Dr. Valeria Tosello, Biologist

Research topic

De-regulated signaling pathways in T-leukemia/lymhoma, mechanisms of resistance and relapse.

Background

T-lineage acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of pediatric and 25% of adult ALL cases. The introduction of intensive combination chemotherapy protocols has led to remarkable improvements in survival for this disease; however, in contrast with the favorable response to therapy in patients at diagnosis, the prognosis of T-ALL patients with relapsed leukemia remains poor, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective anti-leukemic drugs. Our research interest focuses particularly on those alterations which result still poorly understood.

Research activities

1. NOTCH1 pathway results mutated in over 60% of cases of T-ALL cases, making NOTCH1 oncogene an appealing molecular target in T-ALL. In the last years, different attempts to target NOTCH signaling in T-ALL have been developed: the administration of GSI, which block cleavage of NOTCH receptors and the use of anti-NOTCH1 antibodies that more specifically target T-ALL cells carrying NOTCH1 activation. In this scenario, the understanding of the molecular mechanisms downstream of NOTCH1 signaling is fundamental to design novel therapeutic strategies. In particular, an altered metabolism downstream NOTCH1 is recently emerging. Our laboratory is now focused on the role of NOTCH1 pathway in deregulated metabolism with particular respect to amino acid metabolism. Always in the context of oncogenic NOTCH1 signaling, our laboratory is studying the role of microRNA in T-ALL growth and survival.
2. The diagnosis of lymphoid malignancy remain challenging in about 10% of lymphoproliferative disorders and clonality tests are often requested to confirm diagnostic hypotheses. Currently, the goal standard method to analyze clonaltity for clinical molecular diagnostic is based in PCR-based approaches. Our laboratory is currently implementing this analysis with next generation sequencing approaches. This analysis will allow the identification of clonality at diagnosis with a more quantitative a sensitive approach and the eventual re-emergence of these clones after the treatment.

Conclusions and perspectives

Approximately 20% of pediatric and 50% of adult T-ALL cases still relapse and ultimately die because of refractory disease, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective anti-leukemic drugs. The better understanding of the mechanistic role of each of alterations will help the design of new targeted combination therapies incorporating specific inhibitors to conventional anti-leukemic drugs.