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Researchers Find Genetics Affect Effectiveness of Leukemia Treatment
Though 5-year survival rates for children with acute myeloid leukemia (AML) have improved dramatically from 1975 to 2010 (from 20 percent to 70 percent), advances in survival rates have stalled since then. But new data uncovered by Ohio State University College of Pharmacy pharmacogenetics researchers suggest that genetic variants affect the way chemotherapy is transported through the system, making the case for more personalized therapies. Christina Drenberg (Guttke), PhD, was the first author on a study that was published in Clinical Pharmacology and Therapeutics.
Primarily a cancer of bone marrow and lymph nodes, AML produces an overload of immature and abnormal cells, known as blasts. These blasts circulate throughout the blood stream and lymph system where they disrupt normal function of organs. AML progresses rapidly and affects people of all ages. It is the second-most common form of leukemia in children. Left untreated, AML be fatal in a matter of weeks.
“In the 2015 State of the Union address President Obama announced the Precision Medicine Initiative to support advances in research, technology, and policies that empower patients and ultimately develop individualized care,” said Drenberg. “Essentially, this project is an effort to advance precision medicine. With follow-up studies, we could ultimately tailor dosing and treatment at the individual level based on a person’s genotype.”
Starting with a study at St. Jude’s Children’s Hospital in Memphis, Tenn., this investigation sought to uncover whether transporters and drug metabolizing enzymes, which can affect anti-cancer drug pharmacokinetics and disposition, impact drug efficiency if mutated. “Increasingly, science is using genotypes to identify determinants of treatment outcome,” she said. “We want to understand the association of this particular genotype as it relates to drug exposure and outcome, and are trying to figure out what this alteration is doing."
Drenberg and her colleagues studied the DNA of 164 pediatric patients with de novo (previously untreated) AML who were receiving a combination therapy for four chemo drugs. They looked at some 2000 variants in genes that involved drug absorption, distribution, metabolism and excretion. They also examined the variants in relation to age and other known biological factors related to treatment outcome.
The team found that certain mutations alone affected how the drug interacted with organs affecting drug disposition and normal host tissues involved in drug-induced toxicities. In one variant, there was less uptake of a drug combination in the liver; in another, more toxicity was caused. Through this study, Drenberg was able to identify two new drugs as substrates, which cause chemical reactions, and confirm two more.
Moving forward, Drenberg and researchers at Ohio State hope to work with clinicians here and at Nationwide Children’s Hospital to better understand the role of these variants via prospective evaluation in patients. She sees a future with increasingly personalized medicine, but admits that there is much more to do. “Pharmacogenetics research in cancer therapeutics is a neglected field. We’re still just discovering things.”
Other authors in the College of Pharmacy, Division of Pharmaceutics that contributed to this work were Sharyn Baker, Alice Gibson, Shuiying Hu and Alex Sparreboom.