Ricerc@Sapienza

Childhood cancers are the main cause of death for disease in children between 0 and 15 years of age. Although many advances have been done in their treatment, patients with high-risk and aggressive tumors still have a very poor prognosis. In this context, neuroblastoma and medulloblastoma are certainly the more common high-risk cancers, especially in the cases in which MYCN amplification occurs. Hence, searching a new effective therapy is extremely needful.
MYCN, like others oncogene, induces replication stress, a condition in which replication fork progression is prematurely interrupted leading to fork stalling or collapse. This requires activation of several cellular response to restrain it and to avoid DNA damage and finally to preserve cell survival. Therefore we believe that interfering these protective mechanisms could exacerbate MYCN-induced replication stress leading cancer cells to death.
It is well documented the role of PARP and CHK1 proteins in both replication stress response and DNA damage repair. In addition, we have recently shown that PARP and CHK1 inhibition enhances replication stress and causes mitotic catastrophe in MYCN amplified and overexpressing neuroblastoma cells, in agreement with their firmly established role in controlling RS and DNA repair.
Based on these findings obtained in cellular models, we propose to translate them into in vivo models using two tumor xenograft: human MYCN amplified neuroblastoma cells and mouse tumor-derived medulloblastoma spheres, in order to validate the anti-tumor activity of PARP and CHK1 inhibition.
The drugs we have planned to use are already approved for human administration. Therefore, by eventually showing that targeting the replication stress response by their means is possible and effective, our work will be immediately translatable into clinical trials for a number of MYC(N)-dependent deadly tumors including, but not limited to, neuroblastoma and medulloblastoma.