Pharmacogenomics of Anticancer Agents Research in Children
|Mary V. Relling, Pharm.D.|
|St. Jude Children's Research Hospital, Memphis, TN|
PGRN 2010 Retreat Poster
Abstract (Updated as of March 2015)
The goal of PAAR4Kids is to fully define the pharmacogenomics of childhood acute lymphoblastic leukemia (ALL), the most common childhood malignancy, in order to improve the lives of children with this disease, as well as any patients treated with the same medications.
Our aims are to define genomic variations (germline and acquired) important for interpatient variability in treatment response and toxicity from medications used to treat childhood ALL, to translate pharmacogenomics into clinical treatment strategies, and to collaborate with pharmacogenomics investigators to leverage relevant pharmacogenomic knowledge from pediatric ALL to other diseases and disciplines (and vice-versa). This is accomplished by a multidisciplinary team of leaders in the field.
The research harnesses the power of studying patients with ALL treated on Children's Oncology Group (COG) and St. Jude Children's Research Hospital protocols, achieving near-population-level coverage for ALL in the US. Pediatric ALL provides outstanding opportunities for pharmacogenomic discoveries and translation to the clinic, because this is an otherwise fatal disease that is cured through extensive use of agents that have a narrow therapeutic index. The agents are broadly used in cancer and in general medical practice and thus the findings from PAAR4Kids have applicability outside of pediatric ALL, as demonstrated by multiple collaborations within and outside of the PGRN. PAAR4Kids studies the pharmacogenomics, pharmacokinetics (cellular and plasma), antileukemic and toxic effects of glucocorticoids, methotrexate, thiopurines, asparaginase, anthracyclines, and vincristine.
The approach is summarized in four major Steps. In Step 1 genotype/phenotype studies are undertaken in a set of core phase III front-line clinical trials involving over 10,000 patients that serve as discovery and replication cohorts. Non-genetic covariates are included. In Step 2, genomic variation is prioritized for further follow-up. Step 3 is confirmation and validation, consisting of mechanistic experimental laboratory models, surveys of human tissues, and/or additional genotype/phenotype analyses in other clinical trials, often using PGRN resources. In Step 4, validated genomic associations with large effect sizes are integrated into clinical settings.
To expand on Step 4, PAAR4Kids has taken a leading role in the Clinical Pharmacogenetics Implementation Consortium (CPIC), a collaboration between the PGRN and PharmGKB. CPIC is creating and making publicly available specific clinical guidelines for modifying therapy based on genetic test results (https://www.pharmgkb.org/page/cpic ). PAAR4Kids is an active member of the PGRN’s TPP, and as part of its PG4KDS protocol (www.stjude.org/pg4kds ), PAAR4Kids is implementing CPIC clinical guidelines into all of patient care at St. Jude (patients with and without cancer), using computational decision support tools to guide prescribing.
PAAR4Kids has world class scientists applying state-of-the-art genomics techniques to the germline and tumor cells of impeccably cataloged specimen collections from extensively phenotyped patients, and outstanding statisticians, pharmacologists, and clinicians. PAAR4Kids is poised to comprehensively attack the pharmacogenomics of childhood ALL, and to implement pharmacogenomics into patient care.
St. Jude Team
Mary V. Relling, Pharm.D.
William E. Evans, Pharm.D.
Jun J. Yang, Ph.D.
Cheng Cheng, Ph.D.
Wenjian Yang, Ph.D.
Erin G. Schuetz, Ph.D.
Ching-Hon Pui, M.D.
James Downing, M.D.
Charles Mullighan, M.D.
Geoffrey Neale, Ph.D.
Deqing Pei, Ph.D.
Laura Ramsey, Ph.D.
John Schuetz, Ph.D.
University of California, San Francisco
Mignon Loh, M.D.
University of Florida, Gainesville
Meenakshi Devidas, Ph.D.
Nationwide Children's Hospital, Columbus, OH
Julie Gastier-Foster, Ph.D.
City of Hope, Duarte, CA
Smita Bhatia, M.D.
University of Texas MD Anderson Cancer Institute, Houston
Paul Scheet, Ph.D.
John Hopkins University, Baltimore, MD
Gary Rosner, Ph.D.