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).

Immunology and Molecular Oncology Unit
– Department of Translational Oncology and Health Services, IOV-IRCCS
– Section of Oncology and Immunology-DiSCOG, University of Padova

Research activity

Targeted therapeutic approaches in T cell acute lymphoblastic leukemia (T-ALL) and Diffuse Large B-cell lymphoma (DLBCL)

Evaluation of the de-regulated signaling pathways involved in the pathogenesis of T-ALL and DLBCL will open new possibilities for targeted therapies.

RESEARCH TOPIC AND BACKGROUND

T-lineage acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of pediatric and 25% of adult ALL cases. Our research interest focuses on identifying therapeutic targets in this disease. The research topics include: (i) evaluating the role of aberrant Hedgehog (Hh) signaling in T-ALL through gene knock-out studies complimented with gene expression profiling studies and quantitative proteomics; (ii) identifying pathways implicated in patient survival/prognosis and proteins associated with drug resistance in Diffuse Large B-cell Lymphoma (DLBCL) through a novel proteomics approach based on Forward Phase Protein Arrays (FPPA) applicable to routine FFPE specimens; (iii) identifying novel metabolic vulnerabilities in T-ALL.

MAIN RESEARCH LINES

  1. 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.
  2. 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.
  3. Identifying novel metabolic vulnerabilities in T-ALL by studying the role of non-conventional metabolic pathways such as Branched chain amino acid (BCAA) and AMP-activated protein kinase (AMPK) pathways in the growth of T-ALL cells.

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 reliable molecular prognostic markers or markers predictive of response will be critical for improving patient survival.

Team members

Co-leader

  • Valeria Tosello

Post-doc

  • Deborah Bongiovanni

PhD Fellow

  • Ludovica De Martino

Thesis student

  • Ilaria Talli

SUPPORTED BY

  • Fellowship Program 2018, Gilead;
  • AIRC 2018 (IG2018#22233);
  • Finanziamento di Ateneo SID, Università degli Studi di Padova
  • Fondi 5 per mille, Istituto Oncologico Veneto

Selected references