By Terry Taylor
June 13, 2011
Recovery Act Investment: “Pharmacogenomics of Childhood Leukemia (ALL)”; William E. Evans; St. Jude Children’s Research Hospital; 2009: $661,549 (3R37CA036401-26S1). Funded by the National Cancer Institute.
Publications listing this Recovery Act Investment as providing grant support: Pottier N, et al. Promoter polymorphisms in the ß-2 adrenergic receptor are associated with drug-induced gene expression changes and response in acute lymphoblastic leukemia. Clinical Pharmacology and Therapeutics, 2010; 88(6):854–861.
Kawedia JD, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood, 2011; 117(8):2340–2347.
Chen SH, et al. A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Leukemia, 2011; 25(1):66–74.
Yang JJ, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nature Genetics, 2011; 43(3):237–241.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, especially among children younger than 10 years old, with a sharp spike in incidence among 2 and 3 year olds. More than 95 percent of affected children today attain complete remission, and between 75 and 85 percent are free of disease for five years following treatment and are considered cured. Nevertheless, the prognosis for some patients is not good, and the treatment is long and often fraught with serious side effects. African Americans and Hispanics with childhood ALL have poorer survival rates than children from other racial/ethnic groups. Drug resistance remains the principal reason for treatment failure among children with ALL.
When an American Recovery and Reinvestment Act (ARRA) funding opportunity became available, William E. Evans, Pharm.D., director and CEO of St. Jude Children’s Research Hospital in Memphis, Tenn., had a body of preliminary data available, making him a successful applicant. His ARRA grant allowed him to hire a full-time postdoctoral researcher and to retain two full-time research technicians, enabling him to develop those preliminary findings into a full-blown research program focused on improving diagnosis, prognosis, treatment regimens, and outcomes for children affected by this cancer.
With his ARRA-funded personnel collaborating with other NIH-funded colleagues, and with leadership from Dr. Mary Relling, the group has rapidly produced an impressive body of work.
Here are a few highlights published in major peer-reviewed journals:
- Located variations in the DNA sequence of a gene (ADRB2) that are strongly associated with relapse. Knowledge of whether a patient has these variations could help direct treatment, and the pathway itself is a potential new drug target.
- Found variation in another DNA region (SH3YL1-ACP1) that is strongly associated with treatment-induced bone death, a serious side effect of ALL therapy. This finding suggests a mechanism for the development of bone death, pointing to a possible target for preventive therapies.
- Identified genetic variations in a pathway involved in processing the ALL chemotherapy drug asparaginase. These variations influence the drug’s toxicity, which differs from one patient to another. This knowledge might lead to ways to block this toxicity.
- Discovered a set of genetic variations found in Native American and Hispanic populations, groups subject to high relapse rates. Providing a single extra phase of chemotherapy reduced the risk of relapse among these populations, showing that ancestry-related relapse risk may be overcome with modifications to therapy.
Dr. Evans predicts that the data already obtained with the aid of his ARRA grant “will be used for many years to come and could ultimately reveal novel targets for therapeutic intervention using more targeted agents.”