bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1886: Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation
Authors: Cho Byoung Chul , Kim Sun Mi , Solca Flavio , Kim Joo-Hang 
Published: August 2012

Abstract
Advanced non-small cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutation respond preferentially to reversible first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib, but drug resistance invariably emerges. Acquisition of secondary T790M mutation in EGFR is the most common mechanism of acquired resistance to EGFR TKIs in these tumors. Although second-generation irreversible EGFR TKIs, such as BIBW2992 or PF00299804, have been introduced to overcome acquired resistance by the T790M mutation, showing they showed a limited clinical activity in patients with T790M mutant tumors. In this study, we first demonstrated in vitro and in vivo that JAK1-dependent STAT3 activation via autocrine IL-6 production was the key mechanism of de novo resistance to the irreversible EGFR TKIs in NSCLC cells harboring T790M mutation. Both BIBW2992 and PF00299804 induced STAT3 activation via JAK1, but not JAK2 or TYK2, and inhibition of JAK1/STAT3 signaling by small interfering RNA or pyridone 6 (P6, pan-JAK inhibitor) significantly increased sensitivity to BIBW2992 in H1975 or PC9-GR cells. BIBW2992-induced JAK1/STAT3 activation is mediated by interleukin-6 receptor (IL-6R) signaling pathway via autocrine IL-6 production. Cancer cells showed a stronger STAT3 activation and enhanced resistance to BIBW2992 in the presence of conditioned medium from MRC-5 (MRC5-CM) fibroblasts. Blocking of IL-6R/JAK1 signaling significantly inhibited MRC5-CM-induced STAT3 activation and increased the sensitivity to BIBW2992 in the presence of MRC5-CM, suggesting a critical role of IL-6R/JAK1/STAT3 signaling between fibroblasts and cancer cells in the development of drug resistance. Treatment of PC9-GR cells with BIBW2992 for 10 days in the presence of MRC5-CM significantly increased expression of several mesenchymal markers including snail, twist, vimentin, and N-cadherin. The epithelial-mesenchymal transition (EMT) upon short-term BIBW2992 treatment was not suppressed by the addition of P6, but was prevented by early concurrent administration of P6 with BIBW2992. In PC9-GR xenograft model, combination treatment with BIBW2992 and P6 showed a synergistic anti-tumor activity compared with BIBW2992 or P6 alone. Taken together, we suggest that inhibition of IL-6R/JAK1/STAT3 signaling can be a potential target to enhance therapeutic efficacy of irreversible EGFR TKIs in patients with a T790M resistance mutation.
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 1886. doi:1538-7445.AM2012-1886
Abstract 1887: Targeting oncoprotein stability overcomes lapatinib-resistance due to ERBB2 kinase domain mutations
Authors: Kancha Rama Krishna , Blaeschke Franziska , Bartosch Natalie , Peschel Christian , Duyster Justus 
Published: August 2012

Abstract
ERBB2 kinase domain mutations were recently reported in some solid cancers. Moreover, certain ERBB2 mutations were shown to cause lapatinib resistance in vitro thus predicting their emergence in treated patients. We have recently shown that ERBB2-L755S, ERBB2-L755P and ERBB2-T798M mutants cause lapatinib resistance by stabilizing the active kinase conformation (DFG-in), which is incompatible with lapatinib binding (DFG-out). Using an in vitro cell-based drug resistance screen we also showed that these lapatinib resistant mutations might cause secondary resistance in patients treated with lapatinb. Thus, it is important to search for alternate treatment strategies to overcome lapatinib resistance. ERBB2 kinase is a client for HSP90 and is degraded by HSP90 inhibitor treatment. We thus tested if targeting ERBB2 mutant stability by inhibiting HSP90 overcomes lapatinib resistance. Since the kinase domain is important for the ERBB2 interaction with HSP90, we tested whether ERBB2 kinase domain mutants retained their interaction with the chaperone. Co-immunoprecipitation analysis showed that the interaction of ERBB2 mutants with HSP90 is intact. Importantly, HSP90 inhibitor treatment resulted in the degradation of lapatinib-resistant ERBB2 mutants as observed with the wild type ERBB2 kinase. Thus, HSP90 inhibitors may offer an alternative treatment option to overcome primary or secondary lapatinib resistance in patients harbouring ERBB2 mutations. Moreover, combined targeting of different physiological aspects (enzyme activity and protein stability) may prevent the emergence of secondary drug resistance due to kinase domain mutations.
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 1887. doi:1538-7445.AM2012-1887
Abstract 1896: Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer
Authors: Nanjo Shigeki , Yamada Tadaaki , Takeuchi Shinji , Yano Seiji 
Published: August 2012

