Molecular characterization of drug response pattern in pediatric T-cell acute lymphoblastic leukemia

• Grant number: 24/03384-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2024
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Gabriella de Oliveira Fortes
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Acute Lymphoid Leukemia (ALL) is the most common type of pediatric cancer, being subclassified into B-cell ALL and T-cell ALL (T-ALL). T-ALL is an aggressive neoplasm, responsible for 15% of pediatric ALL cases, and is characterized by the abnormal proliferation of cells similar to T lymphocyte progenitors, which, due to an accumulation of molecular changes, have their maturation cycle interrupted, resulting in the proliferation of leukemic cells in the bone marrow, thymus, and other lymphoid organs. Currently, survival rates reach almost 90% in developed countries, and are achieved thanks to treatment based on relapse risk stratification and intensive chemotherapy. However, around 20% of cases relapse, and the prognosis for these patients is significantly lower. B-ALL relapses can be treated with the CD3-CD19 bispecific antibody Blinatumumab, recently approved by the SUS. T-ALL, however, do not express CD19 and do not benefit from this alternative. Fortunately, in recent years there have been great advances in the knowledge of genetic alterations and oncogenic intracellular signaling pathways in T-ALL. This knowledge, combined with the recent development of target-specific drugs, motivates us to investigate whether some of these drugs would be effective against T-ALL and under what circumstances there are mutations or molecular changes. In the present project, we propose to characterize the transcriptional profile, gene mutations/fusions and DNA methylation of leukemic blasts from patients with T-ALL, correlating these findings with the in vitro response to 61 chemotherapy drugs, from the most diverse classes. It is expected to discover new therapeutic agents for T-ALL, along with biomarkers of response.