Screening of drugs that cross the blood-brain barrier in the identification of new therapies in CNS tumors and Childhood Acute Lymphoblatic Leukemias

• Grant number: 22/09037-3
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2022
• End date: November 30, 2025
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Carlos Alberto Scrideli
• Grantee: Carlos Alberto Scrideli
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Elvis Terci Valera ; Rodrigo Alexandre Panepucci

Abstract

Acute lymphoblastic leukemias (ALL) and central nervous system (CNS) tumors represent the largest group of childhood tumors. Despite therapeutic advances, the prognosis of CNS tumors is still poor, and they continue to be the main cause of cancer mortality in children. In ALL, despite a better prognosis, 10-15% of children relapse and in 40% of cases present CNS infiltration. The chemoresistance and therapeutic failures frequently observed in these tumors have been largely attributed to the inability of conventional chemotherapeutic agents to cross the blood brain-barrier (BHH) and reach their targets in the tumor tissue. Currently, new approaches and therapeutic compounds are being sought that effectively surpass the BBB and reach tumor cells and lead to higher survival rates in CNS tumors/ALL, thus emphasizing the importance of identifying compounds with these characteristics for the most aggressive tumors. The drug screening methodology associated with HCS (High Content Screening) has been widely used to assess the possible efficacy of concomitant drug combinations, in addition to allowing the visualization and monitoring of various cellular phenotypes and protein localization in preclinical trials. Thus, the hypothesis of this project is that new compounds, which surpass the BBB, show promising antitumor effects and/or sensitize tumor cells to conventional chemotherapeutics and offer new therapeutic opportunities for patients with CNS tumors and leukemias. To reach this hypothesis, we will: 1) evaluate the effect of compounds that surpass the BBB on the viability of CNS tumors and leukemia cell lines by a drug screening using HCS; 2) Identify the compounds with the most promising antitumor effects; 3) Evaluate the effects of the most promising compounds on cell migration and invasion, through HCS, using these strains; 4) Evaluate the effects of combining conventional treatment therapies with the compounds selected as most promising through HCS; 5) Assess by RNASeq potential altered target molecules after treatment with the most promising compounds. (AU)