Molecular therapeutic targets in IDH1/2 mutant AML: exploring the links between metabolism and dna damage response to overcome drug resistance

Overview

Project Summary

 Isocitrate dehydrogenase mutations (mIDH), occurring in 15-30% of AML cases, are recognized oncogenic drivers. Approved IDH inhibitors (IDHi) for mIDH AML (ivosidenib for mIDH1, enasidenib for mIDH2) face challenges due to resistance development. Understanding the interplay between metabolism and DNA Damage Response/Repair (DDR) is crucial. Despite known connections, many interactions remain unknown. Filling these gaps is vital for developing therapeutic approaches targeting mIDH inhibition in AML. 

Main Goals

This project aims to identify novel molecular therapeutic targets and explore new synthetic lethality approaches to provide innovative options for the management of mIDH AML resistant to IDHi. We propose to investigate the role of metabolic rewiring and DDR reprogramming in the development of resistance to ivosidenib and enasidenib in mIDH1 and mIDH2 AML, respectively, and identify biological vulnerabilities related to metabolism and DDR systems to be explored as new therapeutic targets.

Project Details