Preclinical study of a colchicine binding site tubulin inhibitor with potent anti-leukemia activity and low toxicity

• Grant number: 17/14737-6
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): December 11, 2017
• Effective date (End): December 10, 2018
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Nathalia Moreno Cury
• Supervisor abroad: Sinisa Dovat
• Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Local de pesquisa : Penn State College of Medicine, United States
• Associated to the scholarship: 14/08247-8 - Preclinical studies of novel inhibitors of DNA methyltransferase in acute leukemia, BP.DR

Abstract

Acute lymphoblastic leukemia (ALL) has an excellent cure rate, but 20% of patients still relapsed. Relapsed leukemia cells show a higher expression of membrane-associated ATP-binding cassette (ABC) transporters when compared to leukemic cells at diagnosis. Overexpression of ABC transporters decreases intracellular drug levels, consequently limiting drug cytotoxicity since they pump drug molecules off the cell. Discovery of new drugs and therapeutic targets can help to improve these rates. Microtubule inhibitors represent a group of promising compound in ALL treatment, since leukemic cells require intact microtubules for proper cell division. We have worked with an acylhydrazone, called compound #12, which exhibited strong anti-microtubule and anti-leukemia activities, in vitro. Besides, compound #12 is not a target of ABC transporters and showed very low in vivo toxicity. The aim of this project is to test compound #12 against xenograft models of high-risk ALL expressing the multidrug resistant (MDR)phenotype, characterizing its cellular mechanism(s) of action. The screening of the high risk ALL xenograft for the MDR phenotype will be performed, using the calceín exclusion assay. The anti-leukemia effect of compound #12 will be tested in comparison to vincristine, by measuring the presence of leukemia cells in peripheral blood, weight loss and survival in three high risk ALL xenografts with the MDR phenotype. Finally, the elucidation of compound #12' mechanisms of action in comparison to vincristine and colchicine will be done using gene expression analysis and functional validation of potential targets. (AU)