bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 59: Identification of RNA editing events in cancer using high-throughput sequencing data
Authors: Radenbaugh Amie , Sanborn John Z. , Zerbino Daniel , Wilks Chris , Stuart Joshua M. , Haussler David 
Published: June 2012

Abstract
RNA editing is a post-transcriptional modification of pre-mRNA that has recently been identified as an additional epigenetic mechanism relevant to cancer development and progression. With projects like The Cancer Genome Atlas (TCGA) providing high-throughput sequencing datasets measuring both DNA and RNA from the same patients across multiple cancers, it is now possible to search for RNA editing events at a genome-wide scale.
Using fully-sequenced tumor and matched-normal genomes and RNA-Seq data from TCGA project, we will identify RNA editing events in acute myeloid leukemia (AML) patients. We have analyzed the tumor and matched normal genomes to identify SNPs, mutations (both germline and somatic), and heterozygosity across the entire genome. By comparing the patient's genomic data to the RNA transcripts assembled by the UCSC RNA-Seq pipeline, we can identify any bases that were transcribed abnormally. All putative RNA editing events will be assessed according to the most common types of RNA editing, such as the deamination of adenosine into inosine (A-to-I) or the conversion of cytosine into uracil (C-to-U). Local phasing information inferred from the genomic sequence will be used to disambiguate potential RNA editing events found at heterozygous locations.
As a positive control, we will confirm RNA-editing events previously discovered experimentally in AML patients, such as an A-to-I conversion in the protein tyrosine phosphatase PTPN6 gene. The PTPN6 gene is recognized as a tumor suppressor gene and is important for the down-regulation of growth-promoting receptors. The A-to-I conversion of adenosine 7866 causes the splicing mechanism to ignore a splicing junction, leading to a non-functional PTPN6 protein via the inclusion of an intron in the mature RNA transcript. Using the TCGA sequencing data, we will identify all AML samples that exhibit this particular A-to-I conversion as well as the inclusion of the intron with the RNA-Seq data. In addition, we will report novel RNA editing events in AML and other cancer types and look for patterns that may be cancer specific or globally relevant to cancer development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 59. doi:10.1158/1538-7445.AM2011-59
Abstract 592: Novel IAP antagonist (822B) induces apoptosis through degradation of IAP proteins which have a BIR3 domain in human pancreatic cancer cells
Authors: Shin Jae Sik , Hong Seung-Woo , Jin Dong-Hoon , Bae In-Hwan , Kim Maeng-Sup , Na Young-Soon , Lee Jae-Lyun , Hong Yong Sang , Kim Tae-Won 
Published: June 2012

Abstract
Several companies recently began to develop inhibitor of apoptosis (IAP) antagonist ‘Smac/Diablo mimetic’ compounds for the treatment of cancer. IAP antagonist compounds (IACs) was, therefore, designated as being able to induce apoptosis through the inhibition of IAP proteins in cancer cells. In our study we demonstrated that the novel-in what sense is it synthetic IAP antagonist, 822B, induces apoptotic cell death through proteasomal-dependent degradation of the inhibitor of apoptosis proteins (IAPs) with a BIR3 domain. We first found that apoptotic cell death is induced by exposure of pancreatic cancer cells to 822B. This apoptotic effect increased after the knockdown of endogenous IAPs using RNA interference. Moreover, 822B-induced apoptosis results from degradation of the inhibitor of apoptosis proteins (IAPs). 822B was preferable to Samc/Diablo for binding to IAPs and it induced ubiquitination. However, we also found that degradation of XIAP is not induced in several pancreatic cancer cell types in response to 822B. Interestingly, resistance to 822B was related to phosphorylation at the ser-87 site of XIAP. This resistant effect was eliminated using the (or “an” if there's more than one . . .) XIAP mutant that was replaced with alanine at 87 amino acid site. AKT CA (constitutive active) mutant and wild type-AKT that can induce phosphorylation at the ser-87 site of XIAP also suppressed the resistant effect to 822B. In addition, mutation in the RING domain of XIAP was not observed. Mutation in the RING domain of XIAP cannot induce XIAP ubiquitination, thus suggesting that the level of phospho-XIAP and phospho-AKT may be used as an indicator for cancer therapy using 822B. These results suggest that a novel synthetic inhibitor of the apoptosis (IAP) antagonist induces apoptosis through ubiquitination of IAPs with a BIR3 domain.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2011-592
Abstract 6: S1, a Bid-like BH3 mimetic, induces apoptosis by dynamic change of Mcl-1 and dependent on Bak, not Bax
Authors: Ting Song , Chao Zhang Zhi , Long Chang Xi 
Published: June 2012

