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Pharmacogenomics Howard Mcleod, Pharm.D NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Pharmacogenomics March 23, 2010 Howard L. McLeod Eshelman Distinguished Professor and Director Institute for Pharmacogenomics and Individualized Therapy (IPIT) UNC – Chapel Hill, NC “A surgeon who uses the wrong side of the scalpel cuts her own fingers and not the patient; if the same applied to drugs they would have been investigated very carefully a long time ago” Rudolph Bucheim Beitrage zur Arzneimittellehre, 1849 1 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. All patients with same diagnosis All patients with same diagnosis 2 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. All patients with same diagnosis Alternate therapy non-responders and toxic responders The clinical problem • Multiple active regimens for the treatment of most diseases • Variation in response to therapy • Unpredictable toxicity $$ $ $ $ $ $ $ $ $ $ $ $ With choice comes decision 3 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Pharmacogenomic examples-2010 • bcr/abl or 9:22 translocation—imatinib mesylate* • HER2-neu—trastuzumab** • C-kit mutations—imatinib mesylate** • Epidermal growth factor receptor mutations—gefitinib • Thiopurine S-methyltransferase—mercaptopurine and azathioprine* • UGT1A1-irinotecan** • CYP2D9/VKORC1-warfarin* • HLA-B*5701-abacavir * • HLA-B*1502-carbamazepine * • CYP2C19-clopidogrel • Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists, antidepressants, ADHD drugs, and codeine derivatives, tamoxifen* 4 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. What needs to be done to determine hope vs hype? • Find the 'right' biomarkers • Validate in robust datasets • Apply them! We do not know very much about drugs Irinotecan cell membrane ABCB1 ???? Irinotecan ???? ???? CES1 CYP3A4 APC Irinotecan CES2 CYP3A5 NPC CES1 ???? CES2 SN-38 ???? UGT1A1 ???? SN-38 ???? ???? SN-38G ABCB1 ???? ABCG2 ABCC1 ???? ABCC2 ???? SN-38 TOP1 ???? ???? ADPRT ???? ???? XRCC1 ???? TDP1 ???? NFKB1 ???? ???? CDC45L Cell Death 5 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. HapMap Linkage Model systems Discovery Strategies cases controls Expression array Association Centre d’ Etude du Polymorphisme Human (CEPH) Cell lines • Large, multigeneration pedigrees widely studied • Immortalized lymphoblastoid cell lines 6 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Methodology Cells counted, plated at 1 x 104 / well Cells incubated with increasing concentrations of drug Alamar blue vital dye indicator added Viability relative to untreated control calculated by spectrophotometry Significant Variation in Cellular Sensitivity to Docetaxel 7 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. 'CE-PH/F-DA' project 126 CEPH cell lines from 14 nuclear families All FDA approved cytotoxic drugs + new kinase inhibitors/MTOR/demethylation No antiestrogen or vitamin A analogues Evaluate degree of heritability, presence of QTL(s), and evidence for correlations between drug sensitivity patterns. HapMap Linkage Model systems Discovery Strategies cases controls Expression array Association 8 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Mammalian Genome 13:175, 2002 Nature Genetics 36:1133, 2004 A/J C57BL6 129S1 NOD NZO PWK CAST WSB Representative CC genome 9 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. What needs to be done to determine hope vs hype? • Find the 'right' biomarkers • Validate in robust datasets • Apply them! Correlative science: business as usual Phase I Phase II Phase III In vivo Biomarker Biomarker Mechanism assessment validation 10 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. 