The development of new therapies for children with cancer presents unique challenges. Firstly, the incidence of cancer in children is relatively low; in the United States, about 12,400 new cases are diagnosed annually in patients under 20 years old. Each year in Texas, almost 1,200 children and adolescents younger than 20 years of age are diagnosed with cancer, representing 10% of all cancers diagnosed in the U.S. Approximately 200 children and adolescents die of cancer each year, making cancer the most common cause of disease-related mortality for Texans 0-19 years of age. Nationally, the overall cure rate for all childhood cancers is approaching seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy, and chemotherapy) are good, with overall 5-year Event-Free Survival approaching 80%. However, current approaches to curative therapy result in significant morbidity and long-term sequelae, including cardiac dysfunction and cognitive impairment. Further, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or metastatic disease. The distribution of cancers in U.S. children is shown below. For rare tumors such as Ewing sarcoma, there are about 250 children diagnosed per year. As a consequence, relatively few trials of experimental agents are possible in these rare tumors.
The Pediatric in Vivo Testing Program (PIVOT)
This is a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models. PIVOT is supported through an NCI UO1 research grant, and testing is conducted at five sites in the U.S. and one site in Australia (leukemias) that has expertise in specific childhood cancers. The primary goal of PIVOT is to identify new agents that have the potential for significant activity when clinically evaluated against selected childhood cancers. The program is based on a substantial body of data showing that appropriate childhood cancer preclinical in vivo models can recapitulate the anti-tumor activity of known effective agents and can prospectively identify novel agents subsequently shown to have clinical activity against specific cancers of children and adolescents.
By facilitating the development of a more reliable pediatric new agent prioritization process, PIVOT has contributed to the goal of identifying more effective treatments for children with cancer.
Over the last 15 years of the program, standardized metrics to assess drug response and presentation of large in vivo data sets have been developed and validated. For each drug, between 2 and 55 models of childhood cancer are used to assess broad-spectrum or tumor-type activity. Over 100 models have been characterized with respect to exome sequencing, expression profiling, and SNP analysis. Thus, a molecular database is available to identify biomarkers of response to a specific agent.
The PIVOT program builds upon 15 years of testing of novel agents against panels of cell lines in vitro and tumor xenografts models in mice that represent childhood solid tumors, brain tumors, and acute lymphoblastic leukemias. Over 80 drugs or drug combinations have been tested in 83 xenograft models of childhood cancer (kidney cancers,
sarcomas, neuroblastoma, brain cancers, and acute lymphoblastic leukemia). These studies have identified novel drugs and drug combinations that are now in clinical trial.
The PPTC has been funded through U01CA263981 since 2020. The major changes from the previous NCI-supported testing programs (PPTP/C) will be a focus on combination drug testing that is based upon either genetic characteristics of particular childhood cancer models or based on specific molecular markers, such as oncogene mutations or tumor-selective expression of cell surface proteins that can be used to direct antibody-drug conjugate therapeutics.