The National Cancer Institute (NCI) has launched an initiative to speed the development of childhood cancer therapies by funding five research teams to participate in the Pediatric Preclinical Testing Consortium (PPTC).
Each team will produce reliable data from studies involving preclinical laboratory and animal models that can help to prioritize which therapeutic agents to pursue in human trials.
Unlike the large universe of agents developed to target adult cancers, the relatively small number of children with specific cancers has resulted in very few new medications specifically developed and approved for kids. Currently, once the FDA approves a new adult drug, it takes about nine years to develop, test and gain regulatory approval for a safe children’s version—due, in part, to the small pediatric population and patient recruitment challenges.
The five pediatric medical research teams, operating under five-year NCI grants, were chosen because of their experience with specific cancers. Each has done preclinical testing and developed a number of preclinical models that underwent comprehensive genomic analyses to demonstrate that they closely resemble the genetic alterations seen in the respective human cancers, according to Malcolm Smith, M.D, Ph.D., associate branch chief of pediatrics in the NCI’s Cancer Therapy Evaluation Program.
The five centers and their specific expertise of childhood cancers are:
“A main problem is in vivo use and different assays, along with the different models and how you effectively prioritize drug candidates to ensure clinical success in cancer patients,” said Xiao-Nan Li, associate professor of pediatrics at Baylor. “Our objective is to make use of our unique panel of animal models to examine therapeutic efficacy of new agents and to analyze mechanisms of action and therapy resistance.”
At Children’s Hospital of Philadelphia, John M. Maris, M.D, professor of pediatric oncology at the University of Pennsylvania’s Perelman School of Medicine, said the new consortium addresses several unmet needs in the pediatric oncology community. He cited the lack of potential new drugs, insufficient funding to efficiently test various agents, and a lack of faithful models of childhood cancers to test the drugs against.
Maris said his hospital laboratory has created animal models of neuroblastoma that incorporate genetic material and patient tumor cells. He stressed that the value of those models is that they allow scientists to design drug tests highly tailored to specific, well-characterized subtypes of human neuroblastoma tumors.
“The PPTC will both accelerate the pace of getting new, effective drugs to the clinic, and also deprioritize agents with little chance of success,” said Maris. “Finally, the consortium will focus on combination therapies, knowing that cancers are too sinister to be defeated by single drugs alone. The consortium will use models that are highly characterized so drug companies can know not just that it works in neuroblastoma, but more importantly, we can provide proof of concept that this efficacy can be predicted ahead of time.”
The foundation of the consortium, Smith said, was the Pediatric Preclinical Testing Program (PPTP), a decade-long initiative where NCI worked with more than 50 pharmaceutical companies to test novel agents for adults in PPTP-provided preclinical models. Among the important findings from testing many agents, according to Smith: The results showed efficacy against adult cancers was limited in pediatric preclinical models.
As for testing pediatric patients differently from adults, children’s developing organs and changing metabolism affect how they process drugs—and that’s something that must be taken into account when treating them, according to Earl Seltzer, Quintiles’ associate director of global feasibility. While there have been incentives and regulatory requirements to spur more pediatric clinical trials, he noted, managing logistical, legal and cultural considerations that come with such research can be daunting.
One solution, Seltzer added, is the use of pediatric clinical trials networks, which are typically part of academic institutions that collaborate with each other and with industry to plan and manage pediatric clinical trials safely, effectively and efficiently.
The NCI consortium is the latest network to focus on specialized childhood diseases research.
“These networks are able to share information across organizational studies and are best able to handle the difficulties in appropriate pediatric trial planning,” said Seltzer. “It’s been said it takes a village to do these types of studies, like networks and the new NCI consortium.”
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