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Epigenetic Regulation of Drug Metabolism

Epigenetic Regulation of Drug Metabolism. Amber Frick, PharmD November 19 , 2013 adfrick@email.unc.edu. Pharmacogenomics. Pharmacogenomics Case.

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Epigenetic Regulation of Drug Metabolism

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  1. Epigenetic Regulation of Drug Metabolism Amber Frick, PharmD November 19, 2013 adfrick@email.unc.edu

  2. Pharmacogenomics

  3. Pharmacogenomics Case You prescribed simvastatin 80 mg daily to a patient with hyperlipidemia. They return to your office with extreme muscle aches, and you suspect rhabdomyolysis. • Why is the patient experiencing these side effects? • What genetic and/or environmental factors may be involved? • What tests should you perform? • What actions should you take next? • If you were designing a clinical trial for a new statin medication, what would you include in the experimental design?

  4. SLCO1B1 Association with Myopathy Estimated Cumulative Risk of Myopathy SLCO1B1 SEARCH Collaborative Group. N Engl J Med 2008;359

  5. EpigeneticsTEDx and RadioLab

  6. Epigenetics • Changes in gene activity caused by mechanisms other than changes in underlying DNA sequence • Patterns vary between gender, age groups, species, tissue, and cells • Involves a network of layered processes: • DNA methylation • Histone modification • Non-protein coding (nc) RNAs

  7. Epigenetic Mechanisms Affect Health

  8. Epigenetic Mechanisms Affect Drug Response Kacevska M, et al. Pharmacogenomics 2012;13.

  9. Epigenetic Machinery Ivanov M, et al. Clinical Pharmacology and Therapeutics 2012;92.

  10. DNA Methylation

  11. Fifth Base of the Genome DNMT1 Read A, and Donnai D. New Clinical Genetics. Bloxham UK: Scion Publishing Ltd, 2007.

  12. Sixth Base of the Genome Branco MR, et al. Nature Reviews Genetics 2012;13.

  13. Aberrant DNA Methylation in Cancer Wright J. Nature 2013;498.

  14. Aberrant DNA Methylation in Cancer Ivanov M, et al. Clinical Pharmacology and Therapeutics 2012;92.

  15. On-Off Switch for Genes Ingelman-Sundberg M, et al. Drug Metabolism and Disposition 2013;41.

  16. Epigenetic Regulation of ADME Genes Ivanov M, et al. Clinical Pharmacology and Therapeutics 2012;92.

  17. Clinical Relevance of Methylation • GSTP1 methylation and DNA methyltransferase inhibitor treatment of prostate cancer and doxorubicin treatment of breast cancer • UGT1A1 and irinotecan treatment of colon cancer • SLC19A1 and methotrexate treatment of lymphomas • GPx3 and cisplatin treatment of head and neck cancer • VDR and calcitriol treatment of breast cancer

  18. Methylation of GSTP1 Rønneberg JA, et al. Cancer Res 2008;68.

  19. DNMT Inhibitors Azacitadine Decitadine

  20. Histone Modification Arrowsmith CH, et al. Nature Reviews 2012;11.

  21. Histone Modification

  22. HDAC and CYP3A4 Wu Y, et al. Journal of Pharmaceutical and Biomedical Analysis 2012;58.

  23. HDAC Inhibitors Romidepsin Vorinostat Arrowsmith CH, et al. Nature Reviews 2012;11.

  24. Non-protein coding RNAs • Only 2% of the genome encodes protein-coding genes via mRNA transcripts • miRNAs are the most widely studied • Approximately 22 nucleotides in length • Mediate post-transcriptional gene silencing • Regulate the translation of >60% of protein-coding genes • lncRNA targets histone-modifying enzymes to specific genomic loci • DNA methylation and histone modification control miRNA levels

  25. miRNAs and Drug Metabolism Kacevska M, et al. Pharmacogenomics 2012;13.

  26. miRNAs and Drug Sensitivity Kacevska M, et al. Pharmacogenomics 2012;13.

  27. Pleiotropic Effects of Non-Epigenetic Drugs Lotsch J. Trends in Molecular Medicine 2013.

  28. Pleiotropic Effects of Non-Epigenetic Drugs Lotsch J. Trends in Molecular Medicine 2013.

  29. Specificity of Epigenetic Agents * Dawson MA, Kouzarides. Cell 2012;150. EPZ004777 *IC50pM Range Arrowsmith CH, et al. Nature Reviews 2012;11.

  30. Specificity of Epigenetic Agents * Compound 6J *IC50 1 μM Arrowsmith CH, et al. Nature Reviews 2012;11.

  31. Specificity of Epigenetic Agents

  32. Epigenetic Targets Dawson MA, Kouzarides. Cell 2012;150.

  33. Full Drug Pipeline

  34. Pharmacoepigenetics Case 1 CYP2W1 is polymorphic with two major allelic variants (*2 and *6). You find hypomethylation in a set of colon cancer samples. Currently, the chemotherapeutic regimens used to treat colon cancer are not tolerated well with numerous non-specific side effects. • As a drug developer, what therapeutic intervention would you design? • What potential issues may arise in terms of drug-drug interactions? Gomez A, Ingelman-Sundberg M. Clinical Pharmacology & Therapeutics 2009; 85.

  35. Pharmacoepigenetics Case 2 Colorectal cancer cells can be made more sensitive to the effects of 5-fluorouracil with the use of lovastatin via an epigenetic mechanism. • What epigenetic mechanism occurs with the administration of lovastatin? • How would therapy be affected by the co-administration of epigenetics targeting therapies? • How would response be affected by capecitabine administration rather than 5-fluorouracil?

  36. Pharmacoepigenetics Case 3 The HDAC and DNMT inhibitors are given to the patient as long as they benefit from treatment. Given that current epigenetic reversing drugs are highly promiscuous in their drug targets: • What are the likely long-term consequences of epigenetic therapeutic regulation? • How does administration affect expression of drug metabolizing enzymes? • What drug-drug interactions are of concern?

  37. Pharmacoepigenetics Case 3 The HDAC and DNMT inhibitors are given to the patient as long as they benefit from treatment. Given that current epigenetic reversing drugs are highly promiscuous in their drug targets: • What are the likely long-term consequences of epigenetic therapeutic regulation? • How does administration affect expression of drug metabolizing enzymes? • What drug-drug interactions are of concern?

  38. Pharmacoepigenetics Case 4 miRNA therapeutics are gaining momentum. For instance,miR-122 (Miravirsin)is being investigated in hepatitis C and hepatocellular carcinoma. • Would you use miRNA-based therapy to regulate drug sensitivity or modulate drug metabolizing enzymes, drug transporters, and nuclear receptors? • What hurdles must you overcome to develop miRNA-based therapy?

  39. Questions, Comments, Suggestions, or Constructive Criticism?

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