The Effect of Combining GSK3b and BCL2 Inhibitors in Acute Myeloid Leukemia

• Grant number: 24/21715-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2025
• End date: December 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mariane Tami Amano
• Grantee: Giulia Amelio Hummel
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

Acute myeloid leukemia (AML) is a malignant, heterogeneous hematopoietic disorder characterized by changes in hematopoietic stem cells due to genetic alterations, which make them unable to differentiate and maturate. The main treatment used is chemotherapy with anthracycline in combination with cytarabine, but there are several patients who are not eligible to continue with chemotherapy due, for example, to their age, showing the need to look for new treatments. The B-cell lymphoma-2 protein inhibitor (BCL-2), known for inhibiting the anti-apoptotic BCL-2 protein by inducing apoptosis via the intrinsic pathway, has been an interesting therapeutic strategy in the treatment of AML. However, 27% of patients do not respond to BCL-2 inhibitor treatment and around 50% of those who do relapse, indicating acquired resistance. The enzyme glycogen synthase kinase 3 (GSK3) plays an important role in regulating metabolism, survival and cell death by participating in various signaling pathways. This enzyme has emerged as an interesting target in various types of cancer and in AML. GSK3 inhibitors were able to decrease the proliferation of AML cells by decreasing the expression and/or phosphorylation of BCL-2, as well as another anti-apoptotic molecule: Bcl-XL. Our hypothesis is that inhibiting GSK3 with a BCL-2 inhibitor has a greater anti-leukemic effect than treating the inhibitors alone. Our aim is to analyze the combination of BCL-2 inhibitor and GSK3¿ inhibitor in AML cell lines. Initially, we will standardize the concentrations of both inhibitors for AML cell lines (MOLM-13 and HL-60) using proliferation assays. We will evaluate the effect of the inhibitors alone and in combination, both by the proliferation assay and analysis of genes associated to proliferation and cell death by qPCR. From these analyses it will be possible to gain a better understanding of the anti-leukemic effect of the inhibitors in isolation, as well as the combined effect of both together, creating a future perspective for a new treatment for acute myeloid leukemia. The development of this project can provide the basis for new therapeutic strategies in AML and eventually offer opportunities to overcome the resistance of BCL-2 inhibitor monotherapy.