bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2210: Integration of preclinical and clinical studies to identify pharmacogenetic markers associated with paclitaxel-induced neuropathy.
Authors: Wheeler Heather E. , Rodriguez-Antona Cristina , Wing Claudia , Komatsu Masaaki , Dolan M. Eileen 
Published: August 2014

Abstract
Paclitaxel is a tubulin-targeting agent used in the treatment of many cancers, including breast, lung, head and neck, and ovarian. Peripheral neuropathy is a common side effect of many chemotherapeutic agents, including paclitaxel, and limits their efficacy in patients. The overall goal of our work is to identify patients at risk for peripheral neuropathy using whole genome preclinical and clinical studies. Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs) have emerged as a promising preclinical model system in the study of the genetics of drug toxicity because the cells provide a cost-effective testing system in which environmental factors such as concomitant medications can be controlled. Most importantly, publicly available genotype and sequencing data is available, to allow for genome-wide association studies between HapMap/1000 Genomes variants and pharmacologic phenotypes measured in the LCLs after drug treatment such as paclitaxel induced growth inhibition and apoptosis. The overall genetic architecture of paclitaxel-induced neuropathy is well captured by the cell-based models as evidenced by significant enrichment of paclitaxel-induced toxicity SNPs from the preclinical model in clinical genome-wide association studies of peripheral neuropathy. We utilized iCell Neurons, which are commercially available cells derived from induced pluripotent stem cells, to study the effects of gene modulation on paclitaxel-induced cell growth inhibition using Cell Titer Glo and on neurite parameters of outgrowth, processes and branching using the ImageXpress Micro system. Through transient knockdown in iCell Neurons of RFX2, a gene identified through clinical and preclinical studies to be associated with paclitaxel neuropathy, sensitivity to paclitaxel increased as measured by a decrease of neurite outgrowth, processes and branching. The ability to identify cancer patients at risk of paclitaxel-induced peripheral neuropathy could influence treatment choice, outcome and quality of life for breast, lung, head and neck, and ovarian cancer patients. This work was supported in part by NIH/NIGMS UO1GM61393.
Citation Format: Heather E. Wheeler, Cristina Rodriguez-Antona, Claudia Wing, Masaaki Komatsu, M. Eileen Dolan. Integration of preclinical and clinical studies to identify pharmacogenetic markers associated with paclitaxel-induced neuropathy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2210. doi:10.1158/1538-7445.AM2013-2210
Abstract 2213: Influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on irinotecan, SN-38 and SN-38G pharmacokinetics.
Authors: Valenzuela Belen , González-Sales Mario , Escudero Vanessa , Navarro Elena , Perez-Ruixo Carlos , Rebollo Joseba , González-Manzano Ramon , Pérez-Ruixo Juan José 
Published: August 2014

Abstract
Background and objective: SN-38 is the active metabolite of irinotecan (CPT-11) and mainly responsible of hematological and intestinal toxicity after CPT-11 treatments. SN-38 is inactivated into SN-38G by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Some polymorphism of these enzymes leads lower clearance (CL) of SN-38 and therefore bigger exposition and bigger risk of hematological and/or intestinal toxicity (1). Therefore, the goal of this study has been to evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of CPT-11 and its metabolites, SN-38 and SN-38G on Caucassian cancer population.
Methods: Plasma concentrations of CPT-11, SN-38 and SN-38G from 72 patients were pooled to develop a joint population pharmacokinetic model using NONMEM 7. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated.
Results: The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. Clearance in patients with some allele (heterozygous or homozygous) associated with low enzymatic activity of UGT1A1*28 was a 35,7% lower (CI 95%: 6,7 - 64,7; p=0,003) than in wild-type patients. Additionally, linkage dissequilibrium indicates a strong interaction between functional UGT1A1, UGT1A7 and UGT1A9 polymorphisms related to the alteration of the UGT enzyme activity.
Conclusion: The impact of UGT1A1*28 genotype on the systemic exposure of SN-38 justifies its routine determination in patients receiving CPT-11 and subsequent dose adjustment.
Citation Format: Belen Valenzuela, Mario González-Sales, Vanessa Escudero, Elena Navarro, Carlos Perez-Ruixo, Joseba Rebollo, Ramon González-Manzano, Juan José Pérez-Ruixo. Influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on irinotecan, SN-38 and SN-38G pharmacokinetics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2213. doi:10.1158/1538-7445.AM2013-2213
Abstract 2216: The role of cytosine modifications in cellular sensitivity to cytarabine.
Authors: Moen Erika L. , Mu Wenbo , Godley Lucy A. , Dolan M. Eileen , Zhang Wei 
Published: August 2014

