bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B95: Statin hydroxamates, novel inhibitors targeting histone deacetylases and HMG-CoA reductase, suppress colorectal carcinogenesis associated with colitis.
Authors: Wei Tzu-Tang , Lin Yi-Ting , Yang Pei-Ming , Chen Jhih-Bin , Fang Jim-Min , Chen Ching-Chow 
Published: August 2014

Abstract
We synthesized statin hydroxamates (JMF3086, JMF3171, and JMF3173), which are small molecules that simultaneously inhibit histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). These statin hydroxamates were found to be cytotoxic in numerous human cancer cell lines, but not in normal cells, and to induce caspase-dependent apoptosis in HCT116 colon cancer cells. A genome-wide ChIP-on-chip analysis demonstrated that JMF3086 downregulated the expression of inflammatory and stemness genes and upregulated tumor suppressor genes. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) predicted that several of the inflammatory genes were regulated by NF-κB and that the apoptosis-related genes were regulated by NR3C1. The oral administration of statin hydroxamates prevented dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colorectal cancer (CRC) in mice by inhibiting inflammation. JMF3086 and JMF3173 exerted a therapeutic effect in mice with CRC by inducing apoptosis. CRC metastasis to the lungs was inhibited by JMF3086. A positive correlation was detected between the inhibition of HMGR and HDACs and the preventive or therapeutic effects of JMF3086. In addition, the self-renewal and stemness of colorectal cancer stem cells were inhibited by the statin hydroxamates both in vitro and in vivo. Thus, statin hydroxamates show potential as lead compounds for the future development of cancer prevention and treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B95.
Citation Format: Tzu-Tang Wei, Yi-Ting Lin, Pei-Ming Yang, Jhih-Bin Chen, Jim-Min Fang, Ching-Chow Chen. Statin hydroxamates, novel inhibitors targeting histone deacetylases and HMG-CoA reductase, suppress colorectal carcinogenesis associated with colitis. [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 B95.
Abstract B97: AS1411-Doxorubicin adduct for targeted liver cancer therapy.
Authors: Trinh Thu Le , Zhu Guizhi , Xiao Xilin , Zhang Xiaokui , Sefah Kwame , Tan Weihong , Liu Chen 
Published: August 2014

Abstract
Background: Aptamer-drug conjugates are promising to be applied to targeted cancer therapy, in which anticancer drugs were selectively delivered into cognate cancerous cells, but not to healthy tissues, in order to reduce side effects and enhance therapeutic efficacy.
Methodology/Principal Findings: In this study, the technology of drug-DNA adduct (DDA) was utilized to prepare drug-aptamer conjugates. Particularly, an anticancer drug, Doxorubicin (Dox), was conjugated with AS1411, a DNA aptamer which specifically recognizes human hepatocellular carcinoma Huh7 cells. The technology enabled a simple and high-payload conjugation of drugs onto aptamers. The resultant AS1411-Dox adduct maintained selectively recognition ability to target liver cancer cells with strong binding affinity (demonstrated by flow cytometry), was able to selectively deliver the conjugated Dox into target cancer cells (observed with confocal microscopy), and exhibited selective and potent cytotoxicity in target liver cancer cells (evaluated by MTS cell viability assay). More importantly, as the first of its kind, AS1411-Dox adduct demonstrated selectively antitumor therapeutic efficacy of this drug-aptamer conjugation technology in a mouse model. The ability of drug-aptamer adducts to deliver anticancer drugs into target cancer cells, while inhibiting nonspecific drug uptake in nontarget cells, enables this technology promising to be implemented in targeted cancer therapy.
Conclusions/Significance: Given the demonstrated ability of targeted liver cancer therapy combined with the aforementioned advantageous features as a simple preparation, the high drug payload capacity, and the wide applicability, this novel drug-DNA adduct technology is anticipated for wide implications for targeted cancer therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B97.
Citation Format: Thu Le Trinh, Guizhi Zhu, Xilin Xiao, Xiaokui Zhang, Kwame Sefah, Weihong Tan, Chen Liu. AS1411-Doxorubicin adduct for targeted liver cancer therapy. [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 B97.
Abstract B98: Development and evaluation of selective, reversible LSD1 inhibitors from fragment startpoints.
Authors: Stowell Alex , Hamilton Niall , Hitchin James , Blagg Julian , Burke Rosemary , Burns Samantha , Cockerill Mark J. , Fairweather Emma , Hutton Colin , Jordan Allan , Mould Daniel , Thomson Graeme , Waddell Ian , Ogilvie Donald 
Published: August 2014

