Despite a concerted European (and global) effort to widely apply next-generation molecular diagnostics and thus identify tailored treatment approaches, cure rates for paediatric solid tumours at relapse remain dismal. Approximately 50% of tumour samples do not harbour an obvious genetic drug target. Our recent paediatric pan-cancer study suggests that a relevant proportion of Ewing sarcoma, osteosarcoma, glioblastoma, medulloblastoma, neuroblastoma and rhabdomyosarcoma, all of which are entities of highmedical need, show a mutational signature compatible with BRCAness, implicating sensitivity to PARP inhibition or other treatment targeting impaired DNA repair.
We hypothesized that a fraction of paediatric solid tumours with a BRCAness mutational signature will be sensitive to PARP inhibition or other treatment targeting impaired DNA repair.
We aimed to (i) assess the sensitivity of BRCAness positive tumours (and negative controls) to combinations of PARP inhibitors/drugs interfering with DNA repair 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 strived to understand the “degree of BRCAness” necessary to sensitize for targeted inhibition, the underlying genetic causes, resistance mechanisms, and the predictivity of in vitro testing.
The preclinical phase II trial within “BRCAddict” was performed as a single mouse trial with 10 different PDX models from six different entities for each of the different treatment arms. BRCAness was assessed by whole-genome and transcriptome sequencing of the models using established and newly implemented bioinformatics workflows. We expected up to 30% of responding tumours in some of the entities of interest. In vitro testing of the same combinations was performed in a cell line panel and drug responses were compared with in vivo data.
The results of this preclinical trial, which are currently being analysed, and the accompanying biomarker evaluation will lay the groundwork for further molecularly stratified phase II studies across paediatric malignancies, including solid and central nervous system tumours within the European Innovative Therapies for Children with Cancer (ITCC) network, in which all applicants are involved.