Download Epigenetic Regulation

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Epigenetic
Regulation
of Drug
Metabolism
Amber Frick, PharmD
November 19, 2013
[email protected]
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Pharmacogenomics
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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.
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Why is the patient experiencing these side effects?
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What genetic and/or environmental factors may be involved?
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What tests should you perform?
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What actions should you take next?
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If you were designing a clinical trial for a new statin medication,
what would you include in the experimental design?
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SLCO1B1 Association with
Myopathy
Estimated Cumulative Risk of Myopathy
SLCO1B1
SEARCH Collaborative Group. N Engl J Med 2008;359
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Epigenetics TEDx and RadioLab
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Epigenetics
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Changes in gene activity caused by mechanisms other than
changes in underlying DNA sequence
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Patterns vary between gender, age groups, species, tissue,
and cells
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Involves a network of layered processes:
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DNA methylation
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Histone modification
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Non-protein coding (nc) RNAs
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Epigenetic Mechanisms Affect
Health
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Epigenetic Mechanisms Affect Drug
Response
Kacevska M, et al. Pharmacogenomics 2012;13.
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Epigenetic Machinery
Ivanov M, et al. Clinical Pharmacology and Therapeutics 2012;92.
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DNA Methylation
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Fifth Base of the Genome
DNMT1
Read A, and Donnai D. New Clinical Genetics. Bloxham UK: Scion Publishing Ltd, 2007.
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Sixth Base of the Genome
Branco MR, et al. Nature Reviews Genetics 2012;13.
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Aberrant DNA Methylation in Cancer
Wright J. Nature 2013;498.
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Aberrant DNA Methylation in Cancer
Ivanov M, et al. Clinical Pharmacology and Therapeutics 2012;92.
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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.
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Clinical Relevance of Methylation
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GSTP1 methylation and DNA methyltransferase inhibitor
treatment of prostate cancer and doxorubicin treatment of
breast cancer
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UGT1A1 and irinotecan treatment of colon cancer
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SLC19A1 and methotrexate treatment of lymphomas
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GPx3 and cisplatin treatment of head and neck cancer
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VDR and calcitriol treatment of breast cancer
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Methylation of GSTP1
Rønneberg JA, et al. Cancer Res 2008;68.
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DNMT Inhibitors
Azacitadine
Decitadine
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Histone Modification
Arrowsmith CH, et al. Nature Reviews 2012;11.
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Histone Modification
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HDAC and CYP3A4
Wu Y, et al. Journal of Pharmaceutical and Biomedical Analysis 2012;58.
+ HDAC Inhibitors
Romidepsin
Vorinostat
Arrowsmith CH, et al. Nature Reviews 2012;11.
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Non-protein coding RNAs
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Only 2% of the genome encodes protein-coding
genes via mRNA transcripts
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miRNAs are the most widely studied
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Approximately 22 nucleotides in length
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Mediate post-transcriptional gene silencing
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Regulate the translation of >60% of protein-coding
genes
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lncRNA targets histone-modifying enzymes to
specific genomic loci
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DNA methylation and histone modification
control miRNA levels
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miRNAs and Drug Metabolism
Kacevska M, et al. Pharmacogenomics 2012;13.
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miRNAs and Drug Sensitivity
Kacevska M, et al. Pharmacogenomics 2012;13.
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Pleiotropic Effects of NonEpigenetic Drugs
Lotsch J. Trends in Molecular Medicine 2013.
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Pleiotropic Effects of NonEpigenetic Drugs
Lotsch J. Trends in Molecular Medicine 2013.
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Specificity of Epigenetic Agents
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Dawson MA, Kouzarides. Cell 2012;150.
EPZ004777
*IC50 pM Range
Arrowsmith CH, et al. Nature Reviews 2012;11.
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Specificity of Epigenetic Agents
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Compound 6J
*IC50 1 μM
Arrowsmith CH, et al. Nature Reviews 2012;11.
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Specificity of Epigenetic Agents
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Epigenetic Targets
Dawson MA, Kouzarides. Cell 2012;150.
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Full Drug Pipeline
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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.
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As a drug developer, what therapeutic intervention would you
design?
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What potential issues may arise in terms of drug-drug interactions?
Gomez A, Ingelman-Sundberg M. Clinical Pharmacology & Therapeutics 2009; 85.
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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.
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What epigenetic mechanism occurs with the administration of
lovastatin?
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How would therapy be affected by the co-administration of
epigenetics targeting therapies?
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How would response be affected by capecitabine administration
rather than 5-fluorouracil?
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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:
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What are the likely long-term consequences of epigenetic
therapeutic regulation?
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How does administration affect expression of drug metabolizing
enzymes?
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What drug-drug interactions are of concern?
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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:
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What are the likely long-term consequences of epigenetic
therapeutic regulation?
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How does administration affect expression of drug metabolizing
enzymes?
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What drug-drug interactions are of concern?
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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?
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Questions, Comments,
Suggestions, or Constructive
Criticism?