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality, the inhibition of two major DNA repair pathways. Therefore, there is a need to characterize ovarian cell lines for their BRCA1/2 status for in vitro studies of novel drugs. Methods: The BRCA1/2 genes were sequenced in 43 ovarian cell lines, mRNA expression of BRCA1/2 and gene methylation of BRCA1 were also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 10 cell lines. Results: Sequencing of BRCA1/2 revealed 18 and 33 different alterations respectively, mostly non-pathogenic polymorphisms. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G&gt;A and is the only deleterious BRCA1/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations which restore the function of the protein. BRCA1 was methylated in three cell lines (A1847, OVCAR8, EF021) and there was a corresponding decrease in gene expression in these cell lines. The deleterious mutant SNU-251 was relatively resistant to PARP inhibition, compared to wild-type cells. However, the methylated cell lines A1847 and OVCAR8 were more sensitive to PARP inhibition than wild-type cells. Conclusions: The incidence of BRCA1/2 deleterious mutations 1/43 cell lines (2.3%) is much lower than the population incidence. The reversion mutations suggest that there is a selective pressure against BRCA1/2 mutations in cell culture. PARP inhibitors may be useful in patients with BRCA1 methylation and reduced gene expression in their ovarian tumour.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 78. doi:1538-7445.AM2012-78
Abstract 811: VAL083, a novel N7 alkylating agent, surpasses temozolomide activity and inhibits cancer stem cells providing a new potential treatment option for glioblastoma multiforme
Authors: Hu Kaiji , Fotovati Abbas , Chen James , Triscott Joanna , Bacha Jeffery , Brown Dennis , Dunn Sandra E. 
Published: August 2012

Abstract
Glioblastoma (GBM) remains one of the most difficult tumors to treat in part because many new agents fail to cross the blood brain barrier (BBB) and secondly due to intrinsic drug resistance. Temozolomide (TMZ) is a front-line therapy for the treatment of GBM, however, it is often ineffective due to drug inactivation by O6-methylguanine-DNA methyltransferase (MGMT). Cancer stem cells (CSC) are a subpopulation of the tumor that resist therapy and give rise to relapse. Here we described VAL083 a novel alkylating agent that creates N7 methylation on DNA, which was initially intriguing because it crosses the BBB. We addressed how it compared to TMZ, whether it could be used to overcome MGMT-driven drug resistance and if it has activity against CSCs. Addressing these questions provides further preclinical support for VAL083, which is currently undergoing human clinical trials in the USA against refractory GBM. VAL083 inhibited U251 and SF188 cell growth in monolayer and as neurospheres better then TMZ and caused apoptosis after 72 hrs. In a 10-day colony formation assay, VAL083 (5uM) suppressed SF188 growth by ∼95%. T98G cells are classically TMZ resistant and express MGMT yet VAL083 inhibited their growth in monolayer after 72 hrs in a dose-dependent manner (IC50&lt;5 uM). VAL083 also inhibited the growth of CSCs by 100% in neurosphere growth assays. In summary, VAL083 has better in vitro efficacy than TMZ against brain tumor cells, can overcome resistance associated with MGMT, and targets brain tumor CSCs demonstrating that it has the potential to surpass the standard-of-care.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 811. doi:1538-7445.AM2012-811
Abstract 813: Mechanism of cellular uptake of Pt drugs: The role of hCTR1
Authors: Ivy Kristin D. , Kaplan Jack H. 
Published: August 2012

Abstract
Cisplatin is an anti-cancer drug used to treat various human malignancies including breast, testicular, ovarian, prostrate, lung, head, neck, and colon cancers. While this drug has been shown to successfully treat tumors, its use is limited by the rapid development of resistance. This drug has been used since the 70's to treat different forms of cancer and recent studies have attempted to understand the mechanism of resistance by examining how this anti-cancer drug is taken into the cell, distributed within the cell, and exported. It has been claimed that hCTR1, the human high affinity Cu transporter, is the major entry pathway for cis-Pt and related anti-cancer drugs in human cells. Furthermore, that the entry mechanism via hCTR1 mimics that of Cu. Since hCTR1 is a very selective transporter for Cu(I), its function as a cisplatin entry pathway is unexpected. We will describe the results of our recent studies on HEK293 cells that over-express wild-type hCTR1 and a number of mutant Cu transporters, ovarian tumor cells that are sensitive or resistant to cis-Pt, and a number of human breast cell tumor lines. We have compared the relative entry rates of Cu and Pt in these cells and, via cell surface biotinylation and imaging, the effects of extracellular Cu, which causes regulatory endocytosis of the transporter, to that of the cis-Pt drugs. Our results suggest that hCTR1 is not the major entry route of Pt drugs into human cells and that the response of the transporter, in a number of these cells, to the presence of extracellular drug is different from its response to Cu. Supported by NIH Grant P01 GM 067166.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 813. doi:1538-7445.AM2012-813
Abstract 835: Epigenetic biomarkers of chemoresistance in colorectal cancer
Authors: Moutinho Cátia , Martinez-Cardús Anna , Martínez-Balibrea Eva , Abad Albert , Esteller Manel 
Published: August 2012

