+ Epigenetic Regulation of Drug Metabolism Amber Frick, PharmD November 19, 2013...

+Epigenetic Regulation of Drug Metabolism

Amber Frick, PharmDNovember 19, 2013adfrick@email.unc.edu

+Pharmacogenomics

+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?

+SLCO1B1 Association with Myopathy

SEARCH Collaborative Group. N Engl J Med 2008;359

SLCO1B1

Estimated Cumulative Risk of Myopathy

+Epigenetics TEDx and RadioLab

+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

+Epigenetic Mechanisms Affect Health

+Epigenetic Mechanisms Affect Drug Response

Kacevska M, et al. Pharmacogenomics 2012;13.

+Epigenetic Machinery

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

+DNA Methylation

+Fifth Base of the Genome

DNMT1

Read A, and Donnai D. New Clinical Genetics. Bloxham UK: Scion Publishing Ltd, 2007.

+Sixth Base of the Genome

Branco MR, et al. Nature Reviews Genetics 2012;13.

+Aberrant DNA Methylation in Cancer

Wright J. Nature 2013;498.

+Aberrant DNA Methylation in Cancer

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

+On-Off Switch for Genes

Ingelman-Sundberg M, et al. Drug Metabolism and Disposition 2013;41.

+Epigenetic Regulation of ADME Genes

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

+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

+Methylation of GSTP1

Rønneberg JA, et al. Cancer Res 2008;68.

+DNMT Inhibitors

Azacitadine Decitadine

+Histone Modification

Arrowsmith CH, et al. Nature Reviews 2012;11.

+Histone Modification

+HDAC and CYP3A4

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

+HDAC Inhibitors

Vorinostat

Romidepsin

Arrowsmith CH, et al. Nature Reviews 2012;11.

+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

+miRNAs and Drug Metabolism

Kacevska M, et al. Pharmacogenomics 2012;13.

+miRNAs and Drug Sensitivity

Kacevska M, et al. Pharmacogenomics 2012;13.

+Pleiotropic Effects of Non-Epigenetic Drugs

Lotsch J. Trends in Molecular Medicine 2013.

+Pleiotropic Effects of Non-Epigenetic Drugs

Lotsch J. Trends in Molecular Medicine 2013.

+Specificity of Epigenetic Agents

Dawson MA, Kouzarides. Cell 2012;150.

EPZ004777*IC50 pM Range

*

Arrowsmith CH, et al. Nature Reviews 2012;11.

+Specificity of Epigenetic Agents

Compound 6J *IC50 1 μM

*

Arrowsmith CH, et al. Nature Reviews 2012;11.

+Specificity of Epigenetic Agents

+Epigenetic Targets

Dawson MA, Kouzarides. Cell 2012;150.

+Full Drug Pipeline

+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.

+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?

+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?

+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?

+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?

+Questions, Comments, Suggestions, or Constructive Criticism?