Jul 28, 2015 genomic heterogeneity in human cancers complicates genecentric personalized medicine. Pharmacogenomics analyzes how the genetic makeup of an individual affects hisher response to drugs. Nov 27, 20 two large scale pharmacogenomic studies were published recently in this journal. Largescale pharmacogenomics studies in which experimental and. Pharmacogenomic agreement between two cancer cell line data sets. Pharmacogenomic and pharmacogeneticguided therapy as a tool in precision medicine. This file shows a summary of the results reported with the supplementary data of cgp and ccle for the 15 compounds assessed by haibekains et al.
Integrating heterogeneous drug sensitivity data from cancer. Dec 19, 20 inconsistency in large pharmacogenomic studies. Such information is not transferable or applicable for newly identified, previously. Consequently, more than 200 anticancer drugs are available on the market. The above considerations suggest that ic 50 calculations and ec 50 calculations, following the same logic are not suitable drug sensitivity metrics to accurately compare and reconcile drug sensitivities from the large pharmacogenomic studies, which contain many incomplete dose response curves. Introduction pharmacogenomics deals with the influence of genetic variation on drug response by corelating gene expression or polymorphism with a drugs efficacy or toxicity it intends to identify individuals who are either more likely or less likely to respond to a drug, as well as those who require. Cancer cell line encyclopedia consortium, genomics of drug sensitivity in cancer consortium. Inconsistency in large pharmacogenomic studies abstract.
Inconsistency in large pharmacogenomic studies nature. Consistency in large pharmacogenomic studies nature. Inconsistency in large pharmacogenomic studies, nature 10. Nov 27, 20 two largescale pharmacogenomic studies were published recently in this journal. Despite the widespread recognition of the scienti c rationale and the clinical implementation of pharmacogenomic tests at several major academic medical. Progress with covalent smallmolecule kinase inhibitors. Lessons learned from two decades of anticancer drugs. Nov 27, 20 inconsistency in large pharmacogenomic studies. Inconsistency in large pharmacogenomic studies europe pmc. Inconsistency in large pharmacogenomic studies ncbi nih. This system is used for most genes with welldefined. Download fulltext pdf revisiting inconsistency in large pharmacogenomic studies article pdf available in f research 5. Aerts and john quackenbush no static citation data no static citation data cite.
Although the source of inconsistencies remains uncertain, it has potential implications for using these outcome measures to assess genedrug associations or select potential anticancer drugs. Adverse drug reactions adrs are discussed in depth in chapter 5, although this chapter will also discuss adrs related to genetic polymorphisms. The integration of largescale drug sensitivity screens and genomewide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous knowledge about drug action. Principles of pharmacogenetics and pharmacogenomics edited. Pdf pharmacogenomics holds great promise for the development of. Development of the theta comparative cell scoring method to.
We downloaded, curated, and annotated the genomic and pharmacological data. Integrative cancer pharmacogenomics to infer largescale drug. Haibekains b, elhachem n, birkbak nj, et al inconsistency in large pharmacogenomic studies. Inconsistency in large pharmacogenomic studies github. Cellline selectivity improves the predictive power of. Two large scale pharmacogenomic studies were published recently 3,4. We automated the analysis pipeline so that minimal manual interaction is required to reproduce our results. I pharmacogenomics and pharmacogenetics andrew a somogyi and janet k coller encyclopedia of life support systems eolss variant is in this case a basepair deletion at position 2549 and the letter b indicates an additional snp at position 1749. Indeed, comparative analysis of large pharmacogenomic studies published by the broad and sanger institutes have resulted in reports of inconsistency between the genetic signatures of drug sensitivity assigned to drugs shared between both studies. Assessment of pharmacogenomic agreement europe pmc. We downloaded, curated, and annotated the genomic and. The synthetic lethal interactions can be screened by measuring the colony size.
