Investigation of the effects of the multikinase inhibitor AD80 on models of acute myeloid leukemia with the FLT3-ITD mutation

• Grant number: 24/02695-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Lívia Bassani Lins de Miranda
• Supervisor: Jan Jacob Schuringa
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Groningen, Netherlands
• Associated to the scholarship: 22/03316-8 - Investigation of the effects of the multikinase inhibitor AD80 in hematological neoplasms with constitutive activation of tyrosine kinase pathways, BP.DD

Abstract

Acute myeloid leukemia (AML) is one of the most common types of leukemiacharacterized by the accumulation of immature blasts on the bone marrow or peripheralblood. Around one-third of the patients diagnosed with AML have mutations on the FLT3protein, a tyrosine kinase membrane receptor, and amongst those individuals around 25%present the FLT3-ITD mutation, which is a duplication of the internal portion of the protein,and 7% the FLT3-TKD mutation, an alteration on the kinase portion of the receptor. Thepresence of FLT3-ITD has been linked to poor prognosis and incidence of cases of relapse,highlighting the relevance of the phenotype to better understand the mechanisms of thedisease and define the best-suited therapy. Additionally, testing for the mutation multipletimes throughout the course of the disease is recommended. Due to the specificity of kinaseinhibitors, several molecules of this class have been developed, with some of them alreadyapproved by the FDA for clinical use. These molecules are divided into generations, first andsecond, and types, I and II. Examples of approved drugs are midostaurin, a first-generationtype I inhibitor, and quizartinib, a second-generation type II inhibitor approved in 2023.Although there are studies for the development of those drugs, patients still rely on a limitednumber of chemotherapy options. AD80 is a multikinase inhibitor described initially as aRET, BRAF, S6K, and Src inhibitor, and later studies showed it has activity against ERK andAKT. The synthetic molecule has been tested in different types of models, including solidtumors and hematological neoplasms, demonstrating potent antineoplastic potential againstcell lines and in murine models. AD80 has been tested in AML cells without FLT3 mutationsand, furthermore, our preliminary results indicate that the presence of the phenotypesignificantly increases the sensitivity of the cells to the treatment, indicating the importanceof the mutation. Our aim with the project is to further expand the knowledge of the effects ofAD80 on FLT3-ITD AML models utilizing cell lines and patient-derived cells, as well ashigh throughput analysis and in vivo models.