Abstract
Introduction: Inter-individual differences in cytosine modifications are a result of genetic and environmental influences. 5-methylcytosine and 5-hydroxymethylcytosine are covalent cytosine modifications that occur in CpG dinucleotides throughout the human genome. Objective: To characterize inter-individual variation in cytosine modifications in HapMap samples and investigate the contribution this may have on downstream phenotypes, such as cellular sensitivity to chemotherapeutics, such as cytarabine. Model: Cytosine modification levels at &gt;485,000 CpGs were measured in the International HapMap lymphoblastoid cell lines (LCLs). We utilized the Illumina Infinium 450K HumanMethylation Beadchip array to measure cytosine modification levels in 73 unrelated African (YRI - Yoruba people from Ibadan, Nigeria) and 60 European ancestry (CEU - Caucasians from Utah, US) LCLs. In addition, we evaluated LCL sensitivity to cytarabine in these HapMap cell lines. Results: We performed a linear regression model in order to identify novel associations between cytosine modifications and cytarabine-induced cytotoxicity. From these analyses, we found that promoter methylation of CDC6 and CCDC37 was associated with cytarabine IC50 (p= 3.75 x 10−6 and p= 5.39x 10−6, respectively). Furthermore, it has been shown previously that SNPs associated with pharmacological traits in LCLs are enriched in expression quantitative trait loci (eQTLs). We interrogated SNPs associated with cytosine modification (mSNPs) to help us understand the role of mSNPs in pharmacologic trait-associated genetic variants. We found that SNPs associated with cytarabine are enriched in cis-acting mSNPs in LCLs derived from individuals of European descent. Next, we integrated genome-wide cytosine modification data with genotype and gene expression data available for HapMap LCLs to allow for a more comprehensive understanding of inter-individual genetic variation. We identified a SNP in SLFN5 that was significantly associated with cytarabine sensitivity that is a cis-acting eQTL and mSNP for SLFN5 gene expression and cytosine modification. Conclusions: Analyzing cytosine modification-drug phenotype data may identify novel candidate genes associated with sensitivity to cytarabine. In addition, integrating genotype and gene expression data allow for a better understanding of the biological function underlying pharmacologic trait-associated SNPs.
Citation Format: Erika L. Moen, Wenbo Mu, Lucy A. Godley, M. Eileen Dolan, Wei Zhang. The role of cytosine modifications in cellular sensitivity to cytarabine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2216. doi:10.1158/1538-7445.AM2013-2216
Abstract 2219: The European Paediatric Oncology off-patent medicines Consortium (EPOC) pharmacokinetic/pharmacodynamic study of doxorubicin.
Authors: Boddy Alan V. , Steel Alison J. , Boos Joachim , Krischke Miriam , Andre Nicolas , Bisogno Gianni , Hempel Georg , Bode Gerlind , D'Incalci Maurizio , Kontny Nina 
Published: August 2014

Abstract
Background: Doxorubicin is a key component of a number of treatment regimens used in paediatric oncology despite the very limited pharmacology data on which current dosing regimens are based. In recognition of this, doxorubicin was included on the EMA priority list for paediatric off-patent medicines for which more information was required, particularly on pharmacokinetics.
Methods: The EPOC consortium, with collaborators in the UK, France, Germany and Italy, performs paediatric oncology pharmacology clinical trials. This study is a multicentre, multinational phase II pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. All patients are being treated according to a tumour-specific national or European therapeutic trial. The aim was to recruit 100 patients, with a particular focus on children less than 3 years. The plasma levels of markers such as troponin T, are being measured to evaluate their use as clinical markers for cardiotoxicity. Data is being analysed using a population pharmacokinetic approach and the impact of pharmacogenetics is being investigated.
Results: The study has been open to recruitment in 20 clinical centres across the four participating countries. The target 100 patients have been recruited from all the contributing study protocols, with 26 patients less than 3 years. Of these 26 patients, 5 patients are less than 1 year. An interim pharmacokinetic analysis has been performed on the data from the first 31 patients. The results of the analysis are consistent with the primary aims of the overall study.
Conclusion: The data generated during this study should provide comparative data on the age-dependent pharmacokinetics and pharmacogenetics of doxorubicin. The results will contribute to optimising the safe use of doxorubicin in children with cancer.
Acknowledgements: Study funded under the seventh framework programme of the European Commission (FP7)
Citation Format: Alan V. Boddy, Alison J. Steel, Joachim Boos, Miriam Krischke, Nicolas Andre, Gianni Bisogno, Georg Hempel, Gerlind Bode, Maurizio D'Incalci, Nina Kontny. The European Paediatric Oncology off-patent medicines Consortium (EPOC) pharmacokinetic/pharmacodynamic study of doxorubicin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2013-2219
Abstract 2223: Identification of novel protein modulators of p53 family function using photochemical crosslinking of stapled peptides.
Authors: Felsenstein Kenneth M. , Headley Kathryn M. , Murray Kevin A. , Russell Elisabeth A. , Bernal Federico 
Published: August 2014

