bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 544: Blockade of CXC chemokines/CXCR2 axis in the tumor microenvironment as a potent therapeutic strategy for pancreatic ductal adenocarcinoma
Authors: Ijichi Hideaki , Tada Motohisa , Miyabayashi Koji , Mohri Dai , Asaoka Yoshinari , Tateishi Keisuke , Ikenoue Tsuneo , Omata Masao , Koike Kazuhiko , Moses Harold L. 
Published: June 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized histologically by expanded stromal components with marked fibrosis, which suggests that tumor-stromal interaction might play an important role in PDAC progression.
We have established pancreas epithelium-specific transforming growth factor-ß receptor type II (Tgfbr2) knockout mice in the context of active Kras (KrasG12D) expression (Kras+Tgfbr2KO), which developed differentiated PDAC with 100% penetrance and recapitulated histology of human PDAC described above.
In the AACR annual meetings 2009-10, we have reported that tumor-stromal interaction in the PDAC model promoted tumor progression and blockade of CXC chemokines/CXCR2 axis inhibited tumor growth and extended survival of the mice.
We further examined the underlying mechanisms of tumor-stromal interaction. The CXC chemokines secreted from the PDAC cells did not change autocrine PDAC cell proliferation nor that of stromal fibroblasts, but induced CTGF expression in the stromal fibroblasts and promoted tumor angiogenesis, which resulted in promotion of tumor growth. Expression of the CXC chemokines was downregulated by TGF-β signaling, whereas, NF-κB signaling was required for the expression. Subcutaneous xenografts coinjected with the PDAC cells and fibroblasts grew faster than those with PDAC cells alone, which suggested tumor-promoting tumor-stromal interaction. We further examined the xenograft growth of CXCR2-knocked down (KD) PDAC cells and CXCR2-intact firbroblasts, compared with that of CXCR2-intact PDAC cells and CXCR2-KD fibroblasts. Results suggested that intact CXCR2 in the stromal fibroblasts was required for the tumor-promoting CXC chemokines/CXCR2 axis. In conclusion, blockade of the CXC chemokines/CXCR2 axis might have a key role in modulating the tumor microenvironment and for development of more effective therapeutic strategy for PDAC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 544. doi:10.1158/1538-7445.AM2011-544
Abstract 5457: Contexts of vulnerability mediating TMZ response in metastatic melanoma
Authors: Yin Holly , Brooks Bradford , Chow Donald , Sereduk Chris , Sekulic Aleksandar , Brown Kevin , Trent Jeff 
Published: June 2012

Abstract
Metastatic malignant melanoma is an incurable disease with average 5-year survival rates for patients with disseminated disease ranging from 5-18%. Despite the recent development of promising targeted and immunological approaches for treatment of melanoma patients, there remains an urgent need to improve the effectiveness of conventional chemotherapeutics such as TMZ treatment for those patients ineligible or unresponsive to these approaches. We hypothesized that genetic alterations or contexts of vulnerability (COVs) exist in melanoma cells that mediate sensitivity to TMZ, and thus developed RNA-interference-based (RNAi) TMZ chemosensitization assays in melanoma cell lines in order to better understand how to pharmacologically augment TMZ response. First, we extensively developed RNAi sensitization assay in 17 melanoma cell lines followed by screening siRNA kinome library in these cell lines. This screening result, combined with our previous melanoma genomic data (gene expression, aCGH, SNP, and gene mutations), would prioritize the critical essential genes in melanoma. In addition, we profiled 17 melanoma cell lines for TMZ sensitivity and subsequently optimized RNAi screening parameters for detection of TMZ sensitization in one sensitive (UACC903) and four resistant (UACC647, UACC1308, UACC91 and UACC1940) cell lines. We then performed high-throughput RNAi screens with a 7,000 gene siRNA library targeting the druggable genome in these five cell lines. The data from the screens were rigorously evaluated and top TMZ-sensitizing hits were identified and confirmed. Based on these data, we prioritized the ATR/ATM/Chk1 pathway for further evaluation. We tested two Chk1 inhibitors for synergistic effects when combined with TMZ. Notably, both Chk1 inhibitors demonstrated good synergistic effects in the TMZ-resistant cell lines, with moderate/marginal effects in the sensitive line UACC903. These data are consistent with previous reports that inhibition of Chk1 can sensitize TMZ-induced cytotoxicity in glioma cells, and suggest that targeting this pathway in melanoma may augment TMZ response in melanoma. We are presently following up these results across a larger panel of melanoma cell lines, as well as evaluating pharmacological inhibitors of additional TMZ-sensitizing siRNA hits and pathways with the hope that these results may serve as a starting point for the development of novel combination therapies for melanoma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5457. doi:10.1158/1538-7445.AM2011-5457
Abstract 5464: Determination of total and encapsulated drug pharmacokinetics for CPX-351, a nanoscale liposomal fixed molar ratio of cytarabine-daunorubicin (Cyt:Daun)
Authors: Ciofani Travis , Harasym Troy , Juan Michael C.Y. , Mayer Lawrence , Cabral-Lilly Donna , Xie Sherwin 
Published: June 2012

Abstract
Background: CPX-351 is a liposomal formulation that delivers elevated concentrations of Cyt and Daun after administration in vivo and maintains the two drugs at a 5:1 molar ratio shown to be synergistic in preclinical studies. Pharmacokinetic analysis of CPX-351 in advanced leukemia patients demonstrated prolonged plasma exposure of the drugs with quantifiable concentrations of both agents being observed as long as 7 days after the final CPX-351 dose. Here we developed a method to separate liposome-bound from unencapsulated drugs, thereby allowing the pharmacokinetics of encapsulated agents to be determined in comparison to total plasma drug concentrations.
