Program will test 10-15 drugs or drug combinations per year to fight pediatric cancers
The National Cancer Institute has announced the establishment of the Pediatric Preclinical Testing Program (PPTP), a program that will systematically test 10-15 agents or combinations of agents annually in preclinical models of common childhood cancers.
The PPTP is supported through an NCI research contract to St. Jude Children's Research Hospital with St. Jude Molecular Pharmacology Chair, Peter Houghton, Ph.D., as the principal investigator.
The program will develop procedures for generating sufficient preclinical information to allow pediatric oncology researchers to reliably prioritize new agents for study in children with specific cancers. The increasing number of anti-cancer agents potentially available for clinical testing makes a rational agent-prioritization process essential for future progress in developing effective new childhood cancer treatments. Without correct prioritization of agents, clinical scientists will have little chance of discovering active treatments in the limited number of clinical trials that can be conducted for any given type of childhood cancer. The PPTP will begin testing agents in early 2005.
"This is the first attempt to evaluate new drugs or biologics in a consistent manner to select those agents that have promising activity for treatment of childhood cancer," Houghton said. "The program builds upon extensive work undertaken at St. Jude and elsewhere that indicates the value of preclinical models, where tumors from children are grown in immune-deficient mice to identify new agents and drug combinations that have significant therapeutic activity in subsequent clinical trials."
Testing will occur both at St. Jude and at subcontract sites that have expertise in specific childhood cancers, including Children's Hospital of Philadelphia (John Maris), Albert Einstein Medical Center (Richard Gorlick), Duke University (Henry Friedman), Children's Hospital of Los Angeles (Patrick Reynolds), and Children's Cancer Institute Australia (Richard Lock).
The PPTP builds upon Houghton's research by demonstrating the ability of preclinical testing using rhabdomyosarcoma and neuroblastoma xenografts to predict for activity of new agents in children with these cancers. The program will attempt to extend these observations to other childhood cancer types and to a broader spectrum of anticancer agents.
The PPTP will test anticancer agents against panels of preclinical models of the most common childhood cancers. The in vivo testing panels will primarily use childhood cancer xenograft lines, with genetically engineered models used when these are available and relevant to the agent being tested. The PPTP will use in vivo test panels for neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, acute lymphoblastic leukemia, renal tumors (Wilms and rhabdoid), embryonal brain tumors and glial brain tumors. Each in vivo panel will consist of four-eight xenograft lines. The in vitro panel will represent a similar range of childhood cancers and will include 20-25 cell lines. Each of the xenograft and cell lines used in the PPTP will undergo extensive molecular characterization. Gene expression profiles for the lines will be available using both cDNA arrays (performed by Javed Khan, NCI) and Affymetrix arrays (performed at St. Jude). Tissue arrays are being prepared that include each of the program's xenograft lines, and these will allow immunohistochemical determination of the expression of proteins relevant to molecularly targeted new agent testing.
New agents will be tested, when feasible, near the time that they are entering evaluation in adults with cancer and before their possible initial evaluation in children. Several standard chemotherapy agents will also be tested in parallel in order to calibrate the PPTP tumor panels using agents of known clinical activity for specific tumor types. For both new agents and standard agents tested, pharmacokinetic studies will be performed in animal models to determine the serum drug levels and systemic drug exposures associated with antitumor activity. For selected molecularly targeted agents, the PPTP will evaluate whether target inhibition/modulation is achieved by the agent under the test conditions and whether this modulation is associated with antitumor activity. Results from the preclinical testing program will be correlated with the clinical activity and the pharmacokinetic profile of the tested agents in children to assess the predictive capabilities of the PPTP's childhood cancer panels and the animal models.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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