Abstract
Mcl-1 is a unique anti-apoptotic member of Bcl-2 family. Its expression has been demonstrated to seriously impede the most authentic BH3 mimetic ABT-737-induced apoptosis in multiple cancer cell lines. S1, which has been previously identified as a pan-Bcl-2 inhibitor and pure BH3 mimetic by our group, was investigated here to challenge Mcl-1's protection. Cell viability assay and apoptosis assay showed S1 exhibits robust anticancer effectiveness in three selected ABT-737-resistant cancer cell lines, SMMC-7721, HCT116 and K562 cells. In contract with ABT-737, S1-induced apoptosis is regardless of the baseline of Mcl-1 expression. Interestingly, it dynamically modulates Mcl-1 through a combination of proteasome and caspase-mediated pathway and this dynamical change is associated well with the resistance, apoptosis onset, and apoptosis burst out induced by S1. To investigate how Mcl-1 dynamics is related with apoptosis at molecular level, we performed time-sequence and dose-dependent analysis of cell viability, western blot, and co-immunoprecipitation experiments. We found the trafficking of Bcl-2 family members determines Mcl-1 dynamical change and in turn apoptosis. First of all S1 untethers Bax and Bim from Bcl-2, but Bim shifts to Mcl-1 which stabilizes Mcl-1 and enforces the binding with Bak. Only when Bak is released by enough dose of S1 or enough exposure time is Mcl-1 downregualted to allow apoptosis occur. Using shRNA, we identified both S1-induced apoptosis and Mcl-1 dynamical modulation depend on Bak, not Bax. As such, much distinct function of Bax and Bak in the S1-induced pathway was illustrated. While Bax can be fully compensated for by Bak, Bak could be partly compensated for by Bax. Consistently, Bax-deficient DU145 cell is sensitive to S1, whereas Bak-mutant MKN-28 cells is much more resistant. NMR analyses revealed that S1 highly mimic tBid to target the BH3-binding pocket of Mcl-1. Cytochrome c release assay in purified DU145 mitochondrial testified a nicely structural-to-functional mimic of tBid, but not Bim. The Bid-like property is also consistent with its Bak-dependent apoptosis induction. The in vitro model could be extended to an in vivo mouse xenograft model that S1 induces apoptosis through Mcl-1 dynamical modulation and released Bak is the biomarker of apoptosis. In conclusion, S1 could be a highly potent therapeutic molecule for the treatment of Mcl-1-driven cancer cells with a mechanism-based model. Bak could serve as a biomarker to specify cancer cells sensitive to S1. In addition, the highly tBid/Mcl-1 binding mimic property could be used to probe the sophisticated network of Bcl-2 family.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 6. doi:10.1158/1538-7445.AM2011-6
Abstract 601: Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer
Authors: Kim Sun Jin , Kim Jang Seong , Kim Seung Wook , Brantley Emily C. , Yun Seok Joong , He Junqin , Marva Maya K. , Zhang Fahao , Wu Qiuyu , Lehembre Francois , Regenass Urs , Fidler Isaiah J. 
Published: June 2012

