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In vivo Repolarization of Tumor-Associated Macrophages (TAMs) towards M1 Anti-Tumor Macrophages in Acute Myeloid Leukemia

Grant number: 23/15512-9
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): March 01, 2024
Effective date (End): February 28, 2025
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Eduardo Magalhães Rego
Grantee:Lucio Henrique Sousa Pinheiro
Supervisor: Stuart Rushworth
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of East Anglia (UEA), England  
Associated to the scholarship:20/16739-9 - Repolarization of Tumor-Associated Macrophages (TAMs) towards M1 anti-tumor macrophages in Acute Myeloid Leukemia: a murine model, BP.DR

Abstract

Acute myeloid leukaemia (AML) is a malignant haematological disorder caused by uncontrolled proliferation and impaired differentiation of myeloid progenitor cells. Recent studies suggest that not only intrinsic mutations drive leukemogenesis but that the bone marrow (BM) microenvironment can facilitate the expansion of leukemic cells. Hence, new therapeutic approaches that target both the leukemic cells and their surrounding environment are of interest to improve the clinical outcome of AML patients. Amongst different niche cells, macrophages are phagocytic immune cells with high inherent plasticity. As a result, macrophages can both eradicate a tumour or promote cancer initiation and progression. A simplified conceptual framework has classified macrophages into two subpopulations: M1 and M2 macrophages. Previously, our group showed that AML-associates macrophages (AAMs) carry M2-like features and are associated with poor prognosis in AML patients by giving support to leukemic cells and creating a more permissive BM niche. Given this data, we aim to repolarize AAMs-M2 towards M1-like phenotype by treating them with plinabulin and selumetinib, two drugs that have been reported to repolarize macrophages from M2 to M1 in solid tumours. Our results showed that treating macrophages with both drugs in vitro increased the expression of M1 markers, while the expression of M2 markers was decreased. Next, we want to test the polarization capacity of these drugs in vivo using the MEIS1/HOXA9 and MN1-driven murine AML models.

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