bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B228: Short hairpin RNA targeting SET suppresses cell proliferation and induces apoptosis in human gastric carcinoma cells.
Authors: Hairong Shi , Lijiang Liu 
Published: August 2014

Abstract
Background: SET is overexpressed in multiple tumors, including human gastric cancer. In this study, we examined the role of SET in regulating gastric cancer cell apoptosis.
Material and Methods: Expression of SET was investigated after transfection with SET short hairpin RNA (shRNA) in gastric cancer cells by Western blotting and immunofluorescence analysis. Next, the effects of SET shRNA on cell proliferation and apoptosis were evaluated by the 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium Bromide assay and flow cytometric analysis. To investigate the precise mechanism of these effects, a comprehensive analysis was performed using a cDNA microarray.
Results: shRNA targeting SET resulted in a significant decrease in SET expression, and cell proliferation. Meanwhile, increased cell apoptosis was confirmed. The comprehensive analysis showed that shRNA targeting SET upregulated a number of apoptosis-related genes (including IL18, TFPI, DKK1 and HSPA5).
Conclusions: Attenuation of SET by shRNA resulted in suppressed cell proliferation and apparent apoptosis, suggesting that SET may be a target for therapy of gastric cancer.
Supported by: National Natural Science Foundation of China (81001082)
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B228.
Citation Format: Shi Hairong, Liu Lijiang. Short hairpin RNA targeting SET suppresses cell proliferation and induces apoptosis in human gastric carcinoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B228.
Abstract B252: The unique mechanism of action of VAL-083 may provide a new treatment option for some chemo-resistant cancers.
Authors: Steino Anne , Bacha Jeffrey A. , Garner William J. , Kanekal Sarath , Siddik Zahid H. , Brown Dennis M. 
Published: August 2014

Abstract
Poor outcomes in cancer therapy due to chemo-resistance remain a significant unmet clinical problem for many solid tumors and leukemias. VAL-083 (dianhydrogalactitol) represents a structurally unique first-in-class N7-bifunctional DNA alkylating agent. VAL-083 primarily mediates guanine N7 DNA cross-links, which separates it from other DNA alkylating chemotherapeutics (e.g. temozolomide) that have their primary cytotoxicity by targeting DNA at the O6 position of guanine. As expected from its mechanism, VAL-083 overcomes resistance associated with O6-methylguanine-DNA methyltransferase (MGMT) overexpression in vitro. Furthermore, unlike other N7-acting drugs, such as cisplatin which primarily induces intrastrand crosslinks, VAL-083 mediates interstrand DNA crosslinks. When tested side-by-side in a standard syngeneic mouse fibrosarcoma model (RIF-1 cell-line in C3H mice), VAL-083 demonstrated superiority to cisplatin in tumor growth delay. For mice treated with a single injection of cisplatin of 4 mg/kg, the tumor growth delay was 1.45 days compared to untreated controls. Single IP injection of VAL-083 at a dose of 10 mg/kg delayed tumor growth by 5.6 days. Combination treatment of VAL-083 followed immediately by cisplatin produced a more than additive effect by delaying growth 8.65 days. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tissue and is effective against brain tumor cells both in vitro and in vivo, and against brain cancer stem cells in vitro. VAL-083 is currently in Phase I/II clinical trials for glioblastoma and recurrent metastatic brain tumors. Studies are underway to further characterize the efficacy of VAL-083 in various tumor cell-lines resistant to chemotherapy. Previous clinical studies showing VAL-083 activity in several tumor models, combined with the new data on MGMT-chemo-resistance and synergy with cisplatin makes VAL-083 a promising alternative for both primary and secondary brain tumors as well as cisplatin-resistant tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B252.
Citation Format: Anne Steino, Jeffrey A. Bacha, William J. Garner, Sarath Kanekal, Zahid H. Siddik, Dennis M. Brown. The unique mechanism of action of VAL-083 may provide a new treatment option for some chemo-resistant cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B252.
Abstract B256: Ring-DIMs induce mitochondrial dysfunction and ER stress in human prostate cancer cells.
Authors: Goldberg Alexander A. , Montes-Grajales Diana , Olivero Jesus , Beach Adam , Titorenko Vladimir , Safe Steven , Sanderson Thomas 
Published: August 2014