Abstract
There is currently considerable interest in lysine-specific histone demethylase 1 (LSD1) as a therapeutic target in human malignancies. Specifically LSD1 has been demonstrated to be an essential regulator of leukaemia stem cell potential, inhibiting differentiation and apoptosis in the MLL-AML setting. There are a variety of potent irreversible LSD1 inhibitors available but here we present two series of reversible aminothiazole inhibitors obtained through the expansion of hits derived from a high concentration biochemical screen of a fragment library. The potency of the initial fragment hits was increased 32-fold through synthesis, with one series of compounds showing clear structure activity relationships (SAR) and inhibitory activities in the range of 7 to 187 µM in a biochemical assay. This series also showed selectivity against the homologous amine oxidase enzyme monoamine oxidase A (MAO-A).
This work represents one of the first reported examples of a reversible small molecule inhibitor of LSD1 with clear SAR and selectivity against MAO-A, and could provide a platform for the development of more potent reversible inhibitors. We also report the first Proof of Mechanism (POM) cell based assay utilizing CD86 expression as a surrogate marker of LSD1 activity in THP1 cells and its use to evaluate both our compounds and some recently reported reversible LSD1 inhibitors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B98.
Citation Format: Alex Stowell, Niall Hamilton, James Hitchin, Julian Blagg, Rosemary Burke, Samantha Burns, Mark J. Cockerill, Emma Fairweather, Colin Hutton, Allan Jordan, Daniel Mould, Graeme Thomson, Ian Waddell, Donald Ogilvie. Development and evaluation of selective, reversible LSD1 inhibitors from fragment startpoints. [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 B98.
Abstract C112: Characterization of TAS-121, a novel mutant-specific EGFR-TKI, on pharmacokinetics, pharmacodynamics, and antitumor activity.
Authors: Kato Masanori , Miyadera Kazutaka , Shibata Yoshihiro , Ito Kimihiro , Aoyagi Yoshimi , Chiba Masato , Yonekura Kazuhiko , Iwasawa Yoshikazu , Utsugi Teruhiro 
Published: August 2014

Abstract
Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), Gefitinib and Erlotinib, show good responsiveness in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Notably, skin rash and diarrhea, the most common EGFR-TKIs-related adverse effects, are due to wild type EGFR inhibition in dermal and intestinal tissue, respectively. Acquired resistance to EGFR-TKIs, however, arises in most cases and is caused in about half the cases by a secondary gatekeeper T790M mutation of EGFR. Therefore, an EGFR-TKI that specifically inhibits EGFR harboring mutations including T790M without affecting wild-type EGFR represents an attractive therapeutic agent.
Materials and Methods: Pharmacokinetics studies were performed in mice, rats, dogs and monkeys, and tumor growth and pharmacodynamics evaluation was analyzed in athymic nude mice bearing NSCLC cell lines, NCI-H1975 (harboring the EGFR T790M/L858R mutation) and HCC827 (harboring the EGFR exon 19 deletion).
Results: TAS-121 is a newly synthesized compound which is a mutant selective EGFR inhibitor with improved oral bioavailability in various animal species and in vivo antitumor potency compared to the previously described prototype compound, TAS-2913. TAS-121 showed a higher plasma concentration than TAS-2913 following oral administration in mice. Once daily dosing of TAS-121 inhibited NCI-H1975 (EGFR T790M/L858R) tumor growth at a low dose, with an ED50 of less than 12.5 mg/kg/day. TAS-121 also showed tumor growth inhibition of HCC-827 cells, harboring an EGFR activating mutation. In an orthotopic lung xenograft model, TAS-121 significantly prolonged survival in mice compared to first- and second-generation EGFR-TKIs. Pharmacodynamics analysis revealed that TAS-121 dose-dependently inhibited phosphorylation of EGFR T790M/L858R in a xenografted tumor, whereas it did not inhibit that of wild-type EGFR in mouse skin.
Conclusion: Our study demonstrates that TAS-121 is a highly potent and mutant-specific EGFR-TKI with a favorable oral bioavailability, and provides a promising therapeutic option for patients harboring T790M mutation after the failure of pre-existing EGFR-TKIs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C112.
Citation Format: Masanori Kato, Kazutaka Miyadera, Yoshihiro Shibata, Kimihiro Ito, Yoshimi Aoyagi, Masato Chiba, Kazuhiko Yonekura, Yoshikazu Iwasawa, Teruhiro Utsugi. Characterization of TAS-121, a novel mutant-specific EGFR-TKI, on pharmacokinetics, pharmacodynamics, and antitumor activity. [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 C112.
Abstract C113: ERBB3 independent activation of the PI3K pathway in EGFR mutant lung adenocarcinomas.
Authors: Song Xiaoling , Fan Pang-Dian , Guha Udayan , Threadgill David , Varmus Harold , Politi Katerina 
Published: August 2014

