The effect of the combination of BRD4 and mTOR pathway inhibitors on immune checkpoint co-receptors in acute myeloid leukemia.

• Grant number: 20/16491-7
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): February 01, 2021
• Effective date (End): January 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mariane Tami Amano
• Grantee: Ana Carolina Costanti do Nascimento
• Home Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

Acute myeloid leukemia (AML) is a complex hematological cancer that mainly affects elderly patients (over 60 years old) and these patients are the ones that have worst response to current treatments. Thus, there is a great need for new therapeutic alternatives for this cancer. In the last decade, the BRD4 (bromodomain-containing protein 4) has been identified as one of the main possible targets for the treatment of AML. The BRD4 protein belongs to the family of proteins with bromodomain and extraterminal domain (BET), which is important for epigenetic regulation, therefore influencing gene expression. Our group observed that the combination of BRD4 inhibitors along with PI3K-AKT-mTOR inhibitors had a synergistic anti-leukemic effect. We also demonstrated that inhibition of the PI3K-AKT-mTOR pathway was able to break the resistance of the treatment of BRD4 inhibitors, suggesting a better therapeutic option for patients with AML. In addition, there is the prominent role that immune checkpoint co-receptors have been acquiring as interesting therapeutic targets in the oncology area. Based on this information, this project aims to investigate the modulation of immune checkpoint co-receptors in acute myeloid leukemia cell lines treated with BRD4 inhibitors in combination with inhibitors of the PI3K-AKT-mTOR pathway. Thus, we can contribute to a better understanding of the mechanisms involved in the response of leukemic cells to BRD4 inhibitors and to PI3K-AKT-mTOR pathway inhibitors, besides adding greater knowledge regarding the regulation of immune checkpoint co-receptors. We will also probably expand the therapeutic alternatives for AML, since the use of ICBs has advanced a lot and has shown to be quite promising, including in hematological tumors.