Membrane transporters and drug resistance in pediatric acute lymphoblastic leukemia

• Grant number: 23/18389-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Adrielli Caroline Soares
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

The primary cause of mortality in pediatric acute lymphoblastic leukemia (ALL) is its relapse. Relapse occurs mainly due to cell resistance to chemotherapy drugs. One of the causes of this resistance is the increased efflux of drugs, mainly carried out by ATP-binding cassette (ABC) transporters, which have been previously associated with cellular resistance to chemotherapy. In this context, this project will assess the possible relationship between resistance to three drugs (vincristine, idarubicin, and cytarabine), the concentration of these drugs within primary ALL cells after 3 hours, the expression of membrane transporters, and the involved polymorphisms. Forty samples will be selected for each drug, comprising 20 samples from sensitive patients and 20 samples from resistant patients. Patient selection is based on the LD50 value obtained in the Ex-vivo Leukemia Drug Advisor (ELDA), a method that is being realized by our laboratory that evaluates the cytotoxicity of 62 drugs in primary ALL cells over an 80-hour period. Using mass spectrometry, we will quantify the intracellular concentration of the three drugs in primary ALL cells. The expression of membrane transporters will also be quantified at the RNA level (RNAseq), and polymorphism analysis will be performed. Finally, the results will be analyzed, and associations will be sought among them. It is anticipated that resistant ALL cells will accumulate a lower concentration of drugs, express more membrane transporters responsible for drug efflux, and exhibit a polymorphism profile favoring the maintenance of low intracellular drug levels compared to sensitive ALL cells.