This application seeks renewal of funding for a Research Program for acute lymphoblastic leukemia
(ALL) in vivo testing as part of the NCI Pediatric In Vivo Testing Program (Ped-In Vivo-TP). Recent US
Government legislation, combined with the relative rarity and higher cure rates of childhood cancer
compared with adults, emphasize the importance of new agent preclinical testing programs aimed at
maximizing the likelihood that only the most active drugs will be advanced into early phase clinical trials.
The broad aim of this application is to improve the treatment options for children with aggressive and/or
drug resistant ALL by prioritizing new drugs for clinical trials in the disease using state-of-the-art
preclinical experimental models. This aim will be accomplished using a large panel of 90 pediatric ALL
patient-derived xenografts (PDXs) that have undergone a high level of cell and molecular
characterization and authentication.
The PDXs to be used in this study were all established as models of orthotopic disease in immune-
deficient (NOD/SCID or NSG) mice from direct patient explants without prior ex vivo culture. The PDXs
develop as systemic disease in NSG mice and infiltrate the same major organs in mice as the primary
disease in human patients. Engraftment and responses to treatment are monitored by measuring the
proportion of human leukemia cells in the peripheral blood of mice on a weekly basis, which provides a
reliable representation of overall leukemia burden in the animals. Where luciferase-expressing PDXs
are available, this testing will be augmented by bioluminescence imaging of animals.
The broad methodology will involve inoculation of PDX cells into NSG mice, a lag time to allow the
disease to establish, followed by drug treatment and monitoring to assess drug responses. Methods of
response evaluation have been developed using stringent criteria modeled after the clinical setting, in
order to minimize the likelihood of over-predicting drug responses in mice leading to failure of drugs in
the clinic. The proposed drug testing will adopt multiple formats, including conventional drug testing (6-
10 mice/group), single-mouse trial testing (1 PDX x 1 mouse x 1 drug) and testing of new agents in
combination with standard-of-care drugs. In this fashion, this Research Program aims to test 8-10 new
agents per year.
By completing the major objectives outlined in this proposal, the long term health benefit aims to
improve the treatment options and quality of life for children with aggressive forms of ALL who would
otherwise succumb to their disease.