Abstract
Resistance acquisition to chemotherapeutic agents is one of the main problems that come up during cancer treatment. The mechanisms of developing resistance are poorly understood, and the causes underlying the loss of sensitivity to common chemotherapy drugs are largely unknown. Promoter hypermethylation of DNA repair genes has been demonstrated to be an excellent biomarker of sensitivity to chemotherapy agents, being the epigenetic silencing of MGMT in gliomas the most remarkable example. In this study, we have focused our research on one of the most common cancer type, the colorectal cancer (CRC). Thus, we propose to assess how DNA methylation alterations can help to explain acquired resistance to oxaliplatin (OXA) in this type of tumours. To address this issue we used LoVo OXA sensitive and resistant cell lines (LoVoS_OXA vs. LoVoR_OXA). Using DNA genomic bisulfite sequencing we found that CpG islands located at some genes promoters (candidate genes) are unmethylated in LoVoS_OXA but hypermethylated in LoVoR_OXA, being these phenomena correlated with lower mRNA and protein expression in the resistant cell line. DNA promoter methylation of theses candidate genes was then checked by Methylation Specific PCR (MSP) in 25 human CRC tumour samples obtained from patients treated with FOLFOX (5-fluorouracil; leucovorin and oxaliplatin)(blind study). Remarkably, one candidate gene promoter hypermethylation was related with worse response to chemotherapy, poor overall survival and poor progression- free survival. In contrast, promoter hypermethylation of a second candidate gene was related with improved treatment response and survival rates. Being this an ongoing project, we are performing in vitro studies in order to check if changes in promoter hypermethylation can modulate cell sensitivity to OXA drug. The results obtained in this study can help to understand the biological processes leading to chemoresistance and also to the future management of cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 835. doi:1538-7445.AM2012-835
Abstract 847: Foretinib, a multi-kinase inhibitor of cMET and PDGFRα, in the treatment of disseminated medulloblastoma
Authors: Faria Claudia C. , Golbourn Brian J. , Smith Christian A. , Rutka James T. 
Published: August 2012

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in childhood accounting for around 10% of all pediatric cancer deaths. Dissemination occurs in 30% of the patients at the time of diagnosis and essentially defines children with incurable disease given that metastatic disease is refractory to current treatments. Therefore, there is an urgent need for new therapies to treat metastatic MB. The hepatocyte growth factor (HGF)/cMET signaling pathway has been recently implicated in the pathogenesis of MB. Overexpression of cMET and HGF is associated with group C tumors which have high incidence of metastasis and poor outcome. Moreover, overexpression of the platelet-derived growth factor receptor (PDGFR) was also identified in metastatic MB. Using foretinib, a multi-kinase inhibitor of cMET and PDGFRα, we aimed to target two important pathways involved in MB dissemination. Using three MB cell lines (Daoy, ONS - 76 and D425) that express different amounts of the receptors (cMET and PDGF), we performed dose-response experiments with foretinib, measuring downstream targets of cMET and PDGFRα activation. We showed that foretinib inhibits proliferation, migration, invasion and anchorage independent growth of MB cell lines in a dose-dependent manner. By immunofluorecence, we observed that foretinib induces polyploidy and using flow cytometry analysis we found that it also induces apoptosis and cell cycle arrest in G2-M phase. To test the efficacy of foretinib in vivo we have created a disseminated mouse model of MB injecting MB cells in the fourth ventricle of nude mice, mimicking the process of dissemination in children. The cells were previously transfected with a luciferase expressing vector allowing weekly monitoring of tumor growth and dissemination by bioluminescence imaging. Foretinib was able to reduce tumor growth and metastasis in xenografts, increasing survival when compared to controls. Altogether these results suggest that small molecule inhibitors of cMET and PDGFR may represent a new therapeutic strategy in the treatment of disseminated MB. Given that foretinib is already being tested in clinical trials for other forms of cancer, the findings from our experiments may lead to the design of identical trials in children with metastatic medulloblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 847. doi:1538-7445.AM2012-847
Abstract 85: RUNX1 and ELK1 directly regulate the transcription of EVI1 during megakaryocytic differentiation
Authors: Maicas Miren , Vazquez Iria , Vicente Carmen , Cortes-Lavaud Xabier , Marcotegui Nerea , Urquiza Leyre , Calasanz Maria J. , Odero Maria D. 
Published: August 2012

