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Abstracts / Toxicology

04-5NA repair pathways as target for cancer therapy

homas Helleday

Karolinska Institutet, Sweden

DNA replication lesions are present in cancer cells owing toncogene expression, hypoxia or defects in the DNA damageesponse or DNA repair. Inhibitors of DNA repair can make theseesions more toxic to cancer cells than normal. One example of thiss the use of PARP inhibitors in BRCA2 tumours, where spontaneousesions underlie the toxicity producing the synthetic lethality.NA lesions produced at replication forks, for instance by manynti-cancer drugs, are significant substrates for homologous recom-ination (HR) repair. Here, different RNAi library screens for RAD51oci and HR activity are presented, as well as our strategy to iden-ify HR inhibitors that can improve anti-cancer treatments. In acreen for novel drugs that selectively kill BRCA2-defective cells, wedentified 6-thioguanine (6TG), which induces DNA double-strandreaks (DSBs) that we show are repaired by HR. Furthermore, wehow that 6TG is as efficient as a PARP inhibitor in selectivelyilling BRCA2-defective tumours in a xenograft model. Sponta-eous BRCA1 defective mammary tumours gain resistance to PARP

nhibitors through p-gycoprotein expression. Here, we show thatTG efficiently kills also such BRCA1 defective PARP inhibitor resis-ant tumours.

oi:10.1016/j.toxlet.2012.03.044

5rom mechanisms of toxicity to biomarkers: Addressingurrent and future needs in drug safety assessment

05-1afety biomarkers: Opportunities and challenges in drugiscovery and development

na Schuppe-Koistinen

AstraZeneca, Sweden

The drug development process has a high attrition rate, withoxicity being one of the main reasons for compound developmenteing delayed or stopped. The opportunities for safety biomarkerso improve the drug R&D process are huge. These include enablinghe prediction or early detection of toxicity in the pre-clinical orlinical setting, patient stratification by identifying patients leastikely to show an adverse event and finally to assist problem solv-ng in order to better understand the mechanisms of toxicity andecrease the likelihood of late stage failures.

Many of the currently used safety biomarkers are neither spe-ific nor sensitive enough and lack predictive value. The discoverynd qualification of new safety biomarkers require a large numberf studies with a diversity of compounds and patient populations.urthermore, a link to histopathological changes in the target organnd demonstrated translatability across species including humansas to be demonstrated and regulators require broad scientific con-ensus on new markers qualified for regulatory decision making.his cannot be achieved by a single Pharma company and consortia

ave been set up to facilitate the process.

The SAFE-T consortium, a public–private partnership of Pharma,cademic institutions and small–medium enterprises started underhe EU’s innovative medicines initiative (IMI), aims at qualify-

s 211S (2012) S4–S23 S9

ing safety biomarkers for drug-induced kidney, liver and vascularinjury. The talk describes the consortium’s scientific qualificationstrategy for safety biomarkers and presents the first results of theexploratory phase studies assessing background variability andestablishing initial ROC curves for candidate markers across dif-ferent populations.

doi:10.1016/j.toxlet.2012.03.046

S05-2Pharmacogenomic biomarkers for drug induced liver injury

Eleni Aklillu

Department of Laboratory of Medicine, Karolinska Institutet, Sweden

Drug induced liver injury (DILI) is a common adverse drugreaction in the treatment of several diseases including HIV/AIDSand Tuberculosis. Genetic predisposition is a key mechanism forDILI. Recent genetic studies are focused on drug-metabolizingenzymes, transporters and immunological mediators, such as HLAmolecules and cytokines to identify variant alleles that may serveas biomarkers to predict patient’s susceptibility to DILI uponexposure. Advanced genetic technologies, such as genome-wideassociation studies and next-generation sequencing explore novelgenetic biomarkers such as HLA-B*5701, HLA-DRB1*1501 andUGT1A1*28, as a risk factor for vulnerability DILI. Antiretroviraland anti-tuberculosis chemotherapy associated DILI is a commonand challenging adverse event causing adherence problem, whichmay cause treatment failure. Screening for genetic markers priorto TB and/or HIV treatment may reduce the incidence of adverseevents and improve treatment adherence. Recently we reportedCYP2B6*6, causing high efavirenz plasma concentration, as a riskfactor for DILI in HIV patients from Tanzania and Ethiopia receivingefavirenz based highly active antiretroviral therapy with or without rifampicin based TB therapy. Incidence of DILI varies betweenpopulations and so do the predictors because of variation in thegenetic profile. Further case-control studies employing advancedgenetic technologies are imperative in different ethnic populationsto identify and validate clinically useful specific pharmacogeneticbiomarkers for drug induced adverse events.

doi:10.1016/j.toxlet.2012.03.047

S05-4Current status and future perspectives of mechanism-basedliver safety biomarkers

Daniel Antoine

University of Liverpool, United Kingdom

Drug-induced liver injury (DILI) represents a significant causeof patient morbidity and mortality and is a major contribu-tor to attrition in drug development. Prediction of clinical DILIremains difficult, particularly in cases characterised by markedinter-individual variation. A lack of sensitivity, specificity and anindirect mechanistic basis of currently used markers of hepaticinjury remains a factor for the delayed identification of DILI. Thereis a need to discover, develop and validate new biomarkers inorder to inform better the medicinal chemist and the clinician.

The ideal biomarker is one that is mechanism-based, organ (cell)selective and one that can be used in both the clinic and lab-oratory models. Traditional biomarkers of DILI include leakagemarkers of cell death and markers of hepatic function. Pre-clinical