bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B235: The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to vemurafenib in melanoma.
Authors: Zhan Yao , Dahabieh Michael S. , del Rincon Sonia V. , Miller Wilson H. 
Published: August 2014

Abstract
In eukaryotic cells, mRNA translation is restricted by the translation initiation step, in which eIF4E has been regarded as a master regulator. Overexpression of eIF4E has been found in different cancer types; however, whether eIF4E is involved in melanoma tumorigenesis and resistance to standard of care in melanoma remains unclear. We hypothesize that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the B-raf inhibitor, Vemurafenib. From our preliminary data, we show that by genetically knocking down eIF4E via siRNA or by using a pharmacological inhibitor of eIF4E, 4EGI-1, we can significantly repress the proliferation of a subset of melanoma cell lines. In addition, eIF4E activity contributes to the proliferation of some melanoma cell lines with acquired resistance to Vemurafenib, since siRNA-silencing eIF4E decreases their proliferation. Similarly, 4EGI-1 seems to be more effective at inhibiting cell proliferation of Vemurafenib resistant lines compared to their parental controls. Finally, we found that autophagy may act as a pro-survival mechanism in melanoma cell lines, based on the observation that the autophagy inhibitors Chloroquine, Bafilomycin, and 3-MA can repress cell proliferation in both BRAF V600E and BRAF WT cell lines. Further investigation with qPCR and western blot showed that eIF4E expression can be significantly downregulated at the mRNA and protein levels with inhibition of autophagy. This implies a role for eIF4E in mediating the pro-survival autophagy pathway in melanoma. Moreover, the expression of key autophagy markers, such as Atg5 and LC-3 II have been upregulated in several Vemurafenib resistant cell lines compared to the parental A375. In conclusion, our data show that eIF4E promotes proliferation of some melanoma cell lines. We also show that eIF4E is involved in maintaining the survival of some melanoma cell lines with acquired vemurafenib resistance. These data suggest that therapeutically targeting eIF4E, and disrupting pro-survival autophagy, may be a viable means of inhibiting melanoma cell proliferation and overcoming vemurafenib resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B235.
Citation Format: Yao Zhan, Michael S. Dahabieh, Sonia V. del Rincon, Wilson H. Miller, Jr.. The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to vemurafenib in melanoma. [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 B235.
Abstract B238: PIN1 (Peptidyl-prolyl cis/trans-isomerase, NIMA-interacting 1) is a potential therapeutic target for EBV-associated nasopharyngeal carcinoma.
Authors: Xu Meng , Chow Chit , Cheung Chartia Ching Mei , Chung Grace Tin-Yun , Lo Kwok Wai 
Published: August 2014

Abstract
Nasopharyngeal carcinoma (NPC) is a common EBV-associated human malignancy in Southern China. NPC is highly radiosensitive and radiotherapy is the mainstay treatment for the patients. However, poor clinical outcome remains the major concern in NPC patients with advanced stage disease. Development of new clinical interventions to treat the disease are importance for control this cancer. PIN1 is a highly conserved enzyme that isomerizes specific phosphorylated Ser/Thr-Pro bonds in multiple proteins. It induces conformational changes and modulates functions of many proteins that promote oncogenesis. We have recently confirmed the high PIN1 expression in almost all NPC primary tumours. The aim of this study was to investigate the potential of PIN1 as a therapeutic target for the treatment of NPC. The oncogenic function of PIN1 was investigated in the EBV-positive NPC cell line C666-1 and an immortalized NP epithelial cells NP69. The antitumor effect of PIN1 inhibition was then studied in both in vitro and in vivo NPC models by using the PIN1 inhibitor juglone. In the stable PIN1-expressing NP cells, we found the upregulation of cyclin D1 and activation of MAPL/JNK pathway. Furthermore, we also demonstrated the interaction between PIN1 and EBNA1 in the NPC cells. PIN1 was also shown to interfere the transcription activity of EBNA1 through binding to the phosphorylation sites of EBNA1. Notably, knockdown of PIN1 by siRNA significantly inhibited cell proliferation, DNA synthesis and colony formation of NPC cells. Treatment with juglone demonstrated significant induction of apoptosis and suppression of cyclin D1 expression in C666-1 cells. The IC50 of C666-1 was approximately 6 μM while that of EBV-negative NPC cells HK-1was 10 μM. A dose-dependent inhibition of tumor growth was observed in mice treated with juglone. A significantly growth suppression and cyclin D1 downregulation was found in the tumours of the mice treated with 1-1.5 mg/kg juglone. In conclusion, our findings imply that targeting Pin1 may serve as a potential therapeutic approach for treating patients suffering from this EBV-associated cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B238.
