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Nick-Thomas.Pdf Innovating Pre-Clinical Drug Development Towards an Integrated Approach to Investigative Toxicology in Human Cell Models Nick Thomas PhD Principal Scientist Cell Technologies GE Healthcare ELRIG Pharmaceutical Flow Cytometry & Imaging 2012 10-11th October 2012, AstraZeneca, Alderley Park Drug Toxicology Current issues – problems & solutions Using animal models to reflect Quality and robustness of Testing multiple endpoints human responses toxicity cell models leading to false-positives • animals ≠ humans • scarcity of primary cells/tissues • multiple testing increases • animal ≠ animal • source variability sensitivity at cost of specificity • cross species testing may • more abundant models • different assay combinations increase sensitivity but (immortalized/genetically yield varying predictivity decrease specificity engineered cells) may have • testing multiple endpoints leads • metabolism & MOA ? reduced predictivity to false positives Sensitivity Specificity Assay Combinations Integrate range of predictive Integrate robust human stem Integrate and standardize human cell models cell derived models most predictive parameters Cytiva™ Cardiomyocytes H7 hESC Cardiomyocytes 109 Expansion Differentiation 0 5 10 15 20 25 30 Media 1 Media 2 Growth Factors Feed Cytiva Cardiomyocytes DNA Troponin I DNA Connexin 43 Troponin I HCA Biochemical Assays Patch Clamp Impedance Multi-Electrode Arrays Respiration HCA Biochemical Assays Patch Clamp Impedance Multi-Electrode Arrays Respiration Cardiotoxicity Profiling of Anticancer Drugs Cytiva Cardiomyocytes & IN Cell Analyzer Cardiotoxicity & Anticancer Drugs Drug Pipelines Toxicity in Drug Development Hepatotoxicity Nephrotoxicity Cardiotoxicity Rhabdomyolysis Other Data from: Drug pipeline: Q411. Mak H.C. 2012 Data from; Wilke RA et al. Nature Reviews Drug Discovery Nature Biotechnol. 30,15 2007 6, 904-916 Cardiotoxicity of Anticancer Drugs Off Target On Target : Off Therapy DOX GATA4 ROS Bcl2 Cell Death Adapted from; Kobayashi S. et.al. FASEB Journal. 2006;20:800-802 Adapted from; Hansel et.al. Nature Reviews Drug Discovery 2010 ;9 325 Small molecules Biologics Cancer & Cardiotoxicity Overlapping Cardiac Signalling & Oncology Targets GSK3 Hypertrophic AKT Cell Proliferation Stimuli RTK PLK JNK Pathological NFAT Stimuli [Ca2+] Hypertrophy GSK3 Physiological PI3K Stimuli RTK AKT mTOR AMPK Autophagy LKB Energy Stress AKT PI3K BAD Cell Death Growth Factors RAF MEK1 RAS ERK Adapted from; Force T & Kolaja K.L. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. 2011; Nature Reviews Drug Discovery 10, 111-126 Cancer & Cardiotoxicity Tyrosine kinase inhibitors Drug TK Target Indications Cardiotoxicity Imatinib Bcr-Abl, c-kit, PDGFR CML, PhALL, GIST, CHF, LVEF depression CMML, CEL, DFSP Dasatinib Bcr-Abl, c-kit, PDGFR, Src CML QT prolongation, Peripheral oedema Nilotinib Bcr-Abl, c-kit, PDGFR CML QT prolongation Sunitinib VEGFR, RET, PDGFR, c-kit RCC, GIST Hypertension, LVEF depression, CHF, MI Sorafenib VEGFR, c-kit, PDGFR, FLT3, RAF1 RCC, HCC Acute coronary syndrome, MI, Hypertension