Abstract
Introduction: In 2009, ovarian cancer was the leading cause of death from gynecologic cancer in the United States. Efforts to develop tools for early detection and therapeutic regimens to overcome drug resistance of the ovarian cancer have not made a significant achievement to prolong the median survial of the patients. Potential treatments for ovarian cancers that have become resistant to standard chemotherapies include modulators of tumor cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice.
Materials and Methods: Mice were injected with one million cells of SKOV3ip1 or IGROV1. Ten days later, mice with established disease were randomized into vehicle (control), paclitaxel (weekly, intraperitoneal injections), macitentan (daily oral administrations) or a combination of paclitaxel and macitentan treatment groups. After 4 weeks of treatment, mice were necropsied and tumor incidence, tumor weight, and incidence of ascites were recorded. Tumor tissues were processed for immunohistochemical analyses.
Results: Treatment with paclitaxel decreased tumor weight and volume of ascites. Combination therapy with macitentan and paclitaxel reduced tumor incidence and further reduced tumor weight and volume of ascites when compared with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but alone had no effect on tumor incidence or ascites. Immunohistochemical analyses revealed that treatment with macitentan and macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of paclitaxel.
Conclusion: Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. Collectively, these results show that administration of macitentan in combination with paclitaxel prevents the progression of ovarian cancer in the peritoneal cavity of nude mice in part by inhibiting survival pathways of both tumor cells and tumor-associated endothelial cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 601. doi:10.1158/1538-7445.AM2011-601
Abstract 607: Restoration of p53 pathway signaling and apoptotic induction by prodigiosin and its structurally-related compound (NSC247562) in p53-deficient human colon carcinoma cells
Authors: Hong Bo , Chen Fang , Dicker David T. , El-Deiry Wafik S. 
Published: June 2012

Abstract
p53 deficiency occurs commonly in human tumors, and contributes to radio- and chemo-resistance as well as an aggressive phenotype. It is believed that specific restoration of p53 will be beneficial in the treatment of aggressive or resistant tumors. Using a p53 mutant cell line (SW480) stably integrated p53-responsive reporter, we sought to identify small molecules with p53 rescue activity by screening of the NCI drug library. We found prodigiosin and its structurally related compound (NSC247562) can activate p53-dependent transcriptional activity in SW480, DLD1 as well as HCT116 p53−/− colon tumor cells. The induction of p53-dependent transcriptional activity by prodigiosin and its related compound (NSC247562) is stronger than that induced by CP31398 or ellipticine, which were previously reported as p53 function-restoring drugs. Furthermore, prodigiosin and its related compound (NSC247562) are found to induce the expression of p53 target genes (p21, Puma, DR5 and DR4) in mutant-p53 containing or p53-null human colon cancer cells. The restoration of p53 transcriptional activity by prodigiosin and its related compound (NSC247562) is accompanied by apoptotic induction as indicated by an increase of sub-G1 population and PARP cleavage. More importantly, prodigiosin and its related compound (NSC247562) induced tumor cell death, but have little or no detectable cytotoxicity towards normal human fibroblasts. Thus prodigiosin and its related compound may serve as promising compounds for the development of anticancer drugs which rescue p53 activity and induce cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 607. doi:10.1158/1538-7445.AM2011-607
Abstract 628: Functional characterization of a diverse set of ERBB3 inhibitory antibodies
Authors: Vincent Sylvie , Weiler Solly , Fleet Christina , Bottega Steve , Prima Michael Di , Wang Fang , McIntosh Donna , Breault Lyne , Tyler Steven , Meetze Kristan , Winston William , Gyuris Jeno 
Published: June 2012