Aug 11, 2017 read the original article in full on fresearch. Mar 24, 2011 pharmacogenomic studies pharmacogenomics uses genomewide approaches to elucidate the inherited basis of differences between persons in the response to drugs. Principles of pharmacogenetics and pharmacogenomics edited by. Although the source of inconsistencies remains uncertain, it has potential implications for using these outcome measures to assess genedrug associations or select potential anticancer drugs on the. Bladder cancer has numerous genomic features that are potentially actionable by targeted agents. Among the most common are the cytochrome p450 cyp genes, encoding enzymes that control the metabolism of more than 70 percent of prescription drugs. Integrating pharmacogenomics into pharmacy practice via. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to targetbased and immunerelated therapies. Recently, two largescale pharmacogenomic studies screened multiple anticancer drugs on over cell lines in an effort to elucidate the response mechanism of anticancer drugs. Encircling the regions of the pharmacogenomic landscape that. This file shows a summary of the results reported with the supplementary data of cgp and ccle for. Pathwaycentric perspectives, which underscore the need to understand key. Evaluating the consistency of largescale pharmacogenomic studies. Introduction pharmacogenomics deals with the influence of genetic variation on drug response by corelating gene expression or polymorphism with a drugs efficacy or toxicity it intends to identify individuals who are either more likely or less likely to respond to a drug, as well as those who require altered dose of.
Gene expression data were downloaded from the ccle website and. Such information is not transferable or applicable for newly identified, previously uncharacterized small. Malignant tumors often share a core group of pathways that are perturbed by diverse genetic mutations. Revisiting inconsistency in large pharmacogenomic studies.
Pubmed abstract publisher full text free full text. We confirmed that spearman rank correlation, used in our 20 study, does not detect consistency for the three targeted therapies profiled by. Revisiting inconsistency in large pharmacogenomic studies article pdf available in f research 5. Nov 30, 2016 consistency in large pharmacogenomic studies. Genes commonly involved in pharmacogenomic drug metabolism and response there are several genes responsible for differences in drug metabolism and response. Jun 30, 2015 recently, two large scale pharmacogenomic studies screened multiple anticancer drugs on over cell lines in an effort to elucidate the response mechanism of anticancer drugs. Research highlights research highlights 20140109 00. If this is the first time you use this feature, you will be asked to authorise cambridge core to connect with your account. Towards pathwaycentric cancer therapies via pharmacogenomic. Case studies in pharmacogenetics mike pacanowski, pharmd, mph office of clinical pharmacology center for drug evaluation and research pediatric advisory committee. Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic makeup and lowering risk of serious adverse events. Anticancer drug sensitivity prediction in cell lines from. See commentary consistency in large pharmacogenomic studies in nature.
Two large scale pharmacogenomic studies were published recently in this journal. Review article scientific challenges and implementation. Recently, two large scale pharmacogenomic studies screened multiple anticancer drugs on over cell lines in an effort to elucidate the response mechanism of anticancer drugs. The curated and structured aspects of our package make it easy to compare largescale pharmacogenomic studies. In this exciting and highly interdisciplinary field we welcome studies of high quality research. Data sharing and research reproducibility in pharmacogenomics benjamin haibekains princess margaret cancer centre university health network university of toronto ontario institute of cancer research 2 open postdoc positions. With reduced risk of toxicity and high selectivity, covalent smallmolecule kinase inhibitors cskis have emerged rapidly. Inconsistency in large pharmacogenomic studies request pdf. Background in 2012, two large pharmacogenomic studies, the genomics of drug sensitivity in cancer gdsc and cancer cell line encyclopedia ccle, were published, each reported gene expression data and measure of drug response for a large number of drugs and hundreds of cell lines. Pdf in 20, we published a comparative analysis of mutation and gene expression profiles and drug sensitivity measurements for 15 drugs characterized. As of june 2019, there are 2 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels.
We created the genomics of drug sensitivity in bladder cancer gdbc database, an integrated database db to facilitate the genomic understanding of bladder cancer in. Dec 19, 20 cancer cell line studies have long been used to test efficacy of therapeutic agents and to explore genomic factors predictive of response 1,2. The case study will investigate the consistency between the gdsc and ccle datasets, recreating the analysis similar to our in consistency in large pharmacogenomic studies paper 4. For showing inconsistency of ccle and gdsc data sets, key factors like aspects or, methods or, sources discussed by different papers have been summarized here. In 2012, two large pharmacogenomic studies, the genomics of drug sensitivity in cancer gdsc and cancer cell line encyclopedia ccle, were published, each reported gene expression data and measures of drug response for a large number of drugs and hundreds of cell lines. Recent progress in clinical therapeutics has led to the discovery of new biomarkers that make it technically easier to identify groups of patients which are more or. Inconsistency in large pharmacogenomic studies by benjamin haibekains, nehme elhachem, nicolai juul birkbak, andrew c. Pharmacogenetics and pharmacogenomics covers all aspects of genetic variation that is of potential relevance for the way drugs or other xenobiotic substances act on the body, and for the way the body acts on drugs, including basic research, clinical translation and applications in drug development. Therefore, one possible solution to overcome the heterogeneity challenge is a shift from genecentric to pathwaycentric therapies. Assessment of pharmacogenomic agreement europe pmc article.
