Abstract IA36: Opportunities and challenges in pediatric oncology translational research: New drug development
Authors: Blaney Susan M. 
Published: May 2015

Abstract
There has been an unprecedented pace of discovery in this era of genomic medicine, particularly in the realm of tumor biology and the molecular pathogenesis of cancer. Simultaneously, the development of anti-cancer therapies such as imatinib and more recently crizotinib, have highlighted the potential for success using molecularly targeted therapies. Despite these scientific advances, improvement in the overall outcome for children with cancer, which had increased dramatically between the 1970's and the 1990's, appears to have plateaued. There are many reasons, both scientific and non-scientific, for these dichotomous results that present both challenges as well as opportunities in our quest to rapidly and safely develop rational and effective new therapies for the treatment of childhood cancers.
A major challenge is that childhood cancers are orphan diseases, comprising only 1% of the cancer diagnoses in the United States, with the total number of new diagnoses for all childhood cancers in the United States combined totaling less than 15,000 per year. The small number of children with cancer and their developmental differences in terms of organ and drug metabolizing enzymes, present distinct scientific as well as pragmatic challenges in the development of new agents and therapeutics for pediatric malignancies.
Scientific challenges are wide ranging and include prerequisite knowledge or elucidation of the target and the associated signaling pathways that drive oncogenesis or that contribute to drug resistance. Other challenges include the identification or discovery of agents that inhibit the identified target(s); the availability of predictive preclinical model systems to evaluate efficacy, including exploration of pharmacokinetic and pharmacodynamic correlates of both single agent as well as combination therapies; the availability of laboratory or radiographic biomarkers not only to enrich clinical trials but also to serve as early predictors of response; and the availability of user-friendly tools to query high-density data sets.
Practical challenges in the development of new therapies for children with cancer, which largely reflect the relatively small patient numbers, include: the consistent availability of pharmaceutical partner(s) willing to provide drug for preclinical and clinical studies, as well as to invest in the development of pediatric-friendly drug formulations; the need for increasingly sophisticated and integrated secure systems for data management, storage, and analyses to seamlessly integrate diverse data systems across countless entities as well as across preclinical, clinical, and research data sets; and a stable funding landscape.
In the United States (US) and the European Union (EU), a variety of legislative initiatives, enacted over the past two decades, provide pharmaceutical companies incentives to evaluate new agents in the pediatric population to ensure their safe and effective use. These efforts, which have similar goals but differ substantially in their implementation between the US and the EU, have been met with mixed success. A frequent obstacle to the timely and efficient conduct of new agent trials in the US, is the fact that many pharmaceutical sponsors are reluctant to initiate early phase clinical trials in until they have an approved Pediatric Investigation Plan by the European Medicines Agency. As a result delays that are sometimes substantial in activating early phase pediatric clinical trials for some new agents is an ongoing challenge.
Other practical challenges encountered in new drug development for childhood cancers are ironically a result of the progress that has been made in understanding tumor biology. We now realize that there is marked tumor heterogeneity in what was heretofore classified at the histopathologic level as a single disease entity. As a consequence of the further sub-classification of histopathologic diagnoses based on molecular or genomic characterization, orphan diseases have now become “orphans of orphans,” directly impacting clinical trial design and duration and underscoring the increasingly relevant need to expand the global network of collaboration and cooperation in the field of pediatric oncology. This challenge and those outlined above require will require an unprecedented level of cooperation and collaboration to develop standards for collection of clinical trial data, biospecimen collection and storage, as well as adherence to protocol guidelines, to ensure the highest quality data and specimens for future discovery and analyses. Herein lies a tremendous opportunity for new partnerships between academia, industry, pediatric oncology cooperative groups, and patient advocates at the national and international level to improve the outcome for children with cancer.
Citation Format: Susan M. Blaney. Opportunities and challenges in pediatric oncology translational research: New drug development. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA36.