Investigation of the antineoplastic potential of new drugs that modulate microtubule dynamics in Acute Myeloid Leukemia

• Grant number: 21/01460-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: July 01, 2022
• End date: July 31, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Hugo Passos Vicari
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute Myeloid Leukemia (AML) is a heterogeneous malignant hematologic neoplasm caused by the accumulation of mutations and molecular changes in Hematopoietic Stem Cells (HTC), culminating in the accumulation of abnormal and immature myeloid cells in the bone marrow and in ineffective hematopoiesis. Despite great advances in understanding the complexity involved in the biology and clinic of AML over the years, very little has been translated into new therapies. Microtubule dynamics are critical for the success of mitosis and, therefore, necessary for cell proliferation. Thus, microtubules are considered one of the key molecular targets for cancer treatment. In this sense, our research group identified a new class of compounds, the cyclopenta[b]indoles, capable of modulating microtubule dynamics and selectively inducing apoptosis in ATRA-sensitive and ATRA-resistant Acute Promyelocytic Leukemia (APL) models. From a molecular point of view, compound 2 inhibited STMN1 expression and induced the expression of DNA damage markers and caspase activation. Given the above, the aim of this project is to investigate the in vitro and in vivo cellular and molecular effects of cyclopenta[b]indole (compound 2) on a broad panel of cell lines and primary cells from AML patients. Our expectation is that the findings so far found in LPA models can be translated into AML models with less established biology and target-specific therapy orphans. (AU)

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)

VICARI, HUGO PASSOS; LIMA, KELI; COSTA-LOTUFO, LETICIA VERAS; MACHADO-NETO, JOAO AGOSTINHO. Cellular and Molecular Effects of Eribulin in Preclinical Models of Hematologic Neoplasms. CANCERS, v. 14, n. 24, p. 15-pg., 2022-12-01. (21/01460-1, 19/23864-7, 19/01700-2, 21/11606-3)