Integrating pharmacogenomics into pharmacy practice via. 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. 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. Download fulltext pdf revisiting inconsistency in large pharmacogenomic studies article pdf available in f research 5. In 2012, two large pharmacogenomic studies, the genomics of drug.
As of june 2019, there are 2 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels. 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. Pharmacogenomic and pharmacogeneticguided therapy as a tool in precision medicine. Despite the widespread recognition of the scienti c rationale and the clinical implementation of pharmacogenomic tests at several major academic medical. Therefore, one possible solution to overcome the heterogeneity challenge is a shift from genecentric to pathwaycentric therapies. Manual search was then applied to match any remaining cell lines or drugs.
We automated the analysis pipeline so that minimal manual interaction is required to reproduce our results. Recently, two largescale pharmacogenomic studies screened multiple anticancer drugs on over cell lines in an effort to elucidate the response mechanism of anticancer drugs. Evaluating the consistency of largescale pharmacogenomic studies. Pdf pharmacogenomics holds great promise for the development of. The curated and structured aspects of our package make it easy to compare large scale pharmacogenomic studies. Such information is not transferable or applicable for newly identified, previously. Consistency in large pharmacogenomic studies nature. In 20, we published a comparative analysis that reported gene expression profiles for the 471. Pathwaycentric perspectives, which underscore the need to understand. Table 4 summarizes the various studies, which support the inconsistency of the large pharmacogenomic studies. Assessment of pharmacogenomic agreement europe pmc article.
Consequently, more than 200 anticancer drugs are available on the market. 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. Two large scale pharmacogenomic studies were published recently 3,4. Cellline selectivity improves the predictive power of. Pharmacogenomics is the study of the role of the genome in drug response. We present here two case studies exploring drug sensitivity and perturbation datasets using pharmacogx.
Two largescale pharmacogenomic studies were published recently in this journal. 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. We will describe how to fully reproduce the figures and tables reported in the main manuscript. The synthetic lethal interactions can be screened by measuring the colony size. 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.
Largescale pharmacogenomics studies in which experimental and. To seek cancer biomarkers that predict sensitivity to therapeutic agents, large pharmacogenomic studies have been performed. Development of the theta comparative cell scoring method to. Bladder cancer has numerous genomic features that are potentially actionable by targeted agents. 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. 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. Revisiting inconsistency in large pharmacogenomic studies article pdf available in f research 5. Cancer cell line studies have long been used to test efficacy of therapeutic agents and to explore genomic factors predictive of response. 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. Haibekains b, elhachem n, birkbak nj, et al inconsistency in large pharmacogenomic studies. Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic makeup and lowering risk of serious adverse events. 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. Recently, the technology for identifying individualspecific genetic variants genotyping has become more.
Cancer cell line encyclopedia consortium, genomics of drug sensitivity in cancer consortium. Inconsistency in large pharmacogenomic studies europe pmc. Among the most common are the cytochrome p450 cyp genes, encoding enzymes that control the metabolism of more than 70 percent of prescription drugs. Genes commonly involved in pharmacogenomic drug metabolism and response there are several genes responsible for differences in drug metabolism and response. 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. The curated and structured aspects of our package make it easy to compare largescale pharmacogenomic studies. Current moa prediction largely relies on prior information including side effects, therapeutic indication, and chemoinformatics. 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. Sep 16, 2016 revisiting inconsistency in large pharmacogenomic studies article pdf available in f research 5. Revisiting inconsistency in large pharmacogenomic studies biorxiv. Pdf in 20, we published a comparative analysis of mutation and gene expression profiles and drug sensitivity measurements for 15 drugs characterized. Pathwaycentric perspectives, which underscore the need to understand key.
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. Despite major advances, we are still far from being able to precisely predict drug. Revisiting inconsistency in large pharmacogenomic studies version 3. Anticancer drug sensitivity prediction in cell lines from. Inconsistency in large pharmacogenomic studies core. With reduced risk of toxicity and high selectivity, covalent smallmolecule kinase inhibitors cskis have emerged rapidly. 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. In our initial comparative study we found that the majority of known biomarkers. Adverse drug reactions adrs are discussed in depth in chapter 5, although this chapter will also discuss adrs related to genetic polymorphisms. Nov 27, 20 two large scale pharmacogenomic studies were published recently in this journal.
