Translational Hematology Laboratory

In Acute Myeloid Leukemia (AML), leukemic cells lose their ability to differentiate into adult white blood cells, remaining immature and dysfunctional; they accumulate in the bone marrow, affecting the production of normal blood cells. Major advances have been made in the last years in the understanding of the genomic and epigenetic landscape of AML: it turned out that AML is an extremely heterogeneous disease, both biologically and clinically. As we learned from APL, differentiating therapy can force leukemic stem cells out of quiescence, significantly increasing the possibility of cure; moreover, despite existing side effects, it is generally better tolerated than chemotherapy, and could be offered to the elderlies. Efforts in dissecting the molecular complexity of acute myeloid leukaemia (AML) have been finally crowned by the recent approval of several targeted therapies. However, compounds like FLT3 and IDH1/2 inhibitors do not address all AML subtypes nor every subclone in a single patient, potentially leading to clonal escape. A promising approach is the so-called synthetic lethality, i.e., a combination of treatments that results lethal to cells. Differentiation therapy could be an essential ingredient in this combination, forcing immature cells to mature and increasing their exposure to other drugs. Indeed, this strategy has already brought acute promyelocytic leukaemia (APL