The research unit Molecular Oncology and DNA Damage Response focuses its studies on the cellular response and the molecular mechanisms leading to resistance to DNA damaging-based therapies, such as platinum-derived agents and PARP inhibitors. The ultimate goal is to develop novel and rationalized therapeutic approaches that eradicate tumors and prevent subsequent relapse.
Implementing breast and ovarian cancer ex vivo models to study the response to PARPi-based therapy
Through a close collaboration with clinicians (oncologists and surgeons), our primary goal is to establish organotypic models from cancer patients to study ex-vivo the mechanisms determining therapy response. In particular, we focus on triple-negative breast cancer, high grade serous ovarian carcinoma and castration resistant metastatic prostate cancer, which frequently harbor mutations in the BRCA1/2 genes.
Studying the role of the kinases DNA-PKcs and ATM in the cellular resistance to PARPi in BRCA-deficient tumors
Another line of investigation is the study of intracellular signaling mechanisms triggered by the DNA damage response kinases DNA-PKcs and ATM. Recent works from our lab have revealed that the use of selective inhibitors against these kinases can augment PARPi sensitivity in BRCA-deficient mammary tumor models (Dibitetto et al. 2022 Molecular Cell; Dibitetto et al. 2024 Nature Communications). The goal of this line of research is to elucidate the cellular pathways controlled by these kinases and to comprehensively identify their phosphorylation targets through phosphoproteomic studies.
Studying the role of the kinases DNA-PKcs and ATM in the cellular resistance to PARPi in BRCA-deficient tumors
The final research objective is to implement molecular tools to study the mechanism of action of PARP inhibitors in ex vivo and in vivo tumor models. The primary outcome will be to elucidate how PARPi affect the structure of replication forks in actively proliferating tumors by combining biochemical tools with state-of-the-art electron microscopy.
International Consensus on Cardiopulmonary Resuscitation.
