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Investigation of the effects of the multikinase inhibitor AD80 in hematological neoplasms with constitutive activation of tyrosine kinase pathways

Grant number: 22/03316-8
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): December 01, 2022
Effective date (End): April 30, 2027
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:João Agostinho Machado Neto
Grantee:Lívia Bassani Lins de Miranda
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):24/02695-0 - Investigation of the effects of the multikinase inhibitor AD80 on models of acute myeloid leukemia with the FLT3-ITD mutation, BE.EP.DD

Abstract

The activation of signaling pathways mediated by tyrosine kinases contributes to the development and progression of hematological neoplasms, of which we can highlight the BCR-ABL1 (Ph+), JAK2V617F and CSF3RT618I positive myeloproliferative neoplasms (MPN), and the FLT3-ITD positive acute myeloid leukemias (AML). These mutations cause constitutive activation of downstream targets, including the PI3K/AKT/mTOR, MAPK and JAK2/STAT signaling pathways. Despite the great success of tyrosine kinase inhibitors in the therapy of Ph positive chronic myeloid leukemia (CML), the emergence of mutations such as BCR-ABL1T315I indicates the need to expand the antineoplastic arsenal even in this context. Treatments with FLT3 have shown to improve the clinical outcomes of AML patients, although it was not as dramatically as seen in CML. On the other hand, JAK2 inhibitors improve symptoms but do not modify the natural history of Ph-negative MPN. There is also chronic neutrophilic leukemia (CSF3RT618I) which has very limited therapeutic options. In this scenario, the search for new antineoplastic agents becomes interesting. AD80 is a multikinase inhibitor able to inhibit the activity of RET, RAF, S6K, ERK and AKT proteins. It is a new molecule and, therefore, few studies have been carried out to date verifying its effects on tumor cells. Current data indicate that AD80 is a potent molecule and presents high toxicity, being able to inhibit proliferation and survival processes in in vivo and in vitro models. The present research project aims to investigate the effects of AD80 in hematological neoplasms models with constitutive activation of signaling pathways mediated by tyrosine kinases, analyzing cellular and molecular aspects. In addition, the research study aims to study the effects of AD80 considering the protection conferred by the hematopoietic niche through co-culture models. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LIMA, KELI; DE MIRANDA, LIVIA BASSANI LINS; GARNIQUE, ANALI DEL MILAGRO BERNABE; DE ALMEIDA, BRUNA OLIVEIRA; DO NASCIMENTO, MARIANE CRISTINA; ALCANTARA, GUILHERME AUGUSTO SOUSA; MACHADO-SANTELLI, GLAUCIA MARIA; REGO, EDUARDO MAGALHAES; MACHADO-NETO, JOAO AGOSTINHO. The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells. CANCERS, v. 15, n. 15, p. 14-pg., . (19/23864-7, 21/11606-3, 20/12842-0, 22/03316-8, 19/25421-5)

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