Abstract
Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinomas are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. EGFR is one member of a family of four receptor tyrosine kinases (EGFR, ERBB2, ERBB3 and ERBB4) that can homo- and/or hetero-dimerize leading to activation of the RAS-MAPK and phosphoinositide 3-kinase (PI3K) pathways. In EGFR mutant lung cancer cell lines, ERBB3 has been implicated in activation of the PI3K pathway. However, the requirement for ERBB3 in the initiation, progression and therapeutic response of EGFR mutant tumors remains undetermined. Using genetically engineered mouse models we investigated the contribution of Erbb3 to the development of EGFR-induced lung adenocarcinomas and their response to TKIs. We found that upon conditional deletion of Erbb3 in the lungs of mice that express mutant EGFR tumorigenesis and erlotinib sensitivity were unaffected. In the absence of Erbb3, tumors retained activation of the Pi3k pathway via the adapter proteins Gab1 and Gab2. Acute loss of ERBB3 in human lung adenocarcinoma cell lines with sensitizing EGFR mutations had a modest effect on phosphorylation of AKT and cell viability that varied among cell lines. These data demonstrate that activation of the Pi3k pathway in EGFR mutant tumors is independent of Erbb3 and has implications for the potential of ERBB3 as a therapeutic target in lung cancer. Knowledge of the role EGFR heterodimerization partners play in mutant EGFR-driven lung cancer can help guide the selection of which EGFR family members to target in the treatment of this disease.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C113.
Citation Format: Xiaoling Song, Pang-Dian Fan, Udayan Guha, David Threadgill, Harold Varmus, Katerina Politi. ERBB3 independent activation of the PI3K pathway in EGFR mutant lung adenocarcinomas. [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 C113.
Abstract C114: Clinical response to a lapatinib-based therapy of a Li-Fraumeni Syndrome patient with a novel HER2-V659E mutation.
Authors: Serra Violeta , Vivancos Ana , Puente Xose , Felip Enriqueta , Silberschmidt Daniel , Caratù Ginevra , Parra Josep-Lluis , De Mattos-Arruda Leticia , Grueso Judit , Hernández-Losa Javier , Arribas Joaquín , Prudkin Ludmila , Nuciforo Paolo , Scaltriti Maurizio , Seoane Joan , Baselga José 
Published: August 2014

Abstract
Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline p53 mutation (Li-Fraumeni Syndrome) identified oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifications, an EGFR-exon 20 insertion, and the first-in-human HER2-V659E mutation showing a phenotypic convergent evolution towards HER2 and EGFR alterations. Following the identification of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A clinical response both symptomatic and radiologic was achieved. HER2-V659E sensitivity to lapatinib was confirmed in the laboratory.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C114.
Citation Format: Violeta Serra, Ana Vivancos, Xose Puente, Enriqueta Felip, Daniel Silberschmidt, Ginevra Caratù, Josep-Lluis Parra, Leticia De Mattos-Arruda, Judit Grueso, Javier Hernández-Losa, Joaquín Arribas, Ludmila Prudkin, Paolo Nuciforo, Maurizio Scaltriti, Joan Seoane, José Baselga. Clinical response to a lapatinib-based therapy of a Li-Fraumeni Syndrome patient with a novel HER2-V659E mutation. [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 C114.
Abstract C116: Em08red, an emodin analog, exhibited anti-proliferative activity against oral cancer through down-regulation of ErbB2 signaling pathway and induction of apoptosis.
Authors: Juang Shin-Hun P. , Liang Fong-Pin , Lien Jin-Chern , Wu Yu-Hwa , Chen Chien-Shu 
Published: August 2014

Abstract
Over-activation of ErbB2 highly correlates with tumor progression and chemoresistance and has become an important biomarker and major target of cancer therapy treatments. Although several chemotherapy agents targeting ErbB2 show promising therapeutic effect, additional therapeutic approaches targeting ErbB2 are still urgently needed. Emodin, a major anthraquinone in the rhizome of Rheum palmatum, has been demonstrated to exhibit anticancer effects on several human ErbB2-overexpressing cancers. Computer modeling analysis determined emodin could be a suitable fit for the ErbB2 active pocket site however, the initial binding was unsatisfactory. In order to improve the anti-ErbB2 activity, a series of emodin analogs were synthesized and evaluated against several ErbB2-overexpressing oral cancer cells. Among them, 1,8-dihydroxy-9(10H)-anthraquinone (Em08red), showed potent antiproliferative effect against ErbB2-overexpessing oral cancers. Further studies showed Em08red treatment significantly reduced the levels of ErbB2 phosphorylation, resulting in G2/M arrested and apoptotic cell death. Moreover, treatment with Em08red, significant reduced the levels of anti-apoptosis proteins (Bcl-x and Bcl-2) and activated the caspase-3 and -9, but not caspase-8. Collectively, our results clearly indicate Em08red can down-regulate ErbB2-signaling, induce intrinsic apoptotic cell death and is a promising potent ErbB2-targeted therapeutic.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C116.
Citation Format: Shin-Hun P. Juang, Fong-Pin Liang, Jin-Chern Lien, Yu-Hwa Wu, Chien-Shu Chen. Em08red, an emodin analog, exhibited anti-proliferative activity against oral cancer through down-regulation of ErbB2 signaling pathway and induction of apoptosis. [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 C116.
Abstract C122: The knockdown of SET protein modulates miRNAs and proteins levels involved in maintenance and progression of oral cancer.
Authors: Sousa Lucas O. , Sobral Lays Martin , Garcia Cristiana Bernadelli , Thomé Carolina Hassibe , Greene Lewis Joel , Leopoldino Andréia Machado 
Published: August 2014

