Novel combination therapies targeting replication stress resistance and DNA damage repair

Neuroblastoma is a pediatric tumor of the sympathetic nervous system associated with poor survival in high-risk cases. Current options for targeted therapy for high-risk neuroblastoma patients are limited and single compound strategies almost invariably fail due to escape mechanisms, driven either by initial tumor heterogeneity or through adaptive (epigenetic) responses or mutations. While initiatives such as ITCC (www.itcc-consortium.org) explore novel therapies in neuroblastoma patients through phase 1 clinical (basket) trials, parallel intensive research programs to identify novel therapeutic vulnerabilities and drug targeting strategies are of utmost importance to fuel these initiatives with novel ideas for more potent drugs and combinations thereof with limited toxicity. Evidence is emerging that cancer cells can adopt a so-called ‘addictive cellular state of replication stress resistance’. Such adaptations can serve as cancer vulnerabilities and potential novel drug targets. Embryonal tumors such as neuroblastoma, a pediatric tumor of the sympathetic nervous system, may even have retained the blueprint of the replicative stress resistance phenotype of (embryonic) stem cells which protects them from DNA damage-induced premature aging. While several important chemotherapeutic compounds impose replication stress in cancer cells to toxic levels, more recent small molecule-based approaches are now emerging which target DNA damage response pathways. Our team exploits the therapeutic power of small molecule inhibitors impacting on key vulnerable therapeutic nodes in the replication stress response or DNA damage repair pathways as novel entry points for innovative and effective combination therapeutic regimens.