1. DiGiulio, Sarah

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Earlier this year the National Cancer Institute launched the Pediatric Preclinical Testing Consortium (PPTC)-a program to develop high-quality preclinical data to help identify which novel agents will be most effective in treating pediatric cancers. The Consortium's Program Director, Malcolm A. Smith, MD, PhD, noted that in some ways it continues the work of the NCI's previous Pediatric Preclinical Testing Program-a collaboration with more than 50 pharmaceutical companies to test novel agents. But, he added: "The new effort focuses on a systemic approach to in vivo testing using large panels of genomically characterized models."

MALCOLM SMITH, MD, P... - Click to enlarge in new windowMALCOLM SMITH, MD, PHD. MALCOLM SMITH, MD, PHD

The new PPTC includes the PPTC Coordinating Center at Research Triangle Institute International and five research programs responsible for the evaluation of agents against pediatric cancer preclinical models, funded through NCI cooperative agreement research grants. The five research programs were chosen based on their preclinical testing capabilities and experience using genomically characterized models in cancer drug evaluation.


In a phone interview, Smith explained some of the challenges of developing pediatric cancer drugs and why the Consortium offers a better pipeline.


1. What makes childhood cancer drugs so difficult to develop in the first place?

"One key challenge is the distinctive biology of many childhood cancers compared with adult cancers, meaning that research findings for many adult cancers may have limited relevance to childhood cancers. Another major challenge is the relatively small number of children with cancer, which means that compared with adult cancers only a limited number of clinical trials can be conducted to identify more effective treatments.


2. How does the new Consortium improve the work of the previous NCI program for pediatric cancer research?

"[The new program] focuses on a systematic approach to in vivo preclinical testing using relatively large panels of genomically characterized models. There are preclinical testing activities-certainly outstanding preclinical testing activities-across the country and the world. But, they more typically focus on in vitro testing, which is less expensive and on a smaller scale than in vivo testing.


"Our program, by focusing on a larger more systematic approach to in vivo testing, is distinctive. It is relatively resource intensive-so it's not the kind of thing that most companies or most academic centers would really be able to do.


"A key point about the PPTC, in the era of precision medicine, is being able to take a range of genomically characterized models and do high-quality in vivo testing to look for whether there's likely utility from using the agents-to learn how to better apply precision medicine principles for childhood cancer clinical trials."


3. What makes in vivo testing better than in vitro testing in this pediatric cancer drug research setting-and how will improving it improve pediatric cancer drug development?

"In vitro testing certainly provides important insights about any cancer agents, but they provide very little limited information about whether an agent is going to have a therapeutic window when it is transferred into the clinic. Most chemicals will kill at high enough concentrations-even something like Clorox-within plastic plates.


"In vivo testing provides a better assessment for a therapeutic window-and especially when we're able to compare the relative tolerability of agents in mice and humans in terms of the drug levels that the mice tolerate compared to the drug levels that humans tolerate. And instead of perhaps using only one or two models of a particular cancer type, with in vivo testing we would typically use six or more models of that type of cancer to try to better interrogate the heterogeneity that exists in the clinic. We get a better idea of the likelihood for activity through testing a larger spectrum of models of each disease.


"A key contribution of the Consortium will be developing data to use in prioritizing agents for clinical evaluation against specific childhood cancers. Unlike the situation for more common adult cancers in which many clinical trials evaluating experimental agents can be conducted in the hopes of finding an active agent, for any given childhood cancer a much smaller number of clinical trials of novel agents can be performed. Hence, the data from the Consortium is important for more rationally selecting agents [that can be tested in a] clinical study-and for increasing the likelihood that truly active agents will be moved forward.


"If we bring ineffective agents into clinical testing for children, then our clinical trials are destined for failure. If we bring truly effective agents into testing, then we have a much better chance of success in the clinical trials that we conduct."


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The Pediatric Preclinical Testing Consortium's Five Research Programs


* The Sarcoma and Renal Tumor Research Program at Greehey Children's Cancer Research Institute at the University of Texas Health Science Center in San Antonio;


* The Neuroblastoma Research Program at The Children's Hospital of Philadelphia;


* The Osteosarcoma Research Program at The Children's Hospital at Montefiore;


* The Leukemia Research Program at Children's Cancer Institute (Sydney, Australia); and


* The Brain Tumor Research Program at Baylor College of Medicine.