Citation Format: Meng Xu, Chit Chow, Chartia Ching Mei Cheung, Grace Tin-Yun Chung, Kwok Wai Lo. PIN1 (Peptidyl-prolyl cis/trans-isomerase, NIMA-interacting 1) is a potential therapeutic target for EBV-associated nasopharyngeal carcinoma. [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 B238.
Abstract B240: Novel protein fusion toxins targeting c-kit positive neuroendocrine tumors.
Authors: Choudhary Swati , Pardo Alessa , Rosinke Reinhard , Barth Stefan , Batra Janendra K. , Verma Rama S. 
Published: August 2014

Abstract
Currently, the treatment options for patients with neuroendocrine carcinomas (NECs) are limited. Stem cell factor is found to have a trophic role in neuroendocrine cancer cells through an autocrine growth loop, which leads to the activation of the c-kit receptor. NECs like neuroblastomas, small cell lung carcinomas and poorly differentiated human colon carcinoma cells (CRCs) over-express both the c-kit receptor and its ligand, stem cell factor (SCF), as compared to normal cells. The role of the known c-kit inhibitor imatinib has already been investigated in these cell types and has shown promising results. We developed SCF-based c-kit targeting protein fusion toxins against neuroendocrine carcinomas, such as neuroblastomas and colorectal carcinomas. In this study, SCF was cloned from the HepG2 cell line and mutated in order to optimize its expression. The mutated SCF was recombinantly fused with bacterial toxins (Diphtheria toxin (DT) and Pseudomonas exotoxin A (PE)) to form c-kit targeting fusion toxins. These proteins were expressed in E.coli and purified by affinity chromatography followed by size exclusion chromatography. Flow cytometric analysis was used to monitor receptor expression on c-kit positive neuroblastoma cell lines (IMR 32 and SHSY5Y), colon carcinoma cell lines (HT-29, HCT 116 and DLD-1), and the c-kit negative cell line, MCF-7. In vitro binding, internalization and toxicity studies were performed on the above cell lines in order to characterize the purified chimeric toxins. Annexin V binding assays and cell cycle analysis were performed additionally, to prove their efficacy. The ID50 values for the toxins were found to correlate with the receptor expression on these cell lines. The novel c-kit targeting protein fusion toxins reported in our study offer a promising strategy for therapeutics against neuroendocrine tumors and warrant further testing in such tumors with c-kit autocrine and paracrine loops.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B240.
Citation Format: Swati Choudhary, Alessa Pardo, Reinhard Rosinke, Stefan Barth, Janendra K. Batra, Rama S. Verma. Novel protein fusion toxins targeting c-kit positive neuroendocrine 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 B240.
Abstract B241: Bispecific antibody targeting EGFR and cMet demonstrates superior activity compared to the combination of single pathway inhibitors.