This file shows a summary of the results reported with the supplementary data of cgp and ccle for. Review article scientific challenges and implementation. 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. In this exciting and highly interdisciplinary field we welcome studies of high quality research. Towards pathwaycentric cancer therapies via pharmacogenomic. Revisiting inconsistency in large pharmacogenomic studies. Principles of pharmacogenetics and pharmacogenomics edited by. Not enough sensitive cell lines were screened in both studies to robustly assess consistency for three other targeted drugs. Dec 19, 20 inconsistency in large pharmacogenomic studies. Inconsistency in large pharmacogenomic studies by benjamin haibekains, nehme elhachem, nicolai juul birkbak, andrew c. Case studies in pharmacogenetics mike pacanowski, pharmd, mph office of clinical pharmacology center for drug evaluation and research pediatric advisory committee. 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. Inconsistency across large pharmacogenomic studies. Inconsistency in large pharmacogenomic studies nature.
Two large scale pharmacogenomic studies were published recently in this journal. We confirmed that spearman rank correlation, used in our 20 study, does not detect consistency for the three targeted therapies profiled by. 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. Identification of drug targets and mechanism of action moa for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Aerts and john quackenbush no static citation data no static citation data cite. Research highlights research highlights 20140109 00. Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development.
We downloaded, curated, and annotated the genomic and. 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 ncbi. Pdf revisiting inconsistency in large pharmacogenomic studies. Progress with covalent smallmolecule kinase inhibitors. 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. 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. Inconsistency in large pharmacogenomic studies request pdf. Pharmacogenomics analyzes how the genetic makeup of an individual affects hisher response to drugs. Nov 30, 2016 consistency in large pharmacogenomic studies. Gene expression data were downloaded from the ccle website and.
Pubmed abstract publisher full text free full text. The top of the figure shows the method of synthetic lethality screening in yeast, using a query strain to mate with the genedeficient strains. Pharmacogenomics aims to study the relationship between an individuals genotype and drug response. Pharmacogenomic agreement between two cancer cell line data sets.
This system is used for most genes with welldefined. In 20, we published a comparative analysis that reported gene expression profiles for the 471 cell lines. Pharmacogenomic studies pharmacogenomics uses genomewide approaches to elucidate the inherited basis of differences between persons in the response to drugs. Results from two largescale pharmacogenomic studies, the cancer genome project cgp. Such information is not transferable or applicable for newly identified, previously uncharacterized small. The full code is provided in supplementary material. Code for revisiting inconsistency in large pharmacogenomic studies full reproducibility of the analysis results. Nov 27, 20 inconsistency in large pharmacogenomic studies.
Aug 11, 2017 read the original article in full on fresearch. 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. 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. Cancer cell line studies have long been used to test efficacy of therapeutic agents and to explore genomic factors predictive of response 1,2. See commentary consistency in large pharmacogenomic studies in nature. Principles of pharmacogenetics and pharmacogenomics edited. The study of pharmacogenetics and pharmacogenomics focuses on how our genes and complex gene systems influence our response to drugs. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to targetbased and immunerelated therapies. Inconsistency in large pharmacogenomic studies, nature 10. Inconsistency in large pharmacogenomic studies github. We downloaded, curated, and annotated the genomic and pharmacological data. Jan 09, 2014 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. Jul 28, 2015 genomic heterogeneity in human cancers complicates genecentric personalized medicine.
Encircling the regions of the pharmacogenomic landscape that. Mar 24, 2011 pharmacogenomic studies pharmacogenomics uses genomewide approaches to elucidate the inherited basis of differences between persons in the response to drugs. Inconsistency in large pharmacogenomic studies abstract. 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. Integrative cancer pharmacogenomics to infer largescale drug. Lessons learned from two decades of anticancer drugs. Pdf revisiting inconsistency in large pharmacogenomic.
Malignant tumors often share a core group of pathways that are perturbed by diverse genetic mutations. Assessment of pharmacogenomic agreement europe pmc. Genebased medicine will help create more effective treatments for large patient subpopulations and is currently being used in practice to treat individual patients. Nov 27, 20 two largescale pharmacogenomic studies were published recently in this journal. Pharmacogenomics is the branch of science concerned with the identification of the genetic attributes of an individual that. 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. Genomic heterogeneity in human cancers complicates genecentric personalized medicine.
Two largescale pharmacogenomic studies were published recently 3,4. Inconsistency in large pharmacogenomic studies ncbi nih. Nevertheless, both preclinical and clinical research using molecular targeted agents have been very limited in bladder cancer. 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. 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. Integrating heterogeneous drug sensitivity data from cancer. Haibekains b1, elhachem n2, birkbak nj3, jin ac4, beck ah5, aerts hj6, quackenbush j7.