PAAR4Kids: Pharmacogenomics of Anticancer Agents Research in Children
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Research

Steps of research, essential elements, and overall approach in PAAR4Kids.

research_diagram

Step 1: Discovery/replication: The core prospective clinical trials of COG and St. Jude serve as the primary discovery and replication cohorts for PAAR4Kids. Detailed phenotypes, genome-wide and candidate genotyping in germline and in ALL tumor DNA, and nongenetic covariates affecting phenotypes are analyzed in genotype/phenotype association studies.

Step 2: Prioritization: a number of criteria (e.g. pleiotropy, biological pathways, MAF, effect size, conservation) are used to prioritize which associations are most important to further confirm.

Step 3: Validation: can entail additional genotype/phenotype association analyses in other “non-core” ALL trials (e.g. European collaborators, COG AALL03N1, other PGRN trials, NHANES, etc) and can encompass surveys of other human tissues (e.g. human liver resource, HapMap LCLs) and mechanistic follow-up studies (e.g. in murine models or in vitro tools such as knock-down, directed expression).

Step 4: Clinical integration: For those genotype/phenotype associations with large effect sizes that have been solidly validated, whether they emanate from our own work or that of others, we will work to incorporate pharmacogenomic-based drug dosing into clinical trials or routine patient care. After treatment is modified based on polymorphisms with the greatest effect, then other polymorphisms may emerge in future discovery/replication studies (back to Step 1)--hence the circle.

Medications used to treat childhood ALL

  • Prednisone/Dexamethasone
  • Asparaginase
  • Vincristine
  • 6-mercaptopurine/thioguanine
  • Methotrexate
  • Daunorubicin
  • Cyclophosphamide
  • Cytarabine
  • Etoposide/clofarabine/imatinib/dasatinib

    • Core and Non-Core Clinical Trials

    Core and non-core clinical trials that are primary discovery/replication sources for PAAR4Kids.

    clinical_trials

    Prospective clinical trials included in PAAR4Kids

    Parent protocol*

    Therapeutic trial Mnemonic# (sample sizes)

    		 PI

    Therapeutic trial title

    Examples of evaluable phenotypes

    COG (legacy POG) 9900

    POG 9904/9905 (n~1600)

    		 Martin, Winick

    ALinC 17 Treatment for Patients with Low Risk ALL (9904) or Standard Risk ALL (9905) Phase III Studies

    MRD, relapse, VCR neuropathy

    POG 9906 (n~220)

    Bowman

    ALinC 17: Protocol for Patients with Newly Diagnosed High Risk ALL - Evaluation of the Augmented BFM Regimen: A Phase III Study

    MRD, relapse, VCR neuropathy, ON, asparaginase allergy, pancreatitis, blast gene expression

    COG

    AALL03B1; PI: Loh, Raetz

    AALL08B2; PI: Loh, Relling

    AALL0232 (n~2500)

     Larsen

    High Risk B-precursor ALL

    MRD, relapse, ON, pancreatitis, asparaginase allergy, VCR neuropathy

    AALL0434 (n~1400)

    Winter, Dunsmore

    Intensified MTX, Nelarabine and Augmented BFM Therapy for Children and Young Adults with Newly Diagnosed T-cell ALL

    MRD, relapse, MTX neurotoxicity, pancreatitis, asparaginase allergy, VCR neuropathy

    AALL0331 (n~3800)

    Maloney

    Standard Risk B-precursor ALL

    MRD, relapse, pancreatitis, asparaginase allergy, VCR neuropathy

    NA

    COG AALL03N1 (n~720)

    Bhatia

    Understanding the Ethnic and Racial Differences in Survival in Children with ALL--not a front-line core trial

    Medication compliance, relapse, TPMT activity, erythrocyte thiopurine measures

    NA

    COG ALTE03N1 (n~1261)

    Bhatia

    Key Adverse Events After Childhood Cancer--not a front-line core trial--case control

    Anthracycline cardiotoxicity, ON and controls

    NA

    St. Jude Total XIII (n~400)

    Pui

    Total Therapy Study XIIIA & B for Newly Diagnosed Patients with ALL

    MRD, relapse, ON, pancreatitis, asparaginase allergy, VCR neuropathy, height, weight, PK of MTX, thiopurine and etoposide, in vitro ALL drug sensitivity, blast gene expression

    NA

    St. Jude Total XV (n~500)

    Pui

    Total Therapy Study XV for Newly Diagnosed Patients with ALL

    MRD, relapse, ON, pancreatitis, asparaginase allergy, VCR neuropathy, blast gene expression, height, weight, cortisol, lipids, PK of MTX, thiopurine, and dexamethasone, in vitro ALL drug sensitivity

    * The parent protocols describe biology, induction therapy, and genetic studies but the primary patient enrollments, continuation therapy, and phenotypes are determined in patients enrolled on the therapeutic trials listed under trials column#. VCR=vincristine; ON=osteonecrosis; NA=not applicable. Numbers indicate those with DNA.