2010 Estimated US Cancer Cases* Men Women C90401; n=1020 C40101; 32% Breast n=4646 Prostate 33% 710,040 662,870 12% Lung and bronchus Lung and bronchus 13% C30502; n=270 C30502; 11% Colon n=270 and rectum Colon and rectum 10% 6% Uterine corpus C80203/80405;Urinary bladder n=2200 7% C80203/80405; 4% Non-Hodgkin n=2200 lymphoma Melanoma of skin 5% 4% Melanoma of skin Non-Hodgkin 4% C50303; 3% Ovary n=430 lymphomaC50303; n=430 3% Thyroid Kidney 3% 2% Urinary bladder 2% Pancreas Leukemia 3% C10105; MDS 21% All Other Sites Oral Cavity 3% Pancreas 2% C80303; n=528 All Other Sites 17% C80303; n=528 C80101 gastric; n=800 *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2005. Docetaxel vs. Paclitaxel (Clinical data: SCOTROC1) Accrual of 1077 Pts With: • Stage IC-IV epithelial ovarian cancer • ECOG PS 0-2 • No prior history of CT or RT RANDOMISATION Docetaxel 75 mg/m2 1-hr IV, followed Paclitaxel 175 mg/m2 3-hr IV, followed by by Carboplatin AUC 5* IV Carboplatin AUC 5* IV Repeat q 3 wk for up to 6 cycles Repeat q 3 wk for up to 6 cycles Study End Points Primary: progression-free survival Secondary: response rate, overall survival, toxicity, QOL Sarah McWhinney, Alison Motsinger-Reif, Sharon Marsh, Bob Brown, Jim Paul 11 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Docetaxel vs. Paclitaxel (Clinical data: SCOTROC1) Progression-free survival Overall survival Vasey et al JNCI 2004 Docetaxel vs. Paclitaxel (Clinical data: SCOTROC1) Vasey et al JNCI 2004 12 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Genetics: Biology: Inherited Pharmacology: Nerve function neuropathies Drug Action Genes Chemotherapy SNPs (tag + function) Neurotoxicity: Candidate Gene Illumina Approach GoldenGate™ SNP Array The filtering of Neuro-risk genotypes Quality Assessment 1261 SNPs SNPs Significantly Associated in Test cohort 69 SNPs SNPs Significantly Associated in Validation cohort 5 SNPs Consistent direction of genetic risk 4 SNPs Figure 1: The workflow of the data analysis, represented by the narrowing number of SNPs at each stage of the analysis. 13 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. What needs to be done to determine hope vs hype? • Find the 'right' biomarkers • Validate in robust datasets • Apply them! Biomarker-driven studies Phase I Phase II Phase III Nothing In vivo Biomarker Biomarker Mechanism assessment validation 14 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. 4- h y d r o x y : 3, 4 - h y d r o x y : po t e n t - an t a g o n i s t po t e n t - an t a g o n i s t >1 0 0 % re l . to E2 10 0 % re l . to E2 H3 C O H3 C O N N Tamoxifen H3 C H3 C Metabolism H O H O O H CYP3A4 CYP2D6 4-hydroxy, N-desmethyl: CY P 2 C 9 CY P 2 C 1 9 potent - antagonist CYP2D6 100%rel. to E2 CY P 3 A 4 H C H C 3 O 3 O N N H C H3 C 3 Endoxifen CY P 3 A 4 H O Ta m o x i f e n : CY P 2 C 9 pa r t i a l - a n t a g o n i s t 1% re l . to E2 CY P 2 D 6 O O H O H2C O H O H N H2 N H3 C N- d e s m e t h y l : N- d i d e s m e t h y l : Me t a b o l i t e Y: Me t a b o l i t e E: pa r t i a l - a n t a g o n i s t pa r t i a l - a n t a g o n i s t pa r t i a l - a g o n i s t fu l l ag o n i s t 1% re l . to E2 <1 % re l . to E2 1% re l . to E2 ?% re l . to E2 CYP2D6 variant genotype and CYP2D6 inhibitors lower [Endoxifen] Jin Y, Desta Z, et al, JNCI January, 2005 N = 80 15 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Adjuvant Tamoxifen and CYP2D6 CYP2D6 associated with recurrence – Goetz et al. 2005, 2007 (USA) – Schroth et al. 2007 (Germany) – Kiyotani et al. 2008 (Japan) – Newman et al. 2008 (UK) – Xu et al. 2008 (China) – Okishiro et al. 2009 (Japan) – Ramon et al. 2009 (Spain) – Bijl et al. 2009 (Netherlands) CYP2D6 not associated with recurrence – Wegman et al. 2005, 2007 (Sweden) – Nowell et al. 2005 (USA) Relapse-free Survival 100 80 EM 60 2-year RFS % EM 98% IM 40 IM 92% PM 68% PM 20 Log Rank P=0.009 0 0 2 4 6 8 10 12 Years after randomization CP1229323-16 Goetz et al. Breast Cancer Res Treat. 2007 16 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. Hypothesis: Increasing tamoxifen dose will ‘overcome’ metabolic resistance Endoxifen concentratin 3 months 6 months Hypothesis: Increasing tamoxifen dose will ‘overcome’ metabolic resistance Endoxifen concentratin 3 months 6 months 17 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D. 5 Stages of pharmacogenetics progress Denial (and Isolation) Anger Bargaining Depression Acceptance Apologies to Elizabeth KUBLER-ROSS, MD On Death and Dying (1969) Comprehensive optimization of patient care Disease Genotypes Infection Defense Genotypes Toxicity-risk Genotypes Supportive Care Genotypes 18 NHGRI Current Topics in Genome Analysis 2010 March 23, 2010 Week 10: Pharmacogenomics Howard McLeod, Pharm.D.
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