Activities

The Anaplastic Lymphoma Kinase (ALK) is the “driver” oncogene of several tumor types, including Anaplastic Large Cell Lymphoma (ALCL), Non Small Cell Lung Cancer (NSCLC), Inflammatory Myofibroblastic tumors (IMT) and Neuroblastoma (NB). Most ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, activating ALK mutations (i.e. NB) and ALK copy-number gains have been described. In most ALK-positive tumors maintenance of the neoplastic phenotype is totally dependent on ALK oncogenic signaling and its inhibition is the key for therapy. The development and FDA approval of first and second-generation ALK tyrosine kinase inhibitors (TKI) has revolutionized the therapeutic options for ALK-positive cancers. Nonetheless, therapeutic resistance has limited the efficacy of these treatments. Several molecular mechanisms of resistance have been proposed for TKI resistant tumors, such as alterations in the targeted oncogene (“on-target” resistance), or in other downstream and parallel pathways  (“off-target” resistance). More recently, the heterogeneity of cancer cells and the presence of sub-populations of drug-tolerant cells (the so-called “persisters”) have been associated with resistance to therapy. Thus, there is still limited understanding on how acquired resistance develops and undermines the effects of ALK TKIs.

My laboratory aims at unveiling mechanisms of transformation in ALK-positive tumors in order to define new therapeutic vulnerabilities and to find innovative treatments. In addition, the laboratory is involved in the discovery of novel mechanisms of resistance to ALK TKI treatment, thus providing important evidence for novel therapeutic approaches in ALK-positive tumors. To discover these mechanisms, we will use high throughput screening techniques such as whole genome sequencing (WES), RNA-sequencing and proteomics and we will develop murine models along with more innovative 3D models to study the biology of these mechanisms.

Another line of research is the study of the role of the RHO GTPases in lymphomagenesis, in particular in anaplastic large cell lymphomas (ALK+ and ALK- ALCL). The hypothesis is that RHO GTPases are key biological regulators of both ALK+ and ALK- ALCL representing novel targetable vulnerabilities that can be exploited in ALCL alone or combination with other existing treatments. Our findings can potentially highlight therapeutic targets for other T cell lymphoma.

Projects:

• Unraveling mechanisms of cell transformation by oncogenic ALK
• Identifying putative mechanisms of drug resistance in ALK-driven tumors
• Studying the role of RHO GTPases in T cell lymphomageneis

Group:

• Dr. Claudia Voena, PhD, Tenure Track Researcher (PI) 

• Dr. Chiara Pighi, PhD, Post-doc, Research fellows

• Gloria Giacomello, Student