Authors: Moores Sheri , Chiu Mark , Bushey Barbara , Chevalier Kristen , Chin Diana , Chippari Susan , Haytko Peter , McCabe Frank , Neijssen Joost , Parren Paul , Schuurman Janine , Wu Sam , Attar Ricardo , Anderson Mark 
Published: August 2014

Abstract
Many tumors respond initially to targeted therapy, only to develop resistance over time thereby allowing the tumors to progress. In patients treated with EGFR small molecule inhibitors, the cMet pathway is often upregulated, either through MET gene amplification or an increase in the ligand HGF, to compensate and provide resistance to the EGFR monotherapy. Because both EGFR and cMet signal through some of the same survival and growth-promoting pathways, dual inhibition of these receptors may improve efficacy and prevent resistance through these mechanisms. We have designed a bispecific EGFR-cMet antibody (EM1-mAb) with multiple mechanisms of action resulting in superior activity compared to a combination of single EGFR and cMet inhibitors. Fab arm exchange was used to produce EM1-mAb, a technique that allows for efficient large-scale preparation of bispecific antibodies. EM1-mAb prevented binding of the ligands EGF and HGF to their respective receptors, EGFR (IC50 = 10 nM) and cMet (IC50 = 30 nM). Ligand-induced phosphorylation of each receptor was inhibited in cell-based assays. Blocking signaling from both EGFR and cMet with a combination of single monospecific antibodies resulted in an enhanced inhibition of pERK, a downstream effector of both receptors. The bispecific EM1-mAb further increased the potency of inhibition of pERK (55-65-fold) compared to the combination of single monospecific antibodies, suggesting an avidity effect on downstream signaling. EM1-mAb was evaluated in SCID-beige mice implanted with tumor cells engineered to express human HGF. Complete regression of 8/8 tumors was observed upon treatment with EM1-mAb dosed twice a week at 20 mg/kg. After the dosing period of four weeks, mice were monitored for an additional 10 weeks and no tumor regrowth was observed.
Our data demonstrate that the bispecific antibody EM1-mAb, generated using Fab arm exchange, inhibited EGFR and cMet pathways simultaneously, resulting in superior activity in cellular downstream signaling compared to the combination of single pathway inhibitors. These attributes allow for a more efficient path toward clinical development.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B241.
Citation Format: Sheri Moores, Mark Chiu, Barbara Bushey, Kristen Chevalier, Diana Chin, Susan Chippari, Peter Haytko, Frank McCabe, Joost Neijssen, Paul Parren, Janine Schuurman, Sam Wu, Ricardo Attar, Mark Anderson. Bispecific antibody targeting EGFR and cMet demonstrates superior activity compared to the combination of single pathway inhibitors. [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 B241.
Abstract B250: Evaluation of anticancer efficacy of 6-propionylpterin characterized from native isolate Bacillus subtilis.
Authors: Nisshanthini S D. , Sukirtha R. , Achiraman S. , Palaniswamy M. , Jayaraman Angayarkanni 
Published: August 2014

Abstract
In this context the present study is aimed at purifying a pteridine derivative and studying its apoptotic effect on a cancer cell line. 6-propionyl pterin have been purified from a native strain of Bacillus subtilis and administered via intra peritoneal injection to DLA induced mice. During the course of the experiment reduction in angiogenesis was visualized. Earlier report (Kim et.al., 2011) clearly suggested that sepiapterin, a precursor of tetrahydrobiopterin inhibits VEGF-A induced HUVEC proliferation and adhesion through down-regulation of VEGFR-2 downstream signaling pathways, independently of NO synthesis and this supported the present finding. Based on our preconceived view that administration of 6-pp enhances the activity of iNOS, thereby enhanced production of nitric oxide (NO), an attempt was made to check the pathway of NO induced apoptosis. The expression of iNOS, p53, caspase 3, and mdm2 gene were checked by RT PCR. But only mdm2 gene expression alone was upregulated. p53 downregulation might be due to Mdm2 which block its transcriptional activity, favours its nuclear export and stimulates its degradation (Chene, 2003). Caspase 3 activation does not participate in Mdm2 induced apoptosis as determined by the protein levels or poly (ADP-ribose) polymerase fragmentation (Dilla et al., 2000). The report of Wolf et al., 1999 strongly suggests that caspase 3 is the primary activator of apoptotic DNA fragmentation. This is inconsistent with our present finding wherein there was absence of DNA fragmentation in apoptotic cells and also expression of caspase 3 was absent. Thus overall mechanism may be initiated by expression of Mdm2 which inturn inhibited p53 expression. Mdm2 might have down regulated Bcl2 followed by a cascade of Caspase 2 and Cyt-c expression. Cyt-c activation might have regulated Caspase -7 and ROCK protein. ROCK is responsible for cell shrinking and membrane blebbing and finally leading to apoptosis. Caspase 3 activation does not participate in Mdm2 induced apoptosis and hence DNA fragmentation is not found. This study was done to evaluate the efficacy of the compound as anticancer agent and whether it induces apoptosis or not. Mechanism of action of drug was predicted from the results obtained. To derive the exact mechanism further study on the signaling proteins has to be performed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B250.