Abstract
One important manifestation of the plasticity of cancer is the rapid escape from the effect of anti-cancer agents following initial therapeutic response. ERBB3, a kinase inactive member of the epidermal growth factor (EGFR) receptor family, which also includes EGFR, HER-2 and ERBB-4, has been linked to the development of resistance to multiple cancer therapies. The reactivation of ERBB3 following treatments with EGFR or HER-2 inhibitors has been observed in multiple tumor types following initial responses. The reactivation of ERBB3 signaling is thought to be the consequence of the formation of kinase active heterodimers of ERBB3 with EGFR, HER-2 and c-Met. ERBB3 heterodimer formation is consequence of a conformational change in the ErbB3 ECD (extracellular domain) in response to increased presence of the ERBB3 ligand NRG (neuregulin) or increased membrane concentrations of ERBB3 partners or ERBB3 itself which is often due overexpression or increased membrane localization.
To understand the role of NRG dependent and independent ERBB3 activation mechanisms in the development of resistance to EGFR and/or HER-2 inhibitors, we set out to identify a diverse set of ERBB3 specific inhibitory monoclonal antibodies with different mechanisms of action. Immunizations with a mixture of tethered and opened ERBB3 ECD antigens allowed us to identify a large variety of potent ERBB3 inhibitors. Competition binding experiments have identified at least 5 independent binding sites for these antibodies on ERBB3. Some of these antibodies inhibited NRG binding (ligand neutralizers) while others did not interfere with ligand binding. Since a few of these antibodies bound to the dimerization domain (domain II) of ERBB3, we have inferred that they most likely inhibit the formation of ERBB3 heterodimers (dimerization inhibitors). In vivo activity of these antibodies was tested in tumor models driven by ligand independent and dependent activation of ERBB3 to identify the most promising candidate for the development of a highly potent ERBB3 therapeutic antibody with superior activity against both ligand dependent and independent ERBB3 heterodimers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 628. doi:10.1158/1538-7445.AM2011-628
Abstract 633: Target therapy of glioblastoma by gene transfer of a monovalent antibody against the MET oncogene
Authors: Pacchiana Giovanni , Chiriaco Cristina , Fontani Lara , Comoglio Paolo M. , Vigna Elisa 
Published: June 2012

Abstract
Glioblastoma multiforme is a severe brain tumor refractory to conventional radio-and chemotherapy. The tumor often relies on an autocrine-loop between HGF and its receptor, the product of the met oncogene. Recently we demonstrated that the monovalent form of the DN-30 anti-Met monoclonal antibody (MvDN-30), acting trough a mechanism of receptor shedding, is a potent Met inhibitor (Pacchiana et al., J Biol Chem. 2010; 285:36149-57). We now report its therapeutic effect on glioblastoma, delivering the MvDN-30 to U-87MG cells by mean of gene transfer through a Tet inducible lentiviral vector. Upon doxycicline (Dox) treatment U-87MG correctly express and secret MvDN-30, inhibiting Met receptor expression. Antibody gene transfer results in impairment of U-87MG invasive growth in vitro and tumorigenic properties in vivo. In a preclinical model of “prevention trial” nude mice transplanted with U87-MG were treated with Dox from the day of tumor cell injection. MvDN30 severely impaired tumor onset as, after 16 weeks of treatment, 80% of the mice were still tumor free. Dox treatment was then removed and after 12 weeks mice didn't develop tumors, indicating that MvDN-30 treatment was curative. In a preclinical model of “regression trial” mice bearing tumors of 50 mm3 were treated with Dox. 55% of the mice showed strong slow down of tumor growth or tumor regression that, in the 22% of the cases, took to complete tumor remission. This data highlights MvDN-30 as a candidate for glioblastoma target therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2011-633
Abstract 651: Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-xL
Authors: Mayeenuddin Linnia , Yu Yunkai , Kang Zhigang , Helman Lee , Cao Liang 
Published: June 2012

