Dr. Erich Piovan, MD, PhD
During my research career I have contributed to determining the role of Epstein Barr virus reactivation and de novo infection of B lymphocytes to tumor outgrowth in Severe Combined Immunodeficient (SCID) mice injected with human peripheral blood mononuclear cells (hu/SCID), a relevant B lymphomagenesis model (Leukemia 2003). I subsequently went on to study the role of chemokines and chemokine receptors in the pathogenesis of human B cell lymphomas which arise in immunodeficient mice (hu/SCID lymphomas), demonstrating the importance of the CXCL12/CXCR4 axis in lymphoma generation in this experimental model (Blood 2005). Stemming from these observations, I went on to dissect the role of hypoxia in the regulation of the CXCL12/CXCR4 axis in malignant B cells (Cancer Res 2007). Following my experience in Adolfo Ferrando’s Laboratory (New York) and my return to Padua University, I have contributed to elucidate the role of constitutive AKT activation (often due to PTEN alterations) in regulating glucocorticoid response in T-cell acute lymphoblastic leukemia (T-ALL) patients. More specifically, we found that AKT1 is able to interact and modify (phosphorylate) the glucocorticoid receptor, leading to an alteration of its functional properties (Cancer Cell 2013). Recently, we have investigated the role of constitutive calcineurin activation in the pathogenesis of T-ALL and executed a proteomics approach to identify core interacting proteins and signaling pathways associated with Calcineurin complex (Oncotarget 2016). With this comprehensive analysis of proteomic data, we have identified novel combination therapies including Calcineurin and GSK-3 inhibition for treatment of T-ALL (Leukemia 2015).
Targeting de-regulated signalling pathways in T cell acute lymphoblastic leukemia (T-ALL)
Evaluation of the de-regulated signaling pathways involved in the pathogenesis of T-ALL will open new possibilities for targeted therapies.
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 antileukemic drugs. Our research interest focuses particularly on those alterations which result still poorly understood.
- The role of calcineurin/nuclear factor of activated T cells (NFAT) pathway activation in leukemogenesis is unclear, in particular its key molecular regulators and substrates that could have an important role in tumor development and could be potentially targeted by drugs remain to be elucidated. NFATs play critical roles in many developmental processes, the immune response, and have been recently implicated in the induction and progression of haematological malignancies. The molecular mechanisms that account for the sustained activation of calcineurin in leukemic cells remain to be identified. It is thus critical to identify in specific leukemias and lymphomas the signaling cascades that function upstream of the calcineurin/NFAT signaling and the genetic and epigenetic mechanisms that drive constitutive nuclear localization of NFATs, as well as the genes that drive these malignancies.
- The evolutionary conserved Hedgehog (Hh) signaling pathway plays a crucial role in patterning and organogenesis during early development, in adult tissue maintenance and repairing functions. Aberrant Hh signaling has been described in numerous tumors. Recently, Hh signaling has been shown to be activated in a subgroup of T-ALL cases, however the role of Hh signaling in the pathogenesis of T-ALL is still unclear. Through gene knock-out studies complimented with gene expression profiling studies and quantitative proteomics we aim at elucidating the mechanistic role of Hh signaling in T-ALL.
- Diffuse Large B-cell Lymphoma (DLBCL) represents an heterogeneous disease, which can be molecularly (as determined by GEP) sub-divided into 3 main groups: activated-like (ABC), germinal center-B cell like (GC-B) and unclassified/primitive mediastinal B-cell lymphoma. Retrospective analyses have shown that the ABC-subgroup has a significantly worse prognosis than the GC-B subgroup when treated with the standard R-CHOP chemotherapy. Currently, IHC based assays used to distinguish the two subgroups using routine FFPE sections have demonstrated poor reproducibility and incapacity to obtain a meaningfull stratification of patients. To try to address this issue and improve the possibility of identifying key pathways implicated in patient survival/prognosis and identify mechanisms of drug resistance, we are evaluating a novel proteomics approach based on Forward Phase Protein Arrays (FPPA) applicable to routine FFPE specimens.
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 these pathways lay the grounds for targeted combination therapies incorporating specific inhibitors to conventional anti-leukemic drugs. Amongst DLBCL patients, even with GC-B type, >30% relapse after standard R-CHOP, so the identification of resistance mechanisms and the identification of reliable molecular prognostic markers or markers predictive of response will be critical for improving patient survival.
- Valeria Tosello (co-leader)
- Valentina Saccomani
- Deborah Bongiovanni
- Tosello V., Saccomani V., Yu J., Bordin F., Amadori A., Piovan E (2016). Calcineurin complex isolated from T-cell acute lymphoblastic leukemia (T-ALL) cells identifies new signaling pathways including mTOR/AKT/S6K whose inhibition synergize with Calcineurin inhibition to promote T-ALL cell death. ONCOTARGET, ISSN: 1949-2553, doi: 10.18632/oncotarget.9933
- Tosello V, Bordin F, Yu J, Agnusdei V, Indraccolo S, Basso G, Amadori A, Piovan E. Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation. LEUKEMIA, ISSN: 0887-6924, doi: 10.1038/leu.2015.335
- Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, Sanchez-Martin M, Perez-Garcia A, Rigo I, Castillo M, Indraccolo S, Cross JR, de Stanchina E, Paietta E, Racevskis J, Rowe JM, Tallman MS, Basso G, Meijerink JP, Cordon-Cardo C, Califano A, Ferrando AA. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell. 2013 Dec 9;24(6):766-76. doi: 10.1016/j.ccr.2013.10.022. Epub 2013 Nov 27.