Abstract
SET (TAF-1/I2PP2A) is a multifunctional protein that participates in cell cycle control, apoptosis, migration and histone acetylation. It has been reported to be increased in head and neck squamous cell carcinoma (HNSCC) and oral squamous cell carcinoma (OSCC). The participation of SET in the inhibitory complex of histone acetylation contributes to the maintenance of histone hypoacetylation, which presumably prevents transcription. The objective of the present study was to identify changes in the levels of miRNAs after the knockdown of the protein SET mediated by short hairpin RNA (shRNA) against mRNA coding for SET in the HNSCC cell line HN12 (HN12shSET) compared to its negative control (HN12shCTRL). After confirming the reduction of the amount of SET protein and the increase of histone acetylation, 88 miRNAs known to be related to several types of cancer were analyzed by quantitative real time PCR (PCR array - SYBR-Green®). The levels of miR-21, miR-133b, miR-137, miR-193a-3p, miR-15a, miR-29b, miR-100 and miR-125b, and others, were increased in HN12shSET cells. This increase was confirmed in HN12shSET cells and in the OSCC cell line Cal 27 with knockdown of SET using small interfering RNA against SET (siRNA; Cal 27siSET) after reverse transcription by quantitative real time PCR using TaqMan® assays. The knockdown of SET resulted in increased levels of Snail and vimentin proteins, characteristic of mesenchymal cells, and in reduced amounts of the epithelial cell marker protein, E-cadherin. These changes are characteristic of cells in epithelial-mesenchymal transition. Functional assays in transwell® chambers revealed that the HN12shSET cells migrate and invade more than HN12shCTRL cells. In contrast, transfection of pre-miR with a consequent increase of miR-29b (one miRNA up-regulated in HN12shSET) reduced cell migration and invasion in HN12shCTRL and HN12shSET lines, reversing the effect of the knockdown of SET on migration and invasion. The data indicate that the protein SET, which is accumulated in malignant cells, is involved in the regulation of miRNA levels and the modulation of the ability of migration, invasion and differentiation of HNSCC, in part by its action on the levels of proteins related to disease progression.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C122.
Citation Format: Lucas O. Sousa, Lays Martin Sobral, Cristiana Bernadelli Garcia, Carolina Hassibe Thomé, Lewis Joel Greene, Andréia Machado Leopoldino. The knockdown of SET protein modulates miRNAs and proteins levels involved in maintenance and progression of oral cancer. [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 C122.
Abstract C139: Oncogenic ARAF mutation in a metastatic lung adenocarcinoma from a patient exhibiting sustained sorafenib response.
Authors: Greulich Heidi E. , Imielinski Marcin , Kaplan Bethany , Araujo Luiz , Amann Joseph , Horn Leora , Villalona Miguel , Meyerson Matthew , Carbone David 
Published: August 2014

Abstract
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma who was treated with sorafenib demonstrated a near-complete clinical and radiographic remission for five years. Whole-genome sequencing and RNA sequencing on primary tumor and normal samples from this patient identified a somatic mutation, encoding ARAF S214C, present in the cancer genome and expressed at high levels. ARAF S214 binds 14-3-3 proteins when phosphorylated, and, by analogy to the paralogous residue of RAF1, presumably interferes with binding of ARAF to activated Ras. Mutation of S214 impaired the ability of ARAF to bind 14-3-3ξ, likely contributing to the oncogenic activity of ARAF S214C. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF and RAF1 mutants transformed immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity. These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C139.
Citation Format: Heidi E. Greulich, Marcin Imielinski, Bethany Kaplan, Luiz Araujo, Joseph Amann, Leora Horn, Miguel Villalona, Matthew Meyerson, David Carbone. Oncogenic ARAF mutation in a metastatic lung adenocarcinoma from a patient exhibiting sustained sorafenib response. [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 C139.