Abstract
Considered to be the “guardian of the genome,” the tumor suppressor p53 works to counteract genetic mutation through cell cycle arrest, DNA repair or apoptosis to prevent proliferation of damaged cells. Dysfunction of the p53 pathway is a large driver of tumorigenesis, with an estimated more than 50% of cancers bearing some p53 abnormality; hence, the normalization of p53 function is considered an important clinical goal for cancer therapy. Many of the interactions involving p53 have been extensively studied; however, absent structural information, the identification of the precise nature of the binding interactions proves challenging, more so if they are transient. Using the hydrocarbon stapled peptide methodology previously used by our group to study interactions mediated by alpha-helices, we have begun identifying novel binding targets of the p53 transactivation domain (TAD) as well as its related proteins p63 and p73 through biochemically specific, covalent photochemical crosslinking reactions. Methodologically, we have developed the use of photoreactive stapled alpha helices (pSAHs) representing a unique way to use highly selective, biochemically specific cross-linking reagents. These can be used more broadly to study protein-protein binding interactions in cell-free and cell based assays. The technique has allowed us to learn more about the biologically active state of proteins that interact with the p53-family member TADs as well as the identification of unexplored binding partners and their mechanism of action in disease.
Citation Format: Kenneth M. Felsenstein, Kathryn M. Headley, Kevin A. Murray, Elisabeth A. Russell, Federico Bernal. Identification of novel protein modulators of p53 family function using photochemical crosslinking of stapled peptides. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2223. doi:10.1158/1538-7445.AM2013-2223
Abstract 2226: Structure/function characterization of SBi4225, a novel inhibitor of the calcium-binding protein S100B.
Authors: Cavalier Michael C. , McKnight Laura , Weber David , Wilder Paul 
Published: August 2014

Abstract
The S100 family of proteins displays no enzymatic activity but has been shown to play roles in an array of biological functions such as calcium homeostasis, cellular growth, inflammation, and metabolism. The influence of these homodimeric proteins is mediated through protein-protein interactions in a typically calcium dependent manner and aberrant expression of S100 proteins has been linked to a variety of cancers, cardiomyopathies, and neurological disorders. Of particular interest, S100B is highly over-expressed in many cancers, including malignant melanoma (MM). In MM, S100B is used as prognostic indicator in evaluating treatment success and in predicting relapse. Studies now show that S100B is more than a clinical marker, and that it binds wild-type p53 in a calcium-dependent manner, sequestering it, and promoting its degradation. This results in the loss of p53-dependent tumor suppression activities. As inhibition of S100B expression by RNA interference restores both wild-type p53 protein levels and normal transcriptional activation/apoptosis activities, we have made it our long-term goal is to specifically inhibit the S100B-p53 interaction in order to restore the p53 tumor suppression function as a potential therapy for malignant melanoma. Although we have succeeded in identifying many S100B inhibitors (also known as SBiXs), optimization studies are a necessary part of the development of drugs with useful therapeutic activities. Included amongst these optimization studies are characterizations of structure-activity relationships (SAR). Our initial SAR studies have resulted in the development of a second series of SBiXs. Amongst this series is the novel S100B inhibitor, SBi4225. As part of the cyclical process of SAR studies, the binding of SBi4225 to S100B has been investigated using X-ray crystallography. As described within, SBi4225 binds to S100B in a position and orientation analogous to its predecessors, SBi4211 and SBi1. NMR data including chemical shift perturbations of 15N isotopically labeled protein backbone were consistent with the X-ray crystal structures and demonstrated the relevance of the SBi4225-S100B complex in solution. This new understanding of the SBi4225 structure/function relationship will undoubtedly impact the development and optimization of future SBiXs.
Citation Format: Michael C. Cavalier, Laura McKnight, David Weber, Paul Wilder. Structure/function characterization of SBi4225, a novel inhibitor of the calcium-binding protein S100B. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2226. doi:10.1158/1538-7445.AM2013-2226
Abstract 2235: Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1.
Authors: Urusova Darya V. , Shim Jung-Hyun , Kim Dong Joon , Jung Sung Keun , Zykova Tatyana , Carper Andria , Bode Ann M. , Dong Zigang 
Published: August 2014