Abstract
We have previously shown that a series of brominated and chlorinated analogs of 3,3'-diindolylmethane (DIM) can inhibit can induce apoptosis and necrosis in androgen-dependent and androgen-independent prostate cancer cells and that addition of bromine to the 4 and 4’ position of the indole ring of DIM maximally increases the potency of the anticancer compound. To understand the upstream events leading to the activation of caspases in response to treatment with ring-DIMs in androgen-dependent LNCaP and androgen-independent LNCaP C4-2B cells by monitoring the onset of endoplasmic reticulum (ER) stress and the dysregulation of mitochondrial respiration. We found that 4,4'-dibromo- and 7,7'-dichloroDIM and DIM itself induced ER stress-dependent upregulation of CHOP, ATF4, and GRP78, while only 4,4'-dibromo and 7,7'-dichloroDIM induced phosphorylation of eIF2alpha and JNK. Both ER stress and loss of mitochondrial membrane potential were observed after treatment with 4,4'-dihaloDIMs and DIM, but not 7,7'-dihaloDIMs within 1 hour of exposure, before the appearance of later stage apoptotic events such as condensed chromatin. Salubrinal inhibited cell death induced by 4,4'-dihaloDIMs, but facilitated cell death induced by 7,7'-dihaloDIMs or DIM. Interestingly, salubrinal did not increase eIF2alpha phosphorylation after co-treatment with either DIM or ring-DIMs. However, it did restore mitochondrial membrane potential in cells treated with 4,4'dihaloDIMs and further decreased mitochondrial activity after co-treatment with 7,7'-dihaloDIMs or DIM. Moreover, cyclosporin A inhibited cell death induced by both 4,4’-dihalo and 7,7’-dihaloDIMs but not DIM. Taken together, these data suggest that the ring-DIMs induce cell death via mitochondrial dysfunction and ER stress, and that because salubrinal either stimulates or inhibits cell death in combination with specific ring-DIMs, its effects are related to mitochondrial membrane integrity and not to phosphorylation of eIF2alpha.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B256.
Citation Format: Alexander A. Goldberg, Diana Montes-Grajales, Jesus Olivero, Adam Beach, Vladimir Titorenko, Steven Safe, Thomas Sanderson. Ring-DIMs induce mitochondrial dysfunction and ER stress in human prostate cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B256.
Abstract B270: Discovery and preliminary characterization of novel tyrosine kinase inhibitors with selectivity to BTK.
Authors: Namdev Nivedita D. , Cornell-Kennon Susan , Yu Yi , Hill Jason , Bull Cathy , Volak Laurie , Wang Jianqiang , Lowe Deirdre , Gu Xuibin , Koerner Steffi , Moussa Magdi , Vensel David , Liu Yanbin , Wu Hui , Chen Chang-Rung , Dransfield Daniel T. , Ashwell Mark A. 
Published: August 2014

Abstract
Bruton's tyrosine kinase (BTK) is a non receptor tyrosine kinase and belongs to the SRC-related TEC subfamily. The role of BTK in the B cell receptor (BCR) signaling pathway is well defined and is critical for full activation of phospholipase-C γ and MAPK as well as calcium mobilization. More than 95% of human lymphomas are B cell lymphoma and among them over 70% expresses BCR. Studies in lymphoma cell lines in vitro have demonstrated the role of BTK in BCR signaling.
We have performed in vitro kinase profiling to determine percent inhibition and IC50 for kinase families of interest. An extensive cellular characterization including anti-proliferative assays, Western blot analysis for evaluation of phospho BTK (pY223) and cell cycle analysis was performed in DLBCL TMD8 cells. An in vivo tumor xenograft model was employed to further evaluate the target knockdown and efficacy against tumor growth.
Compounds 1 and 2 were found to exhibit potent inhibition of BTK (IC50 0.6 nM), Src family (IC50 0.6-10 nM) and Trk isoforms (IC50 2-4 nM). Inhibition of cell proliferation was accompanied by reduction of phosphorylation of BTK. In addition to the anti-proliferative activity, following a single oral dose, inhibition of BTK phosphorylation (pY223) was observed in vivo in a TMD8 tumor xenograft model. The growth of TMD8 tumor xenografts was markedly suppressed after daily oral administration for 12 days of these two compounds.
A series of potent multi non-receptor tyrosine kinase inhibitors targeting the Tec, Src and Trk family of kinases have been discovered and characterized.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B270.
Citation Format: Nivedita D. Namdev, Susan Cornell-Kennon, Yi Yu, Jason Hill, Cathy Bull, Laurie Volak, Jianqiang Wang, Deirdre Lowe, Xuibin Gu, Steffi Koerner, Magdi Moussa, David Vensel, Yanbin Liu, Hui Wu, Chang-Rung Chen, Daniel T. Dransfield, Mark A. Ashwell. Discovery and preliminary characterization of novel tyrosine kinase inhibitors with selectivity to BTK. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B270.
Abstract B290: Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
Authors: Akbay Esra A. , Koyama Shohei , Carretero Julian , Altabef Abigail , Tchaicha Jeremy , Christensen Camilla , Shimamura Takeshi , Sholl Lynette , Rodig Scott , Freeman Gordon , Hammerman Peter , Dranoff Glenn , Wong Kwok-Kin 
Published: August 2014

