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Medicines, Genes, and Variability:
A Symposium on Pharmacogenetics
- Gene Profiles May Improve Cure Rate for Kids with Leukemia
- Antidepressants for Hot Flashes (and Genes) May Interfere with Tamoxifen Therapy
- Genes Influence Effect of Corticosteroids on Asthma
These topics and more will be covered at the following special symposium:
“The NIH Pharmacogenetics Research Network: Five Years of Progress”
March 3, 2005 from 1:00-7:00 p.m.
Southern Hemisphere IV/V Ballroom
Walt Disney World Dolphin Hotel
Orlando, FL
Pharmacogenetics is the study of how genes affect the way people respond to medicines. The ultimate goal of pharmacogenetics research is to help tailor medicines to people's unique genetic make-ups. This will make medicines safer and more effective for everyone.
The NIH Pharmacogenetics Research Network (PGRN) is a nationwide collaboration of scientists funded by the National Institutes of Health to study the effect of genes on people's responses to a wide variety of medicines, including antidepressants, chemotherapy, and drugs for asthma and heart disease. The network ( http://www.nigms.nih.gov/pharmacogenetics/) was established in 2000 and is marking its 5th anniversary at the ASCPT (American Society for Clinical Pharmacology and Therapeutics) meeting. News highlights from the anniversary symposium follow.
The director of the NIH Pharmacogenetics Research Network is
Rochelle M. Long, Ph.D.
National Institute of General Medical Sciences
301-594-3827
Assessing the Heritability of Drug Clearance and Absorption
The effectiveness of most oral drugs is directly related to levels of the drug in the blood and varies significantly between individuals. Both genetic and environmental factors (diet, exercise, other medications, etc.) contribute to this variability. Once absorbed, drug levels generally decline in two ways: through metabolism in the liver and through elimination by the kidneys. The drug’s chemistry determines whether it is cleared by the liver, the kidney, or a combination of both organs. Studies have shown that the rate of drug metabolism by liver enzymes is largely heritable, but little is known about renal clearance or drug absorption. The speaker and colleagues conducted the first study to determine the contribution of genetic factors versus environmental factors to renal drug clearance and to oral drug absorption. They examined the clearance of two renally cleared drugs, metformin and digoxin, by normal volunteer pairs of fraternal and identical twins.
Metformin treats type II diabetes and was used to examine the heritability of renal clearance. The investigators found that genes account for a majority (around 60%) of its clearance rate. Between 25% and 30% of patients don’t respond to metformin. For individuals whose poor response is due to low drug levels (poor absorption or rapid clearance), higher doses of the drug may be beneficial.
Digoxin treats heart failure and was used to probe the heritability of absorption. When the researchers examined the fraction of the drug that is absorbed after oral administration, they found that less than 40% of absorption can be accounted for by genetic factors. Digoxin has a narrow therapeutic index, so knowledge of the genetic component of absorption may help doctors adjust dosing in individuals to optimize therapeutic responses.
Seminar 2:30-2:55 p.m. in Southern Hemisphere IV/V Ballroom
Heritability of Digoxin and Metformin Pharmacokinetics
Deanna Kroetz, Ph.D.
University of California, San Francisco
415-476-1159
deanna@itsa.ucsf.edu
Relevant article:
Leabman MK, Giacomini KM: Estimating the Contribution of Genes and Environment to Variation in Renal Drug Clearance. Pharmacogenetics 13: 581-4, 2003.
Gene Profiles May Improve Cure Rate for Kids with Leukemia
Every year in the United States, about 2400 children are diagnosed with acute lymphoblastic leukemia (ALL). Most of these are toddlers around 2-3 years of age. Chemotherapy cures about 80% of ALL cases. Treatment fails in the remaining cases because the patients’ cancer cells are resistant to chemotherapy drugs and because doses are not individualized to maximize cure or minimize adverse effects.
To identify genes responsible for inherent drug resistance, the speaker’s group isolated leukemia cells from 173 newly diagnosed ALL patients and used gene chips to test the cells’ sensitivity to four common chemotherapy drugs. The investigators identified 124 genes that predict resistance to the drugs. The activity levels (expression patterns) of these genes vary in conjunction with the cells’ sensitivity or resistance to the drugs. The researchers also found that the pattern of expression of these genes correlates with the likelihood of relapse years after treatment. These results held true in an independent group of children with ALL. Those children whose leukemia cells had resistant patterns of gene expression had a 3- to 12-fold higher risk of relapse than those whose cells had a sensitive pattern. Interestingly, the identified genes are involved in a wide range of functions, including cell communication, proliferation, and development as well as the metabolism of proteins, nucleic acids, and carbohydrates. Only a handful of the genes had previously been linked with ALL resistance. The genes uncovered in this study point to new targets for future chemotherapy.
In a paper newly published in Blood (see below), the speaker’s group identified genomic variation that affects how a patient’s genetics--and not just the cancer cells’ genetics--affect the risk of relapse. The group analyzed inherited genetic variation at 16 loci in 246 children with ALL. They zeroed in on two genes: glutathione S-transferase (which detoxifies potentially mutagenic electrophiles, including metabolites of several chemotherapeutic agents) and thymidylate synthase (which is necessary for DNA synthesis and is an anticancer drug target). Common variations in these genes were associated with relapse among patients with higher-risk ALL. Different genetic variations were associated with toxicity than were associated with relapse. These genetic variations may provide tests that can allow clinicians to fine-tune chemotherapy for individual patients to adjust for resistance to specific drugs.