Methods: CPX-351 was administered to female Sprague-Dawley rats via IV bolus injection. Plasma samples were harvested at five timepoints from 1 – 24 hours. Unencapsulated drug analysis was conducted by addition of internal standards (gemcitabine (Cyt) and doxorubicin (Daun)) to the plasma, followed by a 5-fold dilution in buffer and ultrafiltration using Microcon YM-30. Unencapsulated drug levels were determined by reversed-phase HPLC-MS (SIM, 244.2 m/z (Cyt) and 528.3 m/z (Daun)). Total analysis was conducted by protein precipitation and analysis was determined by reversed-phase HPLC-UV (Cyt) and reversed-phase HPLC-Fluorescence (Daun).
Results: A separation method was developed to separate 0.22 – 4.33% unencapsulated Cyt and 0.13 – 2.50% unencapsulated Daun from liposome in plasma matrix. Encapsulated drug was calculated by subtracting the amount of unencapsulated analyte from the corresponding amount of total analyte. The total drug curves and the calculated encapsulated drug curves from 1 – 24 hours were superimposable for Cyt and Daun. A maximum of 1.9% unencapsulated Cyt and 0.4% unencapsulated Daun was measured in the plasma at any time point.
Conclusions: Unencapsulated drug levels in rat plasma are insignificant compared to the total drug levels such that levels of total and encapsulated are within the spread of the data and therefore indistinguishable. These results suggest that CPX-351 remains in circulation in rats as intact liposomes at least 24 hours post administration.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2011-5464
Abstract 5470: Potent MEK inhibitor CIP-137401: Preclinical studies
Authors: Khire Uday R. , Bhargava Ajay , Hart Barry , Chordia Mahendra D. 
Published: June 2012

Abstract
In recent years there is a lot of interest in both pre-clinical and clinical setting for the development of MEK kinase inhibitors as therapeutic agents for various cancers. A quite few number of MEK kianse inhibitors are currently undergoing phase I/II clinical trials both as a single agent as well as a combination with variety of other anti-tumor agents. These single agents include AZD-6244, RDEA-119, GSK-1120212, AS-703026 etc. One of the factors favoring MEK kinase as a sought after target besides being a part of very relevant Ras-Raf-MEK-ERK pathway is the identification of an allosteric binding site, which provides excellent selectivity for MEK kinase inhibitors as a class. Constitutive activation of Ras-Raf-MEK-ERK pathway has been a hallmark in several cancer types, including pancreatic, colon, lung, and melanoma. MEK is selective in phosphorylating serine/threonine residues of proteins resulting in regulation of variety of physiological functions of the cell including apoptosis, differentiation, proliferation and gene expression.
We recently discovered a novel, potent, non-ATP competitive, allosteric class of MEK kinase inhibitors. Our lead compound, CIP-1374, in the preliminary in vitro data that include primary enzyme assay, inhibition of ERK phophorylation, and anti-proliferation assays in various cell lines exhibited very potent activity. CIP-1374 also displayed excellent pharmaco-kinetic profile in mice with about 17h of half life with about 30% oral bioavailability. Another molecule in this series, CIP-137401 is also displaying a potent in vitro activity in various assays. We are currently focusing on CIP-137401 as our lead candidate and conducting preclinical studies. In this poster, our results in preclinical studies including rat pharmaco-kinetic, metabolic stability, and in-vitro toxicology data will be presented. The in vitro toxicology assays include its profiling in cardiac toxicity data (hERG channel activation). In addition the efficacy data from in vivo tumor xenograft models will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2011-5470
Abstract 5471: Pharmacokinetic investigation of vandetanib in patients with medullary thyroid carcinoma using liquid chromatography-tandem mass spectrometry
Authors: Broutin Sophie , Deroussent Alain , Paci Angelo , Ryan Anderson Joseph , Schlumberger Martin , Bidart Jean-Michel 
Published: June 2012

Abstract
Introduction: Vandetanib is a once-daily oral multikinase inhibitor with antitumoral activity in patients with advanced medullary thyroid carcinoma (MTC). The aim of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of serum vandetanib levels and to investigate the pharmacokinetic/pharmacodynamic relationship in MTC patients.
