significant antitumor activity in preclinical models of childhood cancers that may be prioritized for clinical testing. The PPTP has characterized a panel of 23 cell lines and 57 xenograft models in the primary testing panel representing most of the more common pediatric solid malignancies and acute lymphoblastic leukemia subtypes (ALL). Additional cell line-derived and PDX models are available for expanded testing should an agent show activity against specific cancer types in the primary screen. Molecular characterization includes expression profiles, SNP analysis, and exome sequencing for all models. Agents tested include small molecule drugs, antibodies, antibody-conjugates, and replication competent viruses. The preclinical models accurately identified known clinically active drugs (vincristine, cyclophosphamide, cisplatin, topotecan), with an overall response rate of 40% (70/175 tests). In contrast, the overall response rate for 21 signaling inhibitors was ~2%, despite clear pharmacodynamic evidence showing target inhibition in several cases. For example, the MEK inhibitor selumetinib (AZD6244) was active against only a BRAF(V600E) mutated glioma xenograft among 45 models tested. Inhibitors of the IGF-1 receptor-TOR pathway induced regressions in 9 of 321 models tested (2.8%), with activity largely limited to sarcoma. Agents showing high activity at exposures in mice not achieved in patients at comparable schedules included the Aurora A kinase inhibitor alisertib, the Polo-like kinase inhibitor BI-6727, and the pre-pro-drug PR-104. At relevant patient exposures PR104 demonstrated activity only in T cell ALL models that have high AKR1C3 activity. The tubulin binding agent eribulin demonstrated broad activity against solid tumors and ALL models at dose levels relevant to clinical exposure, including 4 of 5 Ewing sarcoma models in which vincristine had low activity. Genomic explanations for ‘exceptional responders’ were identified for the MEK inhibitor selumetinib (see above) and for the PARP inhibitor BMN 673 (PALB2 biallelic mutations). Agents demonstrating high activity against leukemia models included the CD19-targeted antibody drug conjugate SAR-3419, the MDM2 inhibitor RG7112 and the Bcl-2 family inhibitor ABT-263. Agents (or combinations) that the PPTP identified as active that have advanced to clinical testing in children include: selumetinib in low-grade glioma (NCT01089101); alisertib in ALL and neuroblastoma (NCT01154816); NTX-010 (NCT01048892); temsirolimus + cyclophosphamide + vinorelbine for rhabdomyosarcoma (NCT01222715); BMN 673 + temozolomide (NCT02116777), and eribulin (NCT02082626). Supported by NO1-CM-42216 from the NCI.