BRCAness as therapeutic target in HR pediatric solid tumors

Despite a concerted European effort to widely apply next-generation molecular diagnostics, cure rates for pediatric solid tumors at relapse remain dismal. Approximately 50% of cases do not have an obvious genetic drug target. Our recent pediatric pan-cancer study (www.pedpancan.com) suggests that a large proportion of Ewing sarcoma, osteosarcoma, glioblastoma, medulloblastoma, neuroblastoma and rhabdomyosarcoma, all of which are entities of high medical need, show a mutational signature compatible with BRCAness, implicating sensitivity to PARP inhibition. We hypothesize that a fraction of pediatric solid tumors with a BRCAness mutational signature will be sensitive to PARP inhibition. We aim to (i) assess the sensitivity of BRCAness positive tumors (and negative controls) to combinations of PARP inhibitors and DNA-damaging chemotherapy in vivo and (ii) tune our BCRAness calling algorithm by using preclinical in vivo response data for its first clinical application. As secondary aims, we strive to understand the degree of BRCAness necessary to sensitize for PARP inhibition, the underlying genetic causes, resistance mechanisms, and the predictivity of in vitro testing. The preclinical phase II trial BRCAddict will be performed in an n=1 fashion with 10 different PDX models from six different entities in each treatment arm. BCRAness will be assessed by whole- genome and transcriptome sequencing of the models using an established bioinformatic algorithm. We expect 30-80% of BRCAness positive cases in the entities of interest. In vitro testing of the same combinations will be performed in a cell line panel and drug responses will be compared with in vivo data. The results of this preclinical trial and the accompanying biomarker evaluation will lay the groundwork for a molecularly stratified phase II study across pediatric solid tumors within the European Innovative Therapies for Children with Cancer (ITCC) network, in which all applicants are involved.