Abstract
The recent clinical success of therapeutic blockade of the immune checkpoint Programmed Death (PD)-1 in advanced lung cancer patients suggests that mechanisms of immune escape may contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a gene signature indicative of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4) and multiple tumor-promoting inflammatory cytokines. Accordingly, we identified a decrease in the number of cytotoxic T cells and an increase in markers of T cell exhaustion in genetically engineered mouse models (GEMMs) of EGFR-driven lung cancer. PD-1 antibody blockade significantly improved the survival of mice with EGFR-driven lung adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor promoting cytokines. Expression of mutant EGFR in human bronchial epithelial cells induced PD-L1 expression, and PD-L1 expression was reduced by treatment with EGFR tyrosine kinase inhibitors (TKIs) in human non-small cell lung cancer (NSCLC) cell lines with an activated EGFR pathway. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, in addition to established effects on cell proliferation, and mechanistically link treatment response to PD-1 inhibition.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B290.
Citation Format: Esra A. Akbay, Shohei Koyama, Julian Carretero, Abigail Altabef, Jeremy Tchaicha, Camilla Christensen, Takeshi Shimamura, Lynette Sholl, Scott Rodig, Gordon Freeman, Peter Hammerman, Glenn Dranoff, Kwok-Kin Wong. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B290.
Abstract B46: Soluble AXL is a candidate circulating biomarker for predicting acquired and intrinsic resistance to molecular-targeted agents in NSCLC cells.
Authors: Ise Nobuyuki , Takemori Nobuaki , Omi Kazuya , Goishi Katsutoshi , Higashiyama Shigeki 
Published: August 2014

Abstract
Background: Drug resistance is an important factor that compromise therapeutic effect of most anti-cancer drugs including molecular-targeted agents. Non-invasive assessment of drug resistance by circulating biomarkers would therefore be useful for determining therapeutic options for resistant patients. Recently, a receptor tyrosine kinase AXL has been implicated in acquired resistance to EGFR inhibitors in NSCLC cells. In this study, we examined the potential utility of AXL as a circulating biomarker to predict acquired or intrinsic drug resistance using NSCLC cells.
Materials and methods: Drug resistant NSCLC cell lines were developed by exposing NSCLC cells with either EGFR inhibitor gefitinib or MET inhibitor PHA-665752. AXL-positive cells in parent and established resistant cell lines were isolated by anti-AXL antibody-immobilized magnetic beads. Drug resistance was assessed by MTS growth inhibition assay. Immunoblot analysis was performed on cell lysate and conditioned medium to evaluate expression and release of AXL. The role of AXL in cell growth and motility was examined by MTS growth inhibition assay and transwell migration assay.
Results: Drug-resistant NSCLC cell lines were successfully established, and increased release of fragmented soluble form of AXL was observed in these cell lines. They showed increased cell motility, which was effectively inhibited by AXL knockdown using siRNA. In contrast, their cell growth was not affected by AXL knockdown, even when these cells were simultaneously treated with molecular-targeted agents. Furthermore, cells highly expressing AXL were immunologically isolated from a gefitinib-sensitive parent cell line. These cells showed partial resistance to gefitinib, indicating that such cells intrinsically exist in NSCLC cell populations.
Conclusions: Soluble form of AXL is a candidate circulating biomarker for predicting acquired and intrinsic resistance to molecular-targeted agents in NSCLC cells. It may also be used to predict AXL-mediated increased motility of resistant cells. Patients harboring such resistant cells may have increased chance of responding to AXL-targeted anti-metastasis therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B46.
Citation Format: Nobuyuki Ise, Nobuaki Takemori, Kazuya Omi, Katsutoshi Goishi, Shigeki Higashiyama. Soluble AXL is a candidate circulating biomarker for predicting acquired and intrinsic resistance to molecular-targeted agents in NSCLC cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B46.
Abstract B59: Zhangfei/CREBZF arrests the growth of osteosarcoma cells by displacing Mdm2 and stabilizing p53.
Authors: Zhang Rui , Misra Vikram 
Published: August 2014

