Exploring mechanisms of resistance in adult and pediatric T-acute lymphoblastic leukemia

Investigador:: Dra. Anna Bigas Salvans
Institució:: FUNDACIÓ INSTITUT MAR D’INVESTIGACIONS MÈDIQUES

Collaborators:

Dr. Josep M. Ribera, INSTITUT D'INVESTIGACIÓ JOSEP CARRERAS

Dra. Núria López Bigas, UNIVERSITAT POMPEU FABRA

Dra. Eulàlia Genescà, INSTITUT D'INVESTIGACIÓ JOSEP CARRERAS

Project description

Leukemia relapse, which is associated with therapy resistance, has been studied for a long time without providing valid alternatives for some groups of patients. The adult T-Acute Lymphoblastic Leukemia (T-ALL) patients belong to one of these groups with a low survival rate (around 50%). It is nowadays that the power of new technologies invites to revisit this old question with a different perspective and expectations.

To provide definitive clues to this particular clinical subject, we have assembled an outstanding consortium comprised by internationally leading experts in three different disciplines of cancer/leukemia research including clinical, experimental and computational research. The current project proposes the identification of genomic alteration driving tumourigenesis and therapy resistance in human T-ALL by studying DNA alterations that are selected during tumour evolution. With this aim, we will perform whole exome sequencing (WXS) of matched adult T-ALL patient samples at diagnosis, remission and relapse. The succession of genomic alterations (and their prevalence) identified at different time points will be analysed computationally to identify potential alterations directly involved in tumor development and relapse, and functionally validated (in terms of T-ALL evolution and therapy resistance) in animal models, patient-derived tumour xenografts, or cellular models. Next, we will use all these information to determine the minimal mutational signature capable to predict tumor relapse in a cohort of >100 T-ALL patient samples. When validated, this signature will be used to design a test (T-ALL-ChIP) that could be clinically implemented for patient stratification and diagnosis. The information obtained will be implemented for studying paediatric T-ALL patients whose overall prognostic and survival rate are much better in the absence of relapse events. Finally, one of the members of our consortium has already generated an in silico-drug-prescription tool that will support the identification of novel therapeutic possibilities exploiting the vulnerabilities offered by the genomic make-up of the tumours.

In summary, this proposal aims to join efforts from groups with different but complementary expertise to uncover the mechanisms of therapy resistance in human T-ALL and provide new avenues for poor prognosis patients. Moreover, this study will potentially contribute to understand more general mechanisms of therapy resistance and clonal evolution of cancer cells.

Contact person: Dra. Eulàlia Genescà

Web link: http://www.carrerasresearch.org