ABSTRACT
Cancer in children is rare with approximately 15,700 new cases diagnosed annually in children 21 years or
younger in the U.S. Through use of multimodality therapy (surgery, radiation therapy, and aggressive
chemotherapy), 70% of patients will be `cured' of their disease, and 5-year Event-Free Survival (EFS) exceeds
80%. Consequently, the number of patients that can be enrolled in phase I/II clinical trials is small, and most
patients will have been extensively treated, hence drug/radiation resistant. Thus, preclinical studies that
accurately translate into effective clinical therapy are an essential component of pediatric drug development. Our
group has contributed to studies in the PPTP/C that have led to clinical studies through Children's Oncology
Group (COG). Of importance, we have developed and characterized over 330 Patient Derived Xenografts (PDX),
developed from tumors both at diagnosis and relapse, that can be used to facilitate pediatric drug development
as directed by FDA under the Research to Accelerate Cures and Equity for Children Act (RACE for Children
Act). Based on our studies, both in and outside the PPTC, we propose to use PDX/CDX models of sarcoma,
kidney cancer, and hepatoblastoma derived from high-risk patients to identify novel agents and combinations,
and to test at least 8-10 agents per year, for which we have expertise. We will explore specific hypotheses to
integrate molecular-targeted agents with conventional chemo-radiation treatment, advanced drug delivery
systems (antibody-drug conjugates, nanoparticles), and the use of Single Mouse Testing (SMT) as the primary
screening approach. In collaborative studies, we will evaluate a new humanized mouse model where testing of
immuno-oncology agents is a priority to treat these PDX models. One of the objective limitations of PPTP/C
testing was that relatively few tumor models representing a specific disease (n=3-8/disease) could be used within
the resource constraints, a number clearly insufficient to recapitulate the genetic/epigenetic heterogeneity of
each clinical disease. Our retrospective analysis of PPTP data, and recent prospective testing in the PPTC,
shows that a single mouse/tumor line gives essentially similar data to conventional testing' (using 10 mice/group
for each tumor line). The advantage of the SMT design is that it allows for incorporation of up to 20-fold more
models, more accurately representing the genetic/epigenetic diversity of each pediatric cancer within the same
resource constraints. The proposed studies will adopt SMT as the primary screening approach to identify agents
that have biologically meaningful activity (i.e. large antitumor effects) and identify tumors that are `exceptional
responders' for validation. The SMT approach, when linked to the molecular characterization of PDX models,
potentially increases the power to identify biomarkers associated with response. Using SMT we can essentially
conduct preclinical phase II trials and simulate the likely clinical response rate more accurately for a given
disease. As part of the Ped-In Vivo-TP, we aim to develop highly effective, less toxic therapies for high-risk
cancers that afflict children and adolescents/young adults (AYA).