Abstract
Osteosarcomas (OS) are the most common malignant bone tumors in humans and dogs. Although there has been dramatic progress in treating OS in both species by surgery and chemotherapy, these therapies often fail, leading to recurrence of the tumor and metastatic spread. Our previous studies showed that Zhangfei/CREBZF, a basic region-leucine zipper (bLZip) transcription factor, is a potent suppressor of growth in some cancer cell lines, including the canine osteosarcoma cell line D-17. However, the mechanisms underlying the suppressive effects of Zhangfei have not been fully elucidated. Furthermore, the effects of Zhangfei are not universal and it has no obvious effects on untransformed cells and some cancer cell lines, suggesting that Zhangfei may act through an intermediary that is either not induced or is defective in cells that it does not affect. The objective of this study was to identify such an intermediary and to determine how Zhangfei exerts its effect. By monitoring the mRNA levels, protein, localization, and transcription activity of tumor suppressor protein p53 and its target genes in D-17 cells infected with adenovirus vectors expressing Zhangfei, we found Zhangfei stabilizes p53 and co-localizes with it in cellular nuclei and that the basic-leucine zipper domain of Zhangfei is required for its profound effects on cell growth and interaction with p53. Suppression of p53 by siRNA at least partially inhibited the effects of Zhangfei on the growth of cells. The effects of Zhangfei on dog osteosarcoma cells (D-17 cells) is mirrored by its effects on the p53 expressing human osteosarcoma cell line U2OS while Zhangfei has no effect on the p53-null osteosarcoma cell line MG63. In U2OS cells Zhangfei displaces the ubiquitin ligase, MDM2, from its association with p53 suggesting a mechanism for the effects of Zhangfei on p53. Overall, we identified that Zhangfei suppressed cell growth in osteosarcoma cells through direct interaction with tumor suppressor protein p53. We demonstrated that Zhangfei stabilized p53 and promoted its nuclear retention by displacing the E3 ubiquitin ligase, Mdm2. Our findings reveal a novel mechanism by which Zhangfei may inhibit tumor growth and metastasis. This may provide a potential application to gene therapy of certain types of osteosarcoma, and perhaps other tumors containing functional p53.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B59.
Citation Format: Rui Zhang, Vikram Misra. Zhangfei/CREBZF arrests the growth of osteosarcoma cells by displacing Mdm2 and stabilizing p53. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B59.
Abstract B86: Potent antitumor effect of TAS-102, a novel oral anti-neoplastic nucleoside agent, on both cetuximab-sensitive KRAS wild-type and cetuximab-resistant KRAS mutated colorectal cancer cells via trifluorothymidine incorporation into DNA.
Authors: Tanaka Nozomu , Yamada Yukari , Fujioka Akio , Yamamura Keisuke , Ito Satoko , Matsuo Kenichi , Utsugi Teruhiro 
Published: August 2014