Seminar 3:55-4:20 p.m. in Southern Hemisphere IV/V Ballroom Pharmacogenetics of Outcome and Toxicity in Children with Acute Lymphoblastic Leukemia
Mary V. Relling, Pharm. D.
St. Jude Children's Research Hospital
901-495-2348
mary.relling@stjude.org |
For media inquiries, also contact:
Jerry Chipman 901-495-2303 or
Bonnie Cameron 901-495-4815 |
Relevant articles:
Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH, Sandlund JT, Rubnitz J, Ribeiro R, Campana D, Pui CH, Evans WE, Relling MV: Pharmacogenetics of Outcome in Children with Acute Lymphoblastic Leukemia. Blood First Edition Paper, DOI 10.1182/blood-2004-11-4544, prepublished online February 15, 2005.
Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM, Pei D, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R, Evans WE: Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment. N. Engl. J. Med. 351: 533-42, 2004.
Antidepressants for Hot Flashes (and Genes) May Interfere with Tamoxifen Therapy
Tamoxifen is commonly used for treating estrogen-sensitive breast cancer, but the drug’s effectiveness varies widely among patients. Many women taking tamoxifen also take SSRI antidepressants to combat hot flashes caused by the anticancer drug. Recent work shows that some SSRIs reduce the level of tamoxifen's active metabolite (endoxifen), possibly hampering tamoxifen's effectiveness. The researchers found similarly low levels of the metabolite in women with a genetic variation in a drug-metabolizing enzyme (CYP2D6). This suggests that these women may not respond well to tamoxifen. New work submitted for publication bears this out. It indicates that women with the genetic variation have a much higher rate of cancer relapse than do patients without the variation. Specifically, those with the variation have an average disease-free survival of 4 years, whereas for those without it, the average is 11 years. In the short term, the work will help doctors choose one SSRI over another for women who are taking tamoxifen. It may also lead to genetic tests to determine which women are most likely to benefit from tamoxifen. For women with the CYP2D6 variation, alternative treatments such as aromatase inhibitors may be more effective than tamoxifen.
Seminar 4:20-4:45 p.m. in Southern Hemisphere IV/V Ballroom
CYP2D6 Polymorphisms and Tamoxifen Response
James M. Rae, Ph.D.
University of Michigan Medical School
734-764-1460
jimmyrae@med.umich.edu
Relevant articles:
Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee K-H, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA: CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment. J. Natl. Cancer Inst. 97: 30-9, 2005.
New Study Reveals Genotype that Causes SSRI Interference with Tamoxifen. NCI Cancer Bulletin 2 (2), January 11, 2005.
Genes Influence Effect of Corticosteroids on Asthma
Corticosteroids, which can dampen immune reactions, are used to treat a wide range of maladies, such as eczema, arthritis, ulcerative colitis, and asthma. For the more than 155 million people in the developed world who have asthma, inhaled corticosteroids are the most common treatment prescribed to prevent symptoms. But many people don't respond well to these drugs or suffer from side effects. In a recent study, researchers screened approximately 500 people with asthma for genetic variations that correlate with improved lung function in response to inhaled corticosteroids. After screening 14 genes, the researchers found that variations in 3 genes were significantly associated with a good response to corticosteroids. The most striking data have come from genes called NR3C1 and CRHR1. NR3C1 codes for the glucocorticoid receptor (the primary receptor for corticosteroids), and CRHR1 encodes a receptor for corticotropin-releasing hormone, which regulates the body’s production of corticosteroids in response to stress. The expression of both of these genes varies in correlation with the therapeutic response to inhaled corticosteroids, suggesting that no single gene is solely responsible for improvement in asthma. Instead, researchers will need to identify a “network” of genetic variants to help predict which patients will respond best to therapy. This kind of detailed understanding of people's molecular responses is rapidly evolving and should help doctors tailor asthma treatments to individuals. The research may also apply to patients with many other diseases that are treated with corticosteroids.
Seminar 4:45-5:10 p.m. in Southern Hemisphere IV/V Ballroom
Association of Glucocorticoid Receptor Gene Variants with Response to Inhaled Corticosteroids in Asthma
Kelan Tantisira, M.D., M.P.H.
Brigham and Women’s Hospital
617-525-0863
kelan.tantisira@channing.harvard.edu
Relevant articles:
Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, Liggett SB, Gelfand EW, Rosenwasser LJ, Richter B, Israel E, Wechsler M, Gabriel S, Altshuler D, Lander E, Drazen J, Weiss ST: Corticosteroid Pharmacogenetics: Association of Sequence Variants in CRHR1 with Improved Lung Function in Asthmatics Treated with Inhaled Corticosteroids. Hum. Mol. Genet. 13: 1353-9, 2004.
Weiss ST, Lake SL, Silverman ES, Silverman EK, Richter BG, Drazen JM, Tantisira KG: Asthma Steroid Pharmacogenetics. A Study Strategy to Identify Replicated Treatment Responses. Proc. Am. Thoracic Soc. 1: 364-7, 2004.
Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG, Peng S, Drazen JM, Glimcher LH, Weiss ST: TBX21: A Functional Variant Predicts Improvement in Asthma with the Use of Inhaled Corticosteroids. Proc. Natl. Acad. Sci. 101: 18099-104, 2004.
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