Federica Di Nicolantonio, Ph.D.
Biomarkers for personalized colorectal cancer therapy
Colorectal cancer patients often show variable responses to treatment. This variation is the result of the molecular heterogeneity underlying the complex biology of cancer cells. Our main interest is therefore focused in understanding the changes that occur in tumor cells on exposure to anti-cancer agents. Our current programme concentrates on projects aimed at determining biomarkers of response or resistance to anti-cancer treatments with the ultimate goal of designing and testing sequences of drugs rationally designed on the modifications induced by the first agent on the tumor molecular landscape.
As a model, we focused on BRAF mutant colorectal cells with acquired resistance to target therapies combinations. Genotyping of resistant cells identified heterogeneous molecular mechanisms of acquired drug resistance that converge on reactivating MAPK signaling. Drug resistance could be overcome by ERK inhibitor-based or other targeted therapy combinations, based upon the selective target(s) identified in resistant cells. Of translational relevance, we demonstrated how the combined data obtained by tumor molecular profiling and functional experiments in cell lines informed physician’s choice of administering a specific sequential regimen, which induced clinical benefit in an individual BRAF mutant colorectal cancer patient.
Conclusions and perspectives:
This approach led us to define sequential strategies suitable for clinical testing in BRAF mutant colorectal cancer patients. As a future perspective, we intend to study how tumor preconditioning with epigenetic drugs could influence the response of BRAF mutant malignancies to subsequent anti-cancer therapies.