Investigation of potential molecular targets in models of acute myeloid leukemias with acquired resistance to venetoclax.

• Grant number: 23/01331-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2023
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Gustavo Nery de Queiroz
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignant hematological neoplasm caused by the accumulation of mutations and molecular alterations in hematopoietic stem cells and corresponds to the highest number of annual deaths from leukemias. The treatment of patients with AML has remained substantially unchanged for over 30 years. Recently, the AML treatment paradigm has been overcome with the emergence of selective target therapies. In this context, venetoclax has gained prominence and is a strong candidate to become first-line therapy in the medium term. Venetoclax (also known as ABT-199) is a selective BCL2 inhibitor and has shown promising results in groups of unfavorable or elderly AML patients. BCL2 family proteins are key regulators of apoptosis, playing an important role in the pathogenesis of AML. The mechanisms involved in the intrinsic resistance to venetoclax are better known in AML, but the acquisition of resistance is still a point to be explored and of clinical interest. The research project aims to induce resistance to venetoclax (acquired resistance) in cellular models of AML through exposure to increasing concentrations of the drug. Resistant cells will be characterized for cell viability, cell cycle progression, clonogenicity, apoptosis and metabolic profile in the presence or absence of venetoclax. The protein expression profile between parental and resistant cells will be evaluated by global proteomics and bioinformatics tools. We hope to identify cellular processes and signaling pathways that may guide pharmacological combinations to overcome acquired resistance to venetoclax.