Citation Format: S D. Nisshanthini, R. Sukirtha, S. Achiraman, M. Palaniswamy, Angayarkanni Jayaraman. Evaluation of anticancer efficacy of 6-propionylpterin characterized from native isolate Bacillus subtilis. [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 B250.
Abstract B257: Identification of new CYP26 inhibitors with efficacy in breast cancer xenograft models.
Authors: Oehlen Bert , Ma Gaifeng , McCormack Siobhan , Lim Dong Sung , Tarrant Jim , Zhu Xiaokang , Panicker Bijoy , Goldberg Itzhak D. 
Published: August 2014

Abstract
Retinoids, such as the prototypical retinoid all trans retinoic acid (ATRA), have been used successfully in the treatment of acute promyelocytic leukemia (APL) patients. They have also been tested for efficacy in solid tumors, including breast cancer. Despite promising preclinical data, the clinical success of using ATRA for breast cancer patients has been limited so far. We hypothesize that this is largely due to three factors: (1) a lack of understanding of the patient population that is likely to respond to retinoid therapy, (2) a significant induction of retinoic acid metabolism with retinoid therapy, resulting in sub-optimal retinoid exposure in tumors and (3) the narrow therapeutic index of ATRA. Several recent studies indicate that breast cancer cells that express the Retinoic Acid Receptor Alpha (RARA) are more likely to respond to retinoic acid than cells without RARA expression. This provides a rationale for selection of patients that are likely to benefit from retinoid therapy in future clinical trials. The cytochrome P450 enzyme CYP26 is the key enzyme involved in ATRA metabolism. CYP26A1 expression is elevated in breast cancer tissue compared to normal tissue and CYP26A1 expression is negatively correlated with patient survival. Angion has identified orally bioavailable small molecule inhibitors of CYP26. Angion's lead inhibitor blocks retinoid metabolism in tumor cells and enhances serum and tumor retinoic acid levels. The compound shows robust single agent efficacy in several murine breast cancer xenograft models. By elevating endogenous serum and tumor retinoic acid levels in a physiological range, CYP26 inhibition therapy is likely to result in a better therapeutic index than systemic retinoid therapy. The identification of orally bioavailable, potent, and selective CYP26 inhibitors eliminates two major drawbacks of systemic retinoid therapy, and– in combination with new insights in selecting patients that are more likely to respond to retinoid therapy– may provide a new impetus for evaluation of retinoic acid signaling modulators as a treatment for breast cancer patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B257.
Citation Format: Bert Oehlen, Gaifeng Ma, Siobhan McCormack, Dong Sung Lim, Jim Tarrant, Xiaokang Zhu, Bijoy Panicker, Itzhak D. Goldberg. Identification of new CYP26 inhibitors with efficacy in breast cancer xenograft models. [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 B257.
Abstract B265: Targeting Wnt signaling: Discovery and characterization of novel thiazole-based Traf2- and NCK-interacting kinase (TNIK) inhibitors.
Authors: Uno Yuko , Moriyama Hideki , Kashimoto Shigeki , Kawase Yusuke , Shitashige Miki , Sawa Masaaki , Yamada Tesshi 
Published: August 2014

Abstract
Introduction: Aberrant activation of Wnt pathway is a major force driving colorectal carcinogenesis, and therefore the Wnt pathway has been thought of as an attractive anticancer drug target. However, its complexity has made it difficult to find druggable targets in the Wnt pathway. Recently, we reported Traf2- and NCK-interacting kinase (TNIK) plays important roles in the Wnt signaling pathway by making a complex with beta-catenin and T-cell factor-4 (TCF4) in a nucleus. We also found that TNIK is activated in human colorectal cancer cell lines, and proliferations of those cells are highly dependent upon the expression and catalytic activity of TNIK. Therefore inhibitors of TNIK may represent a promising therapeutic approach for treating colorectal cancer. Here we describe a discovery and characterization of a novel TNIK inhibitor.