Abstract
Introduction: Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. Methods: Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. Results: HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by co-culture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. Conclusions:HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status.
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 1896. doi:1538-7445.AM2012-1896
Abstract 19: Desmoplakin has a tumor suppressive function through inhibition of Wnt/β-catenin signalling pathway in human lung cancer
Authors: Yang Linlin , Chen Yuan , Cui Tiantian , Knösel Thomas , Zhang Qing , Albring Kai , Huber Otmar , Petersen Iver 
Published: August 2012

Abstract
Desmosomes are intercellular junctions that confer strong cell-cell adhesion thus provide resistance against mechanical stress on epithelial tissues. A body of evidence indicates that decreased expression of desmosomal proteins is associated with poor prognosis in various cancers. As a key component of desmosomal plaque proteins, the role of desmoplakin (DSP) in lung cancer is not yet elucidated. Here, we investigated the anti-tumourigenic activity of DSP in human non-small cell lung cancer (NSCLC). We found that DSP expression was downregulated in 8 out of 11 lung cancer cell lines and in 34 out of 56 primary lung tumours, and DNA methylation was responsible for gene silencing of DSP in both cell lines and primary lung tumours. Ectopic expression of DSP in NSCLC cell line H157 significantly inhibited cell proliferation, anchorage-independent growth, migration, as well as invasion, and also increased the sensitivity of NSCLC cells to apoptosis induced by an anticancer drug, gemcitabine. Furthermore, overexpression of DSP led to enhanced expression of another desmosomal plaque protein plakoglobin (also called γ-catenin), a competitor of β-catenin, resulting in decreased nuclear β-catenin levels and reduced expression of the Wnt/β-catenin target genes Axin2 and MMP14. Knockdown of DSP by siRNA resulted in downregulation of plakoglobin and upregulation of Axin2 and MMP14. Taken together, our data suggest that DSP is inactivated in lung cancer by DNA methylation, DSP increases the sensitivity to anticancer drug-induced apoptosis, and DSP has tumour suppressive function through inhibition of Wnt/β-catenin signalling pathway in NSCLC. The epigenetic regulation of DSP and its ability to increase the sensitivity to anticancer drug-induced apoptosis imply the clinical application.
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 19. doi:1538-7445.AM2012-19
Abstract 192: MiR-34c has an anti-apoptotic role in non-small-cell lung carcinoma
Authors: Catuogno Silvia , Cerchia Laura , Romano Giulia , Laudato Sara , Matarese Maria , Condorelli Gerolama , de Franciscis Vittorio 
Published: August 2012

Abstract
MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that negatively regulate the expression of their target genes. They are involved in many biological processes, including cell proliferation, apoptosis and differentiation, and are considered as promising new therapeutic targets for cancer. However, the identity of miRNAs involved in apoptosis and their respective targets remain largely unknown. Given the elevated complexity of miRNA regulation of gene expression, we performed a functional screening as an alternative strategy to identify those miRNAs that in lung cancer cells may interfere with the apoptotic process. To this aim we generated a derivative of the non-small cell lung carcinoma A549 cell line in which caspase-8, a critical upstream initiator of apoptosis, can be activated by the administration of the small dimerizer drug AP20187. We found a number of miRNAs that may rescue cell viability from caspase-8 activation. They included miRNAs already described as oncogenic such as miR-17, miR-135, miR-520, but also some miRNAs such as miR-124a and miR-34c for which a tumor suppressive role has been instead described or expected. Among them, miR-34c-5p markedly increased resistance to paclitaxel induced apoptosis. We demonstrate that Bmf (Bcl-2 modifying factor) is a target of miR-34c-5p and that its silencing, together with that of c-myc, a known target of miR-34c-5p, contributes to resistance to apoptosis induced by paclitaxel via p53 downregulation.
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 192. doi:1538-7445.AM2012-192
Abstract 1922: 2-Aminothiazoles as potent and selective PI3Kalpha inhibitors: Discovery of NVP-BYL719 and structural basis for the isoform selectivity
Authors: Caravatti Giorgio , Guagnano Vito , Fairhurst Robin , Imbach Patricia , Bruce Ian , Knapp Mark , Furet Pascal , Fritsch Christine , Pover Alain De , Blasco Francesca , Blanz Joachim , Seiler Frank H. , Fabbro Doriano , Lang Marc 
Published: August 2012

