Investigation and comparison of the cellular and molecular effects of IGF1R-IRS1/2 inhibitors and FLT3 inhibitors in acute myeloid leukemia.

• Grant number: 23/12606-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2024
• Status: Discontinued
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fabíola Traina
• Grantee: David Bastos Santos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Acute Myeloid Leukemia (AML) is an aggressive malignant neoplasm that leads to bone marrow failure and has a high potential for infiltration into other organs, often proving fatal if left untreated. AML accounts for approximately 1.9% of cancer-related deaths. Furthermore, data from the same institute indicate that this tumor predominantly affects middle-aged adults, with over 2/3 of cases occurring in patients above 50 years old. Although considered a rare neoplasm, AML exhibits a high mortality rate, as the overall 5-year survival rate is less than 50% of cases. For elderly individuals, this number is even lower, with only 20% surviving beyond diagnosis. LMAs are known for genetic alterations associated with them, such as mutations in FLT3, which play critical roles in the control of hematopoietic cell proliferation, survival, and differentiation. These mutations activate signaling pathways similar to other tyrosine kinase receptors, such as IGF1R. Thus, the objective of this study is to investigate and compare the antineoplastic effects of IGF1R-IRS1/2 inhibitors and FLT3 inhibitors in myeloid neoplasms. To achieve this, cell lines with FLT3 mutations (MV4-11 and MOLM-13) will be used. Functional assays will be conducted to assess the anti-leukemic effects of the inhibitors, including proliferation, viability, apoptosis, analysis of inhibitor-modulated pathways, and metabolic influences caused by the inhibitors. Viability, proliferation, and cell death analyses will be performed using MTT, Ki67, and Annexin V/Propidium Iodide assays. Results will be analyzed using GraphPad Prism 8 software, employing appropriate statistical tests. P-values will be adjusted to 0.05 for significance.