Recombinase-induced genomic structural variants in neuroblastoma (RecoN)

• Applicant: Professor Dr. Anton Henssen
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398299703

Despite intense efforts, the cure rates of childhood solid tumors such as high-risk neuroblastoma are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. To enhance the therapeutic indices of cancer therapies in adults, synthetic lethal cellular relationships have been successfully leveraged. However, little is known about therapeutically targetable synthetic lethal dependencies in childhood solid tumors. Furthermore, Neuroblastoma is characterized by recurrent chromosomal and complex genomic rearrangements, including chromothrypsis, preventing the ready identification of targets for molecular therapies. A conundrum in the field is how the genomic rearrangements observed in some tumors can occur at such a young age in otherwise genetically stable cells. We have now found that the majority of childhood solid tumors, and neuroblastoma in particular, express an active DNA recombinase PGBD5 that can promote sequence-specific genomic rearrangements in human cells. In preliminary experiments for this proposal, we used functional genetic approaches and found that cells deficient in DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified the ATR inhibitor AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce hypersensitivity to AZD6738. These findings delineate a therapeutically actionable synthetic lethal dependency in PGBD5-expressing neuroblastoma. Based on my preliminary data, I aim to elucidate how PGBD5 contributes to the genomic instability of pediatric tumors and to identify functional dependencies resulting from these processes. The long-term goal is to gain insights that are useful for the rational development of innovative personalized treatment strategies for pediatric patients suffering from cancer. The Emmy Noether Programme will enable me to independently work on and successfully complete this project. This study promises to provide key insights into a fundamental biological and clinical problem with the potential for broad and lasting significance in the understanding and treatment of childhood solid tumors.

• DFG Programme: Independent Junior Research Groups