Two largescale pharmacogenomic studies were published recently in this journal. The nci60 human tumor cell line anticancer drug screen the nci60 project started in the late 1980s, and is the first kind of such efforts. In particular, transcriptional signatures of drug sensitivity may guide drug repositioning, prioritize drug combinations, and point to new therapeutic. Revisiting inconsistency in large pharmacogenomic studies biorxiv. Identification of drug targets and mechanism of action moa for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Cancer cell line studies have long been used to test efficacy of therapeutic agents and to explore genomic factors predictive of response. We present here two case studies exploring drug sensitivity and perturbation datasets using pharmacogx. Haibekains b1, elhachem n2, birkbak nj3, jin ac4, beck ah5, aerts hj6, quackenbush j7. Pharmacogenomics is the study of the role of the genome in drug response. The full code is provided in supplementary material. The study of pharmacogenetics and pharmacogenomics focuses on how our genes and complex gene systems influence our response to drugs. Pdf revisiting inconsistency in large pharmacogenomic studies.
Pdf revisiting inconsistency in large pharmacogenomic. The curated and structured aspects of our package make it easy to compare large scale pharmacogenomic studies. To seek cancer biomarkers that predict sensitivity to therapeutic agents, large pharmacogenomic studies have been performed. Current moa prediction largely relies on prior information including side effects, therapeutic indication, and chemoinformatics. Results from two largescale pharmacogenomic studies, the cancer genome project cgp. Recently, the technology for identifying individualspecific genetic variants genotyping has become more. Table 4 summarizes the various studies, which support the inconsistency of the large pharmacogenomic studies. Genebased medicine will help create more effective treatments for large patient subpopulations and is currently being used in practice to treat individual patients. We will describe how to fully reproduce the figures and tables reported in the main manuscript. Two largescale pharmacogenomic studies were published recently 3,4. Manual search was then applied to match any remaining cell lines or drugs. Cancer cell line studies have long been used to test efficacy of therapeutic agents and to explore genomic factors predictive of response 1,2. Genomic heterogeneity in human cancers complicates genecentric personalized medicine. Pharmacogenomicguided drug therapy for patient is based on the premise that a large portion of interindividual variability in drug response e cacy andor toxicity is genetically determined.
Code for revisiting inconsistency in large pharmacogenomic studies full reproducibility of the analysis results. To this aim, we here used gene expression features and drug sensitivity data in cancer cell line encyclopedia ccle to build a predictor based on support vector. Revisiting inconsistency in large pharmacogenomic studies read the latest article version by zhaleh safikhani, petr smirnov, mark freeman, nehme elhachem, adrian she, quevedo rene, anna goldenberg, nicolai j. In 20, we published a comparative analysis that reported gene expression profiles for the 471 cell lines. Jan 09, 2014 research highlights research highlights 20140109 00. Pharmacogenomics aims to study the relationship between an individuals genotype and drug response. Pathwaycentric perspectives, which underscore the need to understand.
Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development. Revisiting inconsistency in large pharmacogenomic studies version 3. Inconsistency in large pharmacogenomic studies core. The top of the figure shows the method of synthetic lethality screening in yeast, using a query strain to mate with the genedeficient strains. To this aim, we here used gene expression features and drug sensitivity data in cancer cell line encyclopedia ccle to build a predictor based on. Not enough sensitive cell lines were screened in both studies to robustly assess consistency for three other targeted drugs. Despite major advances, we are still far from being able to precisely predict drug. Pharmacogenomics is the branch of science concerned with the identification of the genetic attributes of an individual that. Revisiting inconsistency in large pharmacogenomic studies ncbi. Sep 16, 2016 revisiting inconsistency in large pharmacogenomic studies article pdf available in f research 5.