Inhibition of enzymes related to the lipid metabolism for the treatment of acute myeloid leukemia

• Grant number: 24/21384-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Daniel Fábio Kawano
• Grantee: Xisto Antonio de Oliveira Neto
• Supervisor: David Feith
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Virginia (UVa), United States
• Associated to the scholarship: 22/01239-6 - Synthesis of acid ceramidase inhibitors as possible tools for the oral treatment of prostate cancer, BP.DR

Abstract

Acute myeloid leukemia (AML) is a hematologic cancer with poor prognosis, commonly presenting resistance to available treatments. Phospholipid metabolism is severely altered in AML cells and appears to be closely related to malignancy and resistance, suggesting the existence of therapeutic opportunities in the inhibition of participating enzymes. One of these enzymes is acid ceramidase (aCDase), a validated target against AML for which inhibitors have presented reasonable pre-clinical success, which is yet to be translated into viable clinical application. Synergistic therapies against cancer have proven to be an efficient approach to tackle the acquired resistance and evasion mechanisms, limitations often found in monotherapies, with a consistent body of work exploring aCDase in this context. In this project we propose the investigation of the synergistic inhibition of aCDase and cytidine triphosphate: phosphocholine cytidylyltransferase (CCT), an important enzyme belonging to the Kennedy pathway that also serves as an oncologic target, particularly for the treatment of leukemias. The inhibition of CCT ultimately leads to an accumulation of ceramide inside the cell, which would account for part of the apoptotic effects observed. We hypothesize that the lack of antitumoral activity presented by CCT inhibitors could be occasioned by the fast consumption of ceramide by aCDase in tumoral cells, leading to the biosynthesis of pro-tumoral agent sphingosine-1-phosphate (S1P), thus shifting balance towards cancerous behavior. The combined inhibition of aCDase and CCT could lead to high concentrations of ceramide inside cancerous cells presenting lipogenic phenotypes, blocking evasion mechanisms and inducing apoptosis. Aside from investigating the combined therapy with established aCDase inhibitors, this project proposes the application of a novel covalent inhibitor developed by our group, seeking to establish a new treatment for AML with high efficiency and selectivity.