Abstract
The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). The human peptidyl prolyl cis/trans isomerase (Pin1) plays a critical role in oncogenic signaling. Herein, we report the X-ray crystal structure of the Pin1/EGCG complex resolved at 1.9 Å resolution. Notably, the structure revealed the presence of EGCG in both the WW and PP1ase domains of Pin1. The direct binding of EGCG with Pin1 was confirmed and the interaction inhibited Pin1 PP1ase activity. In addition, proliferation of cells expressing Pin1 was inhibited and tumor growth in a xenograft mouse model was suppressed. The binding of EGCG with Arg17 in the WW domain prevented the binding of c-Jun, a well-known Pin1 substrate. EGCG treatment corresponded with a decreased abundance of cyclin D1 and diminution of TPA-induced AP-1 or NFκB promoter activity in cells expressing Pin1. Overall, these results showed that EGCG directly suppresses the tumor promoting effect of Pin1.
Citation Format: Darya V. Urusova, Jung-Hyun Shim, Dong Joon Kim, Sung Keun Jung, Tatyana Zykova, Andria Carper, Ann M. Bode, Zigang Dong. Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2235. doi:10.1158/1538-7445.AM2013-2235
Abstract 2272: Comparison of metformin, pheformin and buformin in mammary carcinogenesis in non-obese, non-diabetic rats.
Authors: Zhu Zongjian , Jiang Weiqin , McGinley John N. , Thompson Henry J. 
Published: August 2014

Abstract
Emerging evidence from studies of human pharmacoepidemiology indicate that metformin, an antidiabetic drug, is associated with reduced breast cancer risk in diabetic individuals. Data from preclinical mammary carcinogenesis studies in the rat indicate that metformin also has protective activity against chemically-induced mammary cancer in non diabetic rats, but the dose required for inhibition is above that used clinically for the treatment of diabetes. Human breast cancer cell growth also is inhibited by metformin, but at concentrations far in excess of anti-diabetic plasma concentrations of the drug. It is likely that pharmacokinetic/pharmacodyanmic factors contribute to this blunted sensitivity, possibly due to carcinogenesis-associated down regulation of organic cationic transporters (OCT) required for cellular uptake of metformin. Since some biguanides such as phenformin and buformin are not dependent on OCT for cellular accumulation, their effects against mammary carcinogenesis were evaluated in comparison to metformin as a proof-in-concept study that could set the stage for development of second generation biguanides. The hypothesis evaluated was that inhibition of mammary carcinogenesis by phenformin and buformin would be superior to metformin. Female Sprague Dawley rats (n=30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter randomized to metformin, phenformin or buformin dietary groups and fed respective biguanides (10 mmol/kg) diets for 6 weeks. Both phenformin and buformin significantly reduced the number of mammary adenocarcinoma per rat (3.6, 1.6, and 0.7 cancers/rat for metformin, phenformin and buformin respectively) and tumor burden (1.61, 0.63, and 0.12 g/rat for metformin, phenformin and buformin respectively) and elongated cancer latency compared to metformin (40, 45, and 48 days post carcinogen for metformin, phenformin and buformin respectively) (p&lt;0.05). Mammary cancer incidence was also lower in animals fed phenformin (77%) or buformin (43%) diet vs metformin (93%), but the difference was only significant between metformin and buformin (p&lt;0.001). Cell culture experiments confirmed the carcinogenesis data. The comparative effects of these biguanides on the LKB1/AMPK axis will be reported. The associated mechanisms of cell growth inhibiton are under investigation. Supported by PHS grant CA52626 from the National Cancer Institute.
Citation Format: Zongjian Zhu, Weiqin Jiang, John N. McGinley, Henry J. Thompson. Comparison of metformin, pheformin and buformin in mammary carcinogenesis in non-obese, non-diabetic rats. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2272. doi:10.1158/1538-7445.AM2013-2272