A Roadmap To Personalized Treatment Of Non Hodgkin Lymphomas (NHL)

Roberto Piva

Lymphoid malignancies are among the most frequent neoplasms characterized by a consistent rise of incidence and a consequent increase of the economic and social burden associated to their treatment.

Our focus is to unravel the molecular pathogenesis of fatal diseases orphan of genetic hallmarks such as Peripheral T-cell Lymphomas (PTCL), and to discover genes/pathways linked to acquired chemoresistance in mature B-cell neoplasms. The main objective is to identify specific therapeutic targets for these patients through the integration of structural and functional genomic approaches.

Specifically, we are pursuing three major tasks:

1. Identification of novel genetic alterations and subclasses of patients

Integrated analysis of gene expression, genomics, and epigenomic profilings, are associated to massive RNA and whole exome sequencing to identify classifiers and genetic lesions portraying primary PTCL.

2. Functional validation of causal defects involved in lymphomagenesis

To recognize “driver” genes causally implicated in the tumor phenotype and define the oncogenic properties of selected candidates, we are applying systematic functional assays using customized shRNA, CRISPR/Cas, and cDNA libraries.

3. Design of new therapeutic approaches for NHL patients

Tumorgrafts from NHL patients and conditional transgenic mice will be generated to dissect in vivo the oncogenic function of candidate genes and to test their susceptibility to molecularly targeted therapies. These new mouse models will reveal instrumental for the design of preclinical trials tailored to specific NHL subclasses.

We expect that the integration of structural and functional genomics methods will contribute to decipher critical somatic mutations, and define regulatory pathways to which lymphomas are addicted.

The unifying concept of our approach is to broaden the knowledge on NHL pathogenesis by discovering novel driving genetic lesions and by exploiting the latter to improve diagnosis, prognostic stratification, and therapeutic outcome.