Abstract
High expression of EVI1 is a negative prognostic indicator of survival in patients with acute myeloid leukemia (AML). The EVI1 gene (3q26) codes for a transcription factor indispensable for the proliferation and self-renewal of HSCs during embryogenesis and in the adult, and is downregulated upon differentiation; however, the regulation of EVI1 in megakaryocytic differentiation should be different, as it is highly expressed in megakaryocytes and platelets, but not in other committed hematopoietic cells. Our aim was to identify transcription factors involved in the regulation of EVI1. Site-directed mutagenesis and ChIP assays identified RUNX1 and ELK1 as putative transcription factors of EVI1. Furthermore, knockdown of RUNX1 and ELK1 led to EVI1 downregulation, and their overexpression to upregulation of EVI1. Of note, in a series of patient samples with AML at diagnosis (n=46), we found a significant positive correlation between EVI1 and RUNX1, and EVI1 and ELK1 mRNA expression levels. RUNX1 has been reported as a key transcription factor in megakaryocytic development. To investigate whether RUNX1 could regulate EVI1 in this process, we treated K562 cells with TPA. After the treatment, we observed an increase in RUNX1, as previously described, and in ELK1 and EVI1. Knockdown of RUNX1 resulted in a marked decrease of the megakaryocytic markers ITGA2B and ITGB3, and of EVI1. Moreover, EVI1 knockdown led to the same effects by blocking the differentiation process, suggesting that the role of EVI1 in megakaryocytic differentiation would be through RUNX1. Interestingly, chromatin immunoprecipitation assay (ChIP) showed that RUNX1 regulates the transcription of EVI1 by acetylation of the histone H3 on its promoter region. In conclusion, we demonstrate that RUNX1 and ELK1, two proteins with essential functions in hematopoiesis, regulate EVI1 in AML. Moreover, our results suggest that these transcription factors could regulate EVI1 expression during megakaryocytic differentiation, and that RUNX1 would activate EVI1 expression through acetylation of the histone H3 on its promoter region. This study opens new directions to further understand the mechanisms of EVI1 overexpressing leukemias.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 85. doi:1538-7445.AM2012-85
Abstract 857: Development of a Bruton's tyrosine kinase (Btk) inhibitor - ONO-WG-307, a potential treatment for B-cell malignancies
Authors: Kozaki Ryohei , Yoshizawa Toshio , Yasuhiro Tomoko , Mirjolet Jean-François , Birkett Joseph , Narita Masami , Kawabata Kazuhito 
Published: August 2012

Abstract
Purpose: Signals from B cell receptors (BCR) play a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. BCR signaling is implicated in the survival of malignant B cells and recent studies indicate that targeting Btk, an essential component of the BCR pathway, may be effective in the treatment of B-cell lymphoma. ONO-WG-307 is a highly potent and selective Btk inhibitor with an IC50 in the sub-nmol/L range. We evaluated the inhibitory effect of ONO-WG-307 alone and in combination with the chimeric type I anti-CD20 antibody rituximab, using in vitro tumor growth assays and mouse xenograft models. Methods: Two types of tumor cell lines (follicular lymphoma (FL) and activated B-cell-like (ABC) sub-type of diffuse large B cell lymphoma (DLBCL)) wereplated on to micro-titration plates (at doses up to 200 umol/L for ONO-WG-307 and 100 ug/mL for rituximab) for in vitro cytotoxic assays. The same cells were also implanted subcutaneously (SC) into female SCID mice to explore ONO-WG-307 anti-tumor activity in vivo (orally at doses up to 50 mg/kg, bid for ONO-WG-307 and intraperitoneally at doses up to 10 mg/kg, q7d). The IC50 of the in vitro cytotoxic activity was determined using a MTS assay 72 and 96 hours after incubation. Anti-tumor activity was defined as the ratio of the median tumor volume of treatment groups versus control group. The determination of combination index (CI) was calculated by the median-effect method. The CI was used to express synergism (&lt;1), additivity (=1) or antagonism (&gt;1). Results: In the MTS assay, ABC-DLBCL cells were much more sensitive to ONO-WG-307 given as single agent compared with FL cell lines, however, the activity of rituximab single agent had no impact on ABC-DLBCL cell lines in contrast to its inhibitory activity against FL cell lines. When ONO-WG-307 was combined with rituximab, a moderate antagonism was observed in vitro on FL cell lines. In an ABC-DLBCL xenograft model, treatment with single agent ONO-WG-307 resulted in a dose-dependent inhibition of tumor growth and also showed moderate anti-tumor activity in a FL xenograft model. Conclusion: ONO-WG-307 is a highly potent and selective oral Btk inhibitor with evidence of efficacy in both the ABC-DLBCL and the FL cell lines and in xenograft models. These preliminary results suggest that ONO-WG-307 may be an effective therapy in the treatment of B-cell malignancies. To determine whether combination of ONO-WG-307 and rituximab is more efficacious, additional in vivo combination work is underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 857. doi:1538-7445.AM2012-857