Abstract
Background: The KRAS gene is mutated in approximately 40% of colorectal cancer (CRC). Patients with KRAS mutant CRC do not benefit from treatment with anti-EGFR antibody cetuximab and panitumumab. TAS-102 is a novel oral anti-neoplastic nucleoside agent, consisting of trifluorothymidine (FTD) as the antitumor component and thymidine phosphorylase inhibitor which prevents degradation of FTD. In a previous report, TAS-102 showed a broad spectrum of antitumor effect against various types of tumors via FTD incorporation into DNA followed by possible DNA dysfunction. Here, we investigated TAS-102 antitumor potency against colorectal cancer cell lines with differing KRAS status.
Materials and Methods: Cytotoxicity of FTD and cetuximab by 72h treatment was evaluated using cancer cell lines with varying of KRAS gene status. The antitumor effect of TAS-102 and cetuximab was compared in mice subcutaneously implanted with colorectal cancer cell lines with KRAS wild-type or mutation. In the same models, the amount of FTD incorporated into DNA was analyzed by HPLC in the TAS-102-treated tumors. EGFR downstream signaling pathways were analyzed by immunoblotting in the cetuximab-treated tumors.
Results: KRAS wild-type cell lines were sensitive to cetuximab in vitro, while some of the KRAS mutants were not. Cetuximab showed antitumor effect against KRAS wild-type tumors with downregulation of EGFR downstream signaling pathways, and it didn't show antitumor effect against KRAS mutants. In contrast to cetuximab, FTD exhibited a broad spectrum of cytotoxicity in vitro irrespective of KRAS status. Additionally, TAS-102 exerted significant antitumor effect against KRAS wild-type and mutant tumors. FTD incorporation into DNA was observed in both tumor types.
Conclusion: TAS-102 appears to exert significant antitumor effects on CRC cell lines irrespective of KRAS status which is consistent with preliminary clinical findings.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B86.
Citation Format: Nozomu Tanaka, Yukari Yamada, Akio Fujioka, Keisuke Yamamura, Satoko Ito, Kenichi Matsuo, Teruhiro Utsugi. Potent antitumor effect of TAS-102, a novel oral anti-neoplastic nucleoside agent, on both cetuximab-sensitive KRAS wild-type and cetuximab-resistant KRAS mutated colorectal cancer cells via trifluorothymidine incorporation into DNA. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B86.
Abstract C121: Genomic characterization of invasive cervical cancer in Guatemala and Venezuela: Common activation of the PIK3CA pathway.
Authors: Dean Michael , Gharzouzi Eduardo , Alvirez Enrique , Villagran Guillermo , Odey Ushie , Sawitzke Julie , Boland Joe , Lou Hong , Yeager Meredith 
Published: August 2014

Abstract
Cervical cancer represents the most dramatic cancer health disparity of women in the world, with over 270,000 deaths annually, concentrated in poor, rural, and indigenous populations. Guatemala and Venezuela are illustrative of this disparity as cervical cancer is the predominant cause of cancer cases and deaths in women. The average age of the subjects is 50, and smoking and oral contraceptive use is low. The affected women have an average of 6 children and adeno- or adenosquamous pathologies represent 25% of the tumors. To determine the genomic changes in invasive tumors, we initiated a prospective collection of invasive cervical cancer tissue. To determine the most frequently mutated genes we sequenced the exomes of 23 tumors in the Ion Torrent Proton and followed up with targeted sequencing of genes by Ampliseq in an additional 280 tumors. The exome sequence revealed potential driver mutations in several known cancer genes such as PTEN, PIK3CA, TSC1, SETD2, HRAS, PTCH, ARID1A, ARID4A and RB1. Targeted resequencing in a larger set of tumors of commonly mutated genes in the COSMIC database (PIK3CA, TP53, STK11, PTEN, KRAS, HRAS, and CDKN2A) revealed 40% mutation in PIK3CA and 11% in PTEN (a negative regulator of the PI kinase pathway). TP53 and STK11 were significantly mutated (10 and 8% of tumors, respectively) but HRAS, KRAS and CDKN2A at a very low level (0-2%). The PIK3CA mutations were concentrated in the known activating sites in the helical domain (E542K and E545K). To determine HPV stain types we amplified the HPV L1 gene found detectable in HPV in 96% of samples with HPV16 in 53%, HPV18 in 12%, HPV45 in 10% and HPV 26, 31, 33, 35, 39, 52, 56, 58, 67, 68, 69, and 73 in 0.8-4.9% of samples. In conclusion, invasive cervical cancers display frequent mutation of the helical domain of PIK3CA and activation of the PI kinase pathway, suggesting that targeted inhibition of this pathway may provide an avenue for therapy in this largely untreatable, common cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C121.
Citation Format: Michael Dean, Eduardo Gharzouzi, Enrique Alvirez, Guillermo Villagran, Ushie Odey, Julie Sawitzke, Joe Boland, Hong Lou, Meredith Yeager. Genomic characterization of invasive cervical cancer in Guatemala and Venezuela: Common activation of the PIK3CA pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C121.