Abstract
Insulin-like growth factors (IGFs) and their receptor, IGF-1 receptor (IGF1R), have important roles in growth, development, stress response, aging and cancer. There are many agents that inhibit IGF1R in oncology clinical development, and in some cases, they have been associated with rapid tumor regression. However, it is not clear by which process these targeted agents induce cancer cell death and how to predict such tumor responses. Here, we showed that IGF1R antibody led to rapid cell death and tumor regression in some rhabdomyosarcoma (RMS) cells. Mechanistic analysis revealed a rapid onset of mitochondrial-dependent apoptosis, including mitochondrial depolarization, cytochrome C release and the activation of specific caspases. The antibody sensitive cells had greater dependence on AKT for maintaining downstream signaling and the expression of a constitutively active AKT, which restored AKT-signaling in these cells, inhibited anti-IGF1R induced cell death. Further analysis showed IGF1R antibody-induced hypophosphorylation of BAD and activation of downstream BAX. Interestingly, the examination of RMS cell lines and tumors revealed an inverse correlation between elevated IGF1R and Bcl-2 level (P=0.033), with the sensitive cells lacking Bcl-2 expression. The overexpression of BAD specific target, Bcl-xL, conferred resistance, whereas Bcl-xL knockdown sensitized cells lacking Bcl-2 to anti-IGF1R-induced cell death. We propose that RMS pathogenesis involves increased IGF1R expression that enhances AKT and Bcl-xL-mediated cell survival, and the blockage of IGF1R results in inhibition of survival signal from Bcl-xL and cell death in the sensitive Bcl-2 negative cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2011-651
Abstract 660: Inhibition of centrosomal clustering suppresses tumor growth in vivo
Authors: Raab Marc S. , Breitkreutz Iris , Leber Blanka , Weitz Ludmila , Hayden Patrick J. , Larsen Thomas O. , Cllausen Mads H. , Fruehauf Johannes , Nissen Felix , Mier Walter , Haberkorn Uwe , Podar Klaus , Ho Anthony D. , Goldschmidt Hartmut , Anderson Kenneth C. , Kraemer Alwin 
Published: June 2012

Abstract
Tumor cells frequently contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles (centrosomal clustering). We recently described a phenotype-based small molecule screening strategy directed to induce tumor cells with supernumerary centrosomes to undergo multipolar mitoses, thereby resulting in apoptotic cell death (Rebacz et al., Cancer Res 2007; 67: 6342-6350). We here describe the novel small molecule GF-15, a derivative of griseofulvin and a potent inhibitor of centrosomal clustering, thereby inducing multipolar spindles followed by apoptosis. We tested more than 25 cancer cell lines from hematologic malignancies (including acute and chronic leukemias, lymphomas), solid tumors (including glioblastoma, colon, cervix, and pancreatic cancers) and a wide array of myeloma cell lines. We found mean inhibitory concentrations (IC50) for proliferation and survival in the range of 1-5μM GF-15, associated with activation of caspases 8, 9, and 3. As expected, tumor cell lines displaying only limited centrosomal aberrations or microsatellite instability were less sensitive to treatment with GF-15. Importantly, non-malignant cells without supernumerary centrosomes including PBMCs, immortalized hepatocytes, and bone marrow stromal cells, did not reach their IC50 even at 30μM GF-15. Specifically, cell cycle analysis of synchronized myeloma cells showed marked G2/M arrest, followed by a dramatic increase of the sub-G1 fraction, after treatment with GF-15. In addition, treatment with GF-15 was associated with inhibition of VEGF- and IGF1-triggered myeloma cell migration. Pharmakodynamic studies in vivo revealed rapid renal clearance of GF-15 and metabolites within 6 hours p.i. No acute or chronic toxicity was observed. Finally, both intraperitoneal and oral GF-15 treatment of murine xenograft models of human multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival associated with significant increase of aberrant mitoses in vivo. Taken together, our results demonstrate the in vitro and in vivo anti-tumor efficacy of the first in class small molecule inhibitor of centrosomal clustering with specificity for tumor cells, and strongly support its clinical evaluation to improve patient outcome in both hematologic malignancies and solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 660. doi:10.1158/1538-7445.AM2011-660