Lapatinib EGFR, ERBB2 Breast Ca Asymptomatic LVEF depression Gefitinib EGFR NSCLC Not reported Erlotinib EGFR NSCLC, Ca pancreas Not reported Data from: Orphanos G.S. et.al. Cardiotoxicity induced by tyrosine kinase inhibitors 2009; Acta Oncologica, 48: 964-970 Cardiotoxicity assay compounds Oncology focus Compound Target Compound Target Amiodarone (+ve control) K+ Channel/Adrenergic Nifedipine (-ve control) Ca2+ Channel Dasatinib (Sprycel) Tyrosine Kinase NVP-BEZ235 PI3K Tasocitinib Tyrosine Kinase PIK 90 PI3K Pazopanib (Votrient) Tyrosine Kinase LY 294002 PI3K Axitinib Tyrosine Kinase SB 202190 p38 Mubritinib Tyrosine Kinase VX 702 p38 Tyrphostin AG1478 Tyrosine Kinase Rapamycin mTOR Vandetanib (Zactima) Tyrosine Kinase Temsirolimus mTOR Vatalanib Tyrosine Kinase PD 98059 MEK1 Sorafenib (Nexavar) Tyrosine Kinase PD 325901 MEK1 Sunitinib (Sutent) Tyrosine Kinase PD 184352 MEK1 Lapatinib (Tyverb) Tyrosine Kinase U 0126 MEK1 Imatinib (Gleevec) Tyrosine Kinase Pimecrolimus FKBP-12 GECT-Y Tyrosine Kinase Entinostat HDAC Functional Cardiotoxicity Disruption of cellular integrity Membrane Integrity Dissipation of gradients, organelle disruption, loss of homeostasis………. 75% Biochemical Integrity Disruption of signal transduction, synthesis, metabolism, cytoskeletal machinery……….. Cardiotoxicity Assay Workflow High-throughput, high-content cell imaging Compounds Probes Cytiva Imaging Image Analysis Data Analysis Cardiomyocytes Cardiotoxicity Assay Workflow High-throughput, high-content cell imaging Cardiomyocytes Cytiva Cardiomyocytes, live-cell assay in 384-well plates Compounds* 7 doses; n=3 replicate wells; 24h, 48h, 72h pre-incubations Fluorescent probes 4 Fluors: Hoechst, TMRM, TOTO-3, Fluo-4 Imaging IN Cell Analyzer 2000, large-chip CCD camera, 40x/0.6NA objective Image Analysis IN Cell Investigator – MTA & Developer : 19 Parameters o 2 Analysis & IN Cell Investigator – Spotfire DecisionSiteTM Visualization *Compounds blinded until data analysis completed Cytiva Cardiotoxicity Assay Control Amiodarone DNA Mitochondria Ca2+ Vatalanib 1.24μM 11.0μM 33.0μM 72 hours DNA Mitochondria Ca2+ Dose response data Nifedipine (-ve control) 4/19 parameters 72 hours Amiodarone (+ve control) Mitochondrial Count Viability Mitochondrial Form Factor Cell Calcium Cardiotoxicity Assay Multi-parameter Phenotypic Profiling -ve Nifedipine Sunitinib Tasocitinib +ve Amiodarone Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Data Profiling Assay reproducibility Nifedipine (n=3) Amiodarone (n=3) Nifedipine (n=3) Amiodarone (n=3) 1.24μM 33.0μM Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Data Profiling Screen reproducibility Nifedipine Amiodarone 0.05μM 1.24μM 33.0μM Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Screen 1 Screen 2 Profiling Anti-Cancer Drugs Tyrosine kinase inhibitors Axitinib Tascotinib Vandetanib Sunitinib Imatinib GECT-Y Drug Concentration Data Profiling Entinostat (HDAC) PD 325901 (MEK1) 33.0μM – mitochondrial count and Δ[Ca2+] 33.0μM – Δ[Ca2+] only Lapatinib (TK – EGFR/HER2) Imatinib (TK – PDGFR/KIT) 2+ 33.0μM – Mitochondrial count, morphology & 33.0μM – Δ[Ca ], mitochondrial count, viability morphology & viability Selected Tyrosine Kinase Inhibitors Range of MOAs Pazopanib GECT-Y Sunitinib Imatinib Lapatinib Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability 1.24μM no effect 1.24μM ∆ [Ca2+] 1.24μM ∆ [Ca 2+] 1.24μM ∆ [Ca2+] 1.24μM ∆ [Ca2+] 33.0μM small ∆ [Ca2+] 33.0μM ∆ [Ca2+] and loss of 33.0μM ∆ [Ca2+], changes 33.0μM ∆ [Ca2+], changes 33.0μM changes in viability in mitochondrial in mitochondrial mitochondrial morphology morphology and loss of morphology and loss of and loss of viability viability viability SOM Clustering 72h all compounds @ 1.24μM 6 5 4 3 1 2 Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability SOM Clustering 72h all compounds @ 33.0μM 6 5 4 3 1 2 Mitochondrial Integrity Calcium Viability Mitochondrial Integrity Calcium Viability Clustering of Anti-Cancer Drugs Classification by automated profile matching Compound Cluster Compound Cluster Nifedipine 1 Entinostat 4 Tasocitinib 1 LY 294002 4 Axinitib 2 NVP-BEZ235 4 Mubritinib 2 PIK 90 4 Pazopanib (Votrient) 2 SB 202190 4 PD 98059 2 Dasatinib (Sprycell)* 5 Tyrphostin 2 PD 184352 5 U 0126 2 Amiodarone* 6 VX 702 2 Imatinib (Gleevec)* 6 GECT-Y 3 Lapatinib (Tyverb)* 6 PD 325901 3 Rapamycin 6 Pimecrolimus 3 Sorafenib (Nexavar)* 6 Vatalanib 3 Sunitinib (Sutent)* 6 Temsirolimus 6 Vandetanib (Zactima) 6 *Reported Clinical Cardiotoxicity Glucose & Galactose Media Modulation of Bioenergetics and Toxicity Cells cultured in glucose can substitute glycolysis for mitochondrial oxidative phosphorylation Culture in galactose media forces cells to use mitochondrial metabolism Culture in galactose media may detect mitochondrial toxicity not observed in glucose media Antimycin A Cytochrome C Reductase Viability and Mitochondrial Integrity +ve Δ Δ -ve Antimycin A Toxicity sensitised at all concentrations at 24 & 72h Mitochondria Calcium V Mubritinib Toxicity sensitised >0.05μM at 24 & 72h Mitochondria Calcium V Sorafenib Toxicity sensitised at >3.7μM at 24 & 72h Mitochondria Calcium V Imatinib No sensitisation; equal toxicity in both media Mitochondria Calcium V Sunitinib No sensitisation; equal toxicity in both media Mitochondria Calcium V Dasatinib Sensitisation at ≥0.05μM at 72h Mitochondria Calcium V Mubritinib (TAK-165) Irreversible ErbB-2 RTK inhibitor 1.24μM Amiodarone Mubritinib Ch 3, mito form factor_mean (Mean) Ch 3, mito form factor_mean (Mean) 0.05μM 100μM Glucose Galactose Cellular Bioenergetics Seahorse XF24 ECAR:OCR [ATP IC20] Mubritinib (TAK-165) Irreversible ErbB-2 RTK inhibitor Further data under analysis Extension of compound set to >100 Complementary data; impedance, biochemistry and bioenergetics Mitochondrial function and apoptosis protein biomarkers Data integration & PBPK modelling, incorporating clinical pharmacology Integrated Cardiotoxicity Assessment Medicinal Liability Reduction Chemistry HCA Data TOX MOA EC50 EPhys Data PBPK Therapeutic index Stem Cell Models in Toxicology Vision for future development Connectivity in cell models Integration of interrogation methods Structural Comprehensive
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