Methods: To identify compounds that inhibit TNIK acitivity, we have produced a recombinant catalytic domain of human TNIK, and developed a high throughput screening (HTS) assay system using a peptide substrate. TCF/LEF reporter gene assay using HEK293 was established to validate hit compounds. To study the effects of TNIK inhbitors on the Wnt signal pathway, Wnt target genes were analyzed by RT-PCR and Western blotting. The selected compounds were subjected to a kinase selectivity panel assay.
Results: By performing a high throughput screening campaigns of our 10K kinase-focused compound library against a recombinant human TNIK, we identified a series of novel thiazole compounds as a potent inhibitor of TNIK. Hit compound, NCB-0001 exhibited potent inhibitory activity for TNIK with an IC50 value of 8.6 nM. After subsequent optimization, N1662 was identified as a lead compound having a strong anti-proliferative activity in colorectal cancer cell lines. N1662 inhibited tumor growth in a mouse xenograft model of colorectal cancer. Further optimization led to compound N5355 that showed good TNIK enzyme inhibition and potent Wnt signal inhibition in the TCF reporter gene assay, as well as down-regulation of Wnt target genes. N5355 showed excellent kinase selectivity against a panel of 311 kinases. Detailed results will be presented in the conference.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B265.
Citation Format: Yuko Uno, Hideki Moriyama, Shigeki Kashimoto, Yusuke Kawase, Miki Shitashige, Masaaki Sawa, Tesshi Yamada. Targeting Wnt signaling: Discovery and characterization of novel thiazole-based Traf2- and NCK-interacting kinase (TNIK) inhibitors. [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 B265.
Abstract B28: Identification of drug-response biomarkers for combined mTORC1/2 and MEK1/2 investigational agents using a large-scale cancer cell line screen.
Authors: Shin Hyunjin , Blair Derek , Li Bin , Hather Greg , Trepicchio William L. , Ecsedy Jeffrey , Gangolli Esha 
Published: August 2014

Abstract
Combination therapy in oncology drug development has the potential to overcome resistance against single agent-based therapy. In many cancers, the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways confer major cell growth and survival mechanisms. Therefore, a greater treatment effect may be achieved by inhibiting both pathways simultaneously through drug combination. In this study, the enhanced anti-proliferative activity of investigational drug MLN0128 (mTORC1/2 investigational agent) when combined with TAK733 (MEK1/2 investigational agent) was assessed using an in-vitro cell viability assay on 240 cancer cell lines. Cells were administered with MLN0128 and TAK-733 in DMSO in ten 2-fold serial dilutions and cell viability was measured using Promega's CellTiter-GLO® assay after a 72 hour incubation period. The data points were fit to a 9-parameter model to obtain a response surface and the effect of the combined administration for each cell line was measured using a non-linear blending score estimated from the response surface. Statistical analysis was conducted to determine if the estimated combination effect was associated with known mutated oncogenes, tumor suppressor genes, or cancer histology reports of the 240 cell lines. Interestingly, the synergy of combined agents appeared to be mainly driven by TAK733, as cell lines sensitive to TAK733 as a single agent demonstrated beneficial combination effect with the addition of MLN0128. Furthermore, cell lines with mutations in KRAS, NRAS, and BRAF showed greater synergy scores of the combination. Likewise, cell lines of colon, pancreatic, and skin origins were more sensitive to the combination. Of particular interest are cell lines with mutated KRAS/NRAS or colon origins since they were generally resistant to single agent MLN0128, but became sensitized to the combination with TAK733. In conclusion, our study of drug combination assays on a large-scale in-vitro cell line panel revealed that mutant KRAS/NRAS or colorectal cancers may be sensitive to combined MLN0128 with TAK733.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B28.
Citation Format: Hyunjin Shin, Derek Blair, Bin Li, Greg Hather, William L. Trepicchio, Jeffrey Ecsedy, Esha Gangolli. Identification of drug-response biomarkers for combined mTORC1/2 and MEK1/2 investigational agents using a large-scale cancer cell line screen. [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 B28.