Phosphoproteomics for ALL Diagnostics and Research

Research Activity

The group is in charge of the Reverse Phase Protein Arrays (RPPA) facility that allows the identification of new disease biomarkers and new therapeutic targets in oncological and non-oncological diseases through phosphoproteomic profiling. To do so we dispose of a library of more than 130 validated antibody belonging to the most deregulated pathways in cancer and inflammation, and a full equipped facility for sample preparation, slides printing and staining. We believe that monitoring the activation status of signal transduction pathways will be key to identify patient subgroups that can benefit from the use of specific kinase inhibitors and to point out proteins suitable for patient risk stratification and targeted therapy. In recent years through RPPA we identified and then validated new potential biomarkers and therapeutic targets for B and T Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML) and T cell Acute Lymphoblastic Lymphoma pediatric patients (T LBL).
In particular, on-going projects include identification of new glucocorticoid resistance mechanisms in T ALL pediatric patients and identification of new biomarkers useful to recognize patients that at relapse could benefit of novel targeted therapeutic approaches.

Identification of new glucocorticoid resistance mechanisms in T ALL pediatric patients

In the past five years our research mainly focused on the study of molecular mechanisms responsible of glucocorticoid resistance in T ALL pediatric patients. Indeed, we observed the hyperactivation of LCK kinase in patients more resistant to glucocorticoids and in ETP T ALL, a subset of patients highly resistant to therapy (Serafin V. et al, Blood 2017). The pharmacological inhibition or the specific gene silencing of this kinase in glucocorticoid resistant cells turn them sensitive to corticosteroids both in vitro and in vivo (Serafin V. et al, Leukemia 2017). Starting from these evidences we identified among the molecular mechanisms underlying the glucocorticoid resistance in T-ALL patients the involvement of NFATs family transcription factors. Thus, we are now designing and testing novel inhibitors able to suppress the NFAT family transcription factor activity (Supported by AIRC “My First AIRC Grant” and FUV).

Identification of new biomarkers useful to recognize patients that at relapse could benefit of novel targeted therapeutic approaches

Nowadays relapse represents the major obstacle in pediatric T-acute lymphoblastic leukemia (T-ALL) patients’ treatment, since for relapse patients the prognosis remains dismal due either to the drug resistance or to the high toxicity for chemotherapy intensification. Thus, by performing the phosphoproteomic profile of poor and good prognosis relapsed T-ALL pediatric patients we aim to identify new biomarkers useful to recognize patients that at relapse could benefit of novel targeted therapeutic approaches, thus allowing the setting-up of novel therapeutic options to prevent therapy resistance occurrence and excessive toxicities (Supported by AIRC fellowship to Giulia Veltri PhD).