Abstract
PI3Ks are lipid kinases that control signaling pathways involved in cell proliferation, motility, cell death and cell invasion. Class I PI3K contains four isoforms, p110α, p110α, p110α and p110α which carry out non redundant signaling functions. The ≤ and ≤ isoforms are ubiquitously expressed, whereas the ≤ and ≤ isoforms are expressed primarily in lymphocytes and engaged in the regulation of immune responses. A gain of function in PI3K signaling is common to many types of human cancer, specifically mutations in PIK3CA which are found in more than 30% of various solid tumor types, including, breast, endometrium, bladder, colorectal cancers as well as lung cancers. As these mutations constitutively activate the lipid kinase activity of the protein, the cancer-specific mutants of p110α appear to be ideal therapeutic targets for anticancer drug development. p110α isoform specific low molecular weight inhibitors could be efficacious against tumors harboring p110alpha mutations and provide an improved safety profile compared to current pan-PI3K modulators. The 2-aminothiazole scaffold proved to be an excellent starting point for the development of potent PI3K inhibitors. Depending on the substitution pattern good PI3Kalpha selectivity can be achieved. Systematic modification of key residues and further optimization of the drug-like and PK properties have led to the identification of NVP-BYL719, a potent and selective PI3Kalpha inhibitor with a promising biological activity. SAR leading to the discovery of NVP-BYL719 and the structural basis for the PI3Kalpha selectivity will be discussed.
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 1922. doi:1538-7445.AM2012-1922
Abstract 1933: Ellagic acid induces apoptosis and cell cycle arrest in HeLa cells and inhibits HPV oncogene expression
Authors: Mohammad Hanan F. , Lindner Daniel J. , Kalafatis Michael 
Published: August 2012

Abstract
Ellagic Acid is a naturally occurring compound that demonstrated anti cancer activity in vitro and in vivo. Ellagic acid inhibits protein kinase CK2, which has been identified as a promoter of tumorogenesis. Blocking CK2 activity can reactivate dormant cellular defensive mechanism and further block signaling pathways that induce cancer. In this study, we are testing HPV 18 positive cervical cancer cells (HeLa) to investigate the effect of ellagic acid on CK2 kinase activity, HPV oncogenes E6 and E7 expression and downstream targets leading to cell death in vitro and in vivo. Treating HeLa cells with ellagic acid induced in vitro cell cycle arrest and caspase mediated apoptosis in both time and dose dependent manner. Ellagic acid inhibited CK2 phosphorylation activity, as well as the expression of viral oncogenes E6 and E7. Inhibition of HPV oncogene expression was accompanied by an increase in P53 and a decrease in cyclin A expression. Ellagic acid treatment induced cytochrome c release in the cytosol and subsequent activation of caspase 3, which led to the fragmentation of Poly (ADP) RibosePolymerase (PARP) at the end of the caspase cascade. Finally, mice treated with ellagic acid demonstrated inhibition of cervical cancer xenograft growth and longer survival compared to vehicle-treated mice confirming the potent anti-tumor activity of ellagic acid. Our results suggest that ellagic acid has anti-tumor and anti-viral properties which could make it suitable for the prevention of HPV induced cervical carcinoma.
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 1933. doi:1538-7445.AM2012-1933
Abstract 1940: Anti-tumor action of adenosine A3 receptor in prostate cancer involves suppression of micro RNA-21
Authors: Jajoo Sarvesh , Kaur Tejbeer , Mukherjea Debashree , Sheehan Kelly , Sheth Sandeep , Rybak Leonard P. , Ramkumar Vickram 
Published: August 2012

Abstract
Introduction: Adenosine-based drugs have shown promising results against various solid tumors including prostate cancer. These drugs exert their effects via adenosine receptors (ARs), and in prostate cancer, the A3AR subtype appears to play a major role in its anti-tumor action. MicroRNAs (miRs) are small non-coding RNAs that regulate the coding RNAs at post-transcriptional level. One of these, miR-21, has been shown to promote prostate cancer growth and invasiveness. In the present study, we hypothesized that A3AR agonists suppressed prostate tumor growth by reducing miR-21 expression. Methods: In vivo studies were performed in xenograft model of prostate cancer in severe combined immunodeficient (SCID) mice. Mice were injected subcutaneously with PC3-MM human prostate cancer cells, treated with vehicle, the agonist N’-(3-iodobenzyl) adenosine-5′-N-methyluronamide (IB-MECA), the antagonist 9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline (MRS1220) or MRS1220 + IB-MECA, on alternate day for 2-3 weeks, and tumor growth was measured. Primary tumors were then excised and used to determine miR-21 (by TaqMan assay) and maspin, PDCD4 and TPM1 (by Western blotting and RT-PCR). In vitro studies were done in PC3-MM cells grown in cell culture plates. The levels of miR-21 were also detected in RNA samples obtained from human prostate cancer tissues (OriGene Technologies), while the levels of maspin and PDCD4 were determined in the formalin-fixed paraffin-embedded (FFPE) prostate tumor sections by immunohistochemistry. Results: IB-MECA suppressed tumor growth in SCID mice. This effect was blunted in presence of the antagonist, MRS1220. Reductions in tumor volume were associated with reduced expression of miR-21 in the primary tumors. Furthermore, we observed up-regulation of the tumor suppressor proteins maspin, PDCD4 and TPM1, which are known to be negatively regulated by miR-21. Similar findings were obtained in in vitro cell culture studies. In human prostate cancer RNA samples from patients with different stages of prostate cancer there was high expression of miR-21. This finding co-related with down-regulation of its target proteins, maspin and PDCD4, in human prostate tumor sections. Conclusions: Based on the data, we conclude that activation of the A3AR reduces the prostate cancer growth by suppressing miR-21 expression and up-regulating tumor suppressor proteins such as maspin, PDCD4 and TPM1. These data support the use of A3AR agonists as a viable therapeutic option against the advanced forms of prostate cancer.
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 1940. doi:1538-7445.AM2012-1940
Abstract 1946: Silencing of EVI1 with siRNA inhibits the growth of ovarian tumor cells
Authors: Chang Bey-Dih , Heidel Jeremy D. , Primiano Thomas 
Published: August 2012