Materials and Methods: A LC-MS/MS method was developed using acetonitrile/water 0.1% acetic acid (80:20, v/v). Serum proteins were precipitated with cold acetonitrile after addition of trazodone used as internal standard (IS). Vandetanib was detected and quantitated by multiple reactions monitoring of the ion transitions m/z 475–&gt;112 (vandetanib) and m/z 372–&gt;176 (IS). Serum from 28 MTC patients (clinical study D4200C00058) was collected during each course of vandetanib treatment (initial dosing 300 mg/day) from 1 week to 36 months and stored at -20°C before analysis. Exposure monitoring was investigated retrospectively on 121 samples.
Results: Mean extraction recoveries from human serum were 103±3% and 94±2 % for vandetanib and IS, respectively. The calibration curve was linear for a range spanning 2.5-5,000 ng/mL. The accuracy was 92% at the lower limit of quantitation of 2.5 ng/mL with good precision (CV &lt;10%). Intra-day and inter-day quality control accuracies ranged from 90 to 97% (CV &lt;5%) and from 90 to 99% (CV&lt; 6%). Median vandetanib serum levels evaluated in MTC patients indicated a progressive rise from ∼400 ng/ml (at 1 week) to ∼800 ng/ml (at 3 months) that persisted over time. Half of patients (n=14) presented serious toxicity that required treatment interruption and/or dose reduction. Interestingly, most patients with serious toxicity (n=11/14) had a maximal vandetanib level greater than 20% above the median level versus only one patient in the non-serious toxicity group (n=14).
Conclusion: We developed and validated a fast and sensitive LC-MS/MS method allowing the quantitation of vandetanib levels in human serum. Results indicated that MTC patients display different vandetanib pharmacokinetic profiles. The relationships between these profiles and toxic side-effects and/or efficacy deserve further investigations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5471. doi:10.1158/1538-7445.AM2011-5471
Abstract 5482: c-Met and DR5 co-expression is an independent prognostic marker for better survival in colorectal carcinoma
Authors: Uddin Shahab , Hussain Azhar R. , Ahmed Maqbool , Al-Sanea Nasser , AbdulJabbar Alaa , Ashari Luai H. , Al-Homoud Samar , Al-Dayel Fouad , Bavi Prashant , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
Recently, dysregulated over-expression of hepatocyte growth factor (HGF) and its receptor, c-Met has been reported in variety of cancers. However, its role in colo-rectal carcinoma (CRC) has not been fully elucidated. Therefore, we investigated the role of c-Met in a large series of Middle Eastern CRC patient samples and CRC cell lines. c-Met was over-expressed in 86.8% of CRC and was strongly associated with expression of p-AKT (p&lt;0.0001), DR5 (p=0.0084) and Ki67 (p=0.011) by immuno-histochemistry. Co-expression of c-Met and DR5 was associated with less aggressive phenotype, a better overall survival (p=0.0027) and was an independent prognostic marker. In vitro, PHA665752, a selective c-Met inhibitor, inhibited growth and induced apoptosis in CRC cells. Additionally, PHA665752 treatment caused dephosphorylation of c-Met, AKT and its downstream effector targets FOXO1, GSK-3 and p-Bad. Interestingly, PHA665752 treatment of CRC cell lines also caused up-regulation of DR5 and combination treatment with TRAIL and PHA665752 significantly synergized CRC cells to undergo apoptosis. In-vivo, co-treatment of CRC xenograft with PHA665752 and TRAIL significantly reduced tumor volume and weight. Protein analysis of in-vivo xenografts by immuno-blotting showed that co-treatment with TRAIL and PHA665752 inactivated met and AKT more effectively as compared to treatment with TRAIL or PHA665752 alone. Finally, activation and cleavage of caspase-3 was more pronounced in CRC xenografts treated with combination of TRAIL and PHA665752. Altogether, these data demonstrate a significant correlation between expression of c-Met and DR5 in CRC patients. Furthermore, inhibition of c-Met signaling by PHA665752 in combination with TRAIL significantly inhibited cell growth and induced apoptosis in CRC cell lines suggesting that this may have significant clinical implications as a therapeutic target in the treatment of CRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5482. doi:10.1158/1538-7445.AM2011-5482
Abstract 5499: Temozolomide (TMZ) cytotoxicity in human melanoma cell lines is enhanced by concomitant treatment with the histone deacetylase (HDAC) inhibitor vorinostat (SAHA) and PARP inhibitor MK-4827
Authors: Tawbi Hussein , Kirkwood John M. , Lin Ying-Chih , Buch Shama C. , Lin Yan , Kublo Lyubov , Beumer Jan H. , Egorin Merrill J. , Chu Edward , Hershberger Pamela 
Published: June 2012

Abstract
Introduction: TMZ is a non-classical alkylating agent that induces DNA damage leading to cytotoxicity, with modest clinical activity in metastatic melanoma. DNA repair modulation with PARP inhibitors enhances TMZ cytotoxicity in vitro and in vivo, and this strategy is being investigated in clinical trials. We hypothesized that HDAC inhibition with SAHA would lead to increased DNA damage and potentiate the effect of the PARP inhibitor MK-4827 on TMZ cytotoxicity.
