Despite some advances, the long-term disease control in many children remains elusive; improved survival has been largely driven by dose escalation and introduction of new agents, but in many survivors, these therapies are coupled to long-term life-threatening sequelae. New therapeutics are desperately needed. Increased understanding of the molecular pathology for many childhood cancers, and growing awareness that 'homogeneous' diseases are in fact heterogeneous at a molecular level provide basis for identification of agents targeted at specific molecular drivers and development of effective therapeutics. This Core will provide a service for testing new agents/combinations, against a large p...

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Despite some advances, the long-term disease control in many children remains elusive; improved survival has been largely driven by dose escalation and introduction of new agents, but in many survivors, these therapies are coupled to long-term life-threatening sequelae. New therapeutics are desperately needed. Increased understanding of the molecular pathology for many childhood cancers, and growing awareness that 'homogeneous' diseases are in fact heterogeneous at a molecular level provide basis for identification of agents targeted at specific molecular drivers and development of effective therapeutics. This Core will provide a service for testing new agents/combinations, against a large panel (~400) of molecularly characterized Patient Derived Xenografts (PDX's; childhood cancers grown in mice) representing both childhood and adolescent/young adult hematologic and solid malignancies. The Core will facilitate pediatric cancer drug development within the context of the Research to Accelerate Cures and Equity for Children Act. The Act requires the Food and Drug Administration (FDA) to develop a list of molecular targets of known and new drugs/biologics. If agents are determined to be substantially relevant to the growth and progression of pediatric cancer, this may trigger the requirement for pediatric investigations by both Pharma and academic centers. Unique aspects of this Core are: • Bioinformatics-driven selection of molecularly appropriate tumor models; • PDX models that encompass molecular heterogeneity of a cancer type; • Testing approaches that facilitate incorporation of clinical heterogeneity. Our strengths include extensive experience of the Core Leaders in development and characterization of pediatric cancer models, successful development of novel agents that have been integrated into standard-of-care clinical protocols, and development of novel approaches to drug testing that encompass molecular heterogeneity of pediatric cancers.

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