Abstract
There is currently no effective treatment for ovarian cancer. EVI1 (ecotropic viral integration site 1) is an oncogenic transcription factor that enables proliferation and inhibits apoptosis of ovarian tumor cells. Small interfering RNA (siRNA) drugs provide ideal means for perturbing intracellular oncogenic targets. Five (5) siRNA (21+21 nt) sequences were identified by in silico analysis that target the coding region of human EVI1 (siEVI1 A-E). Each of these siEVI1 species were transfected with Dharmafect4 at 25nM into SKOV3, ES-2, OVCAR3, OV-90, TOV-112D, PA-1, UWB1.289, and Coav-3 ovarian tumor cells. The non-tumorigenic cell line Hs832.Tc was used as a control. Four species (siEVI1 B-E) decreased the viability of each tumor cell line by at least 70% with none of the five siEVI1 species altered the viability of control cells, demonstrating the anti-proliferative effect of targeting EVI1 with siRNA. Both siEVI1-B and -D potently decreased the viability of ovarian tumor cells, having IC50 values of 0.8 and 0.2 nM, respectively, which compare favorably to an IC50 of 15 nM for paclitaxel. RT-PCR and immunoblot results showing dose-dependent decreases in EVI1 mRNA and protein using either siEVI1-B or-D are consistent with the mechanism of the anti-proliferative effect occurring via RNA interference. Further, dose-dependent increases in annexin staining upon siRNA treatment indicate that induction of apoptosis contributes to the decrease in cell viability, a result consistent with inhibition of EVI1 activity. These results suggest that EVI1 is a good target for ovarian cancer therapy and silencing by siRNAs is an effective means of triggering the death of ovarian tumor cells. These findings also suggest that anti-EVI1 siRNAs have the potential to be effective therapeutics for the treatment of patients with ovarian cancer.
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 1946. doi:1538-7445.AM2012-1946
Abstract 1967: Multi-stage silicon vector-delivered tumor antigen and TLR ligands for dendritic cell-based cancer immunotherapy
Authors: Xia Xiaojun , Ferrari Mauro , Shen Haifa 
Published: August 2012

Abstract
Immunotherapy has shown promise in cancer treatment but achieved limited success in clinic trials. With this strategy, eliciting strong antitumor immune response in vivo remains a challenge, largely due to the immunosuppressive tumor microenvironment and inefficient delivery of cancer vaccine. Nanoparticle-delivered antigen together with adjuvants provides a promising strategy to increase the vaccine delivery efficiency. Recently, our group developed a multi-stage silicon vector (MSV) system for protected and prolonged nano-scale drug delivery. MSV delivered siRNA in vivo induced sustained knockdown of target gene expression and subsequent anti-tumor efficacy in mice. Here we tested the effect of MSV-formulated antigen peptides and Toll-like receptor (TLR) ligands on dendritic cells. By formulating HER-2 antigen peptide together with TLR4 ligand (MPLA) and TLR9 ligand (CpG), we found that MSV-delivered antigen and TLR ligands were uptaken by mouse dendritic cells after 1h co-incubation, and started to be released inside the cells at 3 h after co-incubation. Moreover, MSV-delivered TLR ligands strongly activated mouse dendritic cell expression of co-stimulatory molecules such as CD80 and CD86. It also induced dendritic cells to produce large amount of pro-inflammatory cytokines, such as TNF-alpha, IL-6, and IL-12. In summary, MSV-delivered vaccine efficiently delivered antigen and immuno-activating TLR ligands together into dendritic cells, and promoted dendritic cell maturation and activation. Therefore, MSV formulation of tumor antigen and TLR ligands may serve as a nano-scale cancer vaccine with enhanced in vivo efficacy. Ongoing experiments include testing in vivo T cell responses to MSV-delivered HER-2 antigen peptide and TLR ligands, and determining the antitumor efficacy on mouse mammary gland tumor model.
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 1967. doi:1538-7445.AM2012-1967