Methods: Human melanoma cell lines A375 and FEMX-1 were used. Cells were treated in the absence or presence of TMZ, SAHA, and MK-4827 at the indicated concentrations for 72 hr in 96-well plates. Cell viability was determined using MTS assays and normalized to vehicle-treated control cells. Drugs were used at the final concentrations indicated in Table 1.
Results: MK-4827 at 10 nM increased the cytotoxicity of TMZ in FEMX-1 but not in A375 cells, however 100 and 200 nM MK-4827 moderately potentiated TMZ cytotoxicity in both cell lines. The combination of TMZ with 1 µM SAHA and 200 nM MK-4827 resulted in profound cytotoxicity at reduced doses of TMZ (0.2 mM in FEMX-1 and 1.0 mM in A375), much lower than TMZ alone or in combination with either SAHA or MK-4827. &gt;80% cell kill was achieved in A375 and &gt;95% in FEMX-1 near the IC50 concentration of TMZ and at clinically achievable concentrations.
Conclusion: PARP inhibition offers a strategy to reverse melanoma TMZ resistance. The concomitant inhibition of HDAC with SAHA and of PARP with MK-4827 profoundly enhanced TMZ cytotoxicity at clinically achievable doses of all 3 agents. We are presently optimizing the dosing schedules of the 3 drugs in preclinical models and investigating the mechanism(s) underlying this potentiation. These findings support the investigation of the triple drug combination (TMZ+SAHA+MK-4827) for metastatic melanoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5499. doi:10.1158/1538-7445.AM2011-5499
Abstract 55: Prediction of miRNA target genes using a hidden Markov model
Authors: Lee Chien-Yueh , Hung Jui-Hui , Tsai Mong-Hsun , Hsiao Chuhsing Kate , Chuang Eric Y. , Lai Liang-Chuan 
Published: June 2012

Abstract
MicroRNAs (miRNAs) are short non-coding RNAs about 22 nucleotides in length that play important regulatory roles in animals for translational repression by targeting mRNAs. Recent studies reported that miRNAs may function as tumor suppressors or oncogenes, and the alterations in miRNA expression may be critical in tumor genesis and cancer progression. Using computational methodologies can rapidly identify miRNA targets in massive data, and provide rich gene-related information for human cancer studies. However, it is challenging to predict targets in animals due to imperfect complementarity between miRNAs and mRNA targets. In order to further improve the prediction performance, we proposed a novel miRNA target-gene prediction algorithm that combines several conventional prediction models including the sequence complementary searching for calculating alignment scores and thermodynamic stability approaches for assigning folding free energy to each miRNA-target interaction.
A Hidden Markov Model (HMM), a well known machine learning approach, was implemented in the algorithm to help the prediction decision. However, an HMM cannot consider all global information of the sequences due to its innate limitation. Therefore, forward and backward HMMs were simultaneously utilized in the proposed algorithm to overcome this limitation. As a result, any element information of miRNA-target interactions was able to pass to any other element by bi-directions. The proposed algorithm can predict the cancer-related miRNA target genes through a suitable combination of the proposed models. The results show that the highest sensitivity, specificity, and overall accuracy were 84.25%, 96.78%, and 96.67%, respectively. Based on our analysis, 52.42% prediction result of the proposed algorithm was consistent with other existing prediction algorithms. Furthermore, the predicted target genes obtained by the proposed algorithm could be likely found from the potential cancer-related genes discovered by microarray data. A total of 70.37% predicted target genes were significantly overlapped with the cancer-related genes from microarray data, suggesting these genes were substantially regulated by miRNAs in cancer. In conclusion, our proposed novel algorithm is able to predict miRNA target genes, commonly found among microarray-identified dysregulated genes in previous cancer studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 55. doi:10.1158/1538-7445.AM2011-55