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Genetics and therapy of cancer

Prof. Roberto Chiarle (Principal Investigator)

   

Activities

My laboratory is interested in mechanisms and therapy of cancers. One main focus of the lab is to elucidate the mechanisms that drive transformation of lymphocytes. Most lymphomas, but also an increasing number of solid tumors, are characterized by defined oncogenic events, such as chromosomal translocations. One line of research in the lab is dedicated to the elucidation of basic principles that govern chromosomal translocation formation in normal and neoplastic cells. We contributed to development of a method to comprehensively map translocations at a genome-wide level. By leveraging this method called High-Throughput Genome-wide Translocation Sequencing (HTGTS) we began a series of studies aimed at defining general rules for translocation formation, focusing on how transcription, DNA Double Strand Breaks (DBSs), tissue specificity and other nuclear or DNA repair factors can influence the type and the frequency of translocations found in human cancers.

A large area of research in the lab focuses on tumors driven by oncogenic alterations of the Anaplastic Lymphoma Kinase (ALK) gene, such as translocations and activation mutations that are characteristic of Anaplastic Large Cell Lymphoma (ALCL), Non-Small Cell Lung Cancers (NSCLC) and other types of solid tumors including neuroblastoma. We have extensively studied the role of ALK in lymphoma and in lung cancer using in vitro and in vivo models. We are currently implementing innovative ALK-specific immunotherapies. We developed an ALK vaccine that generates strong and specific immune responses against tumors cells that express ALK as an oncogenic driver. We are also developing ALK-specific chimeric antigen receptor (CAR) T cells to target tumors that express ALK on their surface, such as neuroblastoma. Finally, we aim at discovering and validating novel mechanisms of resistance to targeted therapy in ALK-driven cancers.

Another line of research in the lab is devoted to understanding the pathological role of the Activation-Induced Cytidine Deaminase (AID) in lymphoma and leukemia. Using whole exome sequencing (WES) technology, we aim at identifying AID-dependent mutational signatures of resistance and progression to idelalisib (a PI3Kd inhibitor) or ibrutinib (a BTK inhibitor) treatment in chronic lymphocytic leukemia (CLL). Our study will contribute to discovery of novel therapeutic targets for precision medicine in CLL treatment and in preventing CLL transformation.

Group:

International collaborative project (2018-2020) with the Shanghai Jiao Tong University supported by the Ministero degli Affari Esteri e della Cooperazione Internazionale (MAECI)

European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network (ITN-ETN) Grant, Award No.: 675712 for the European Research Initiative for ALK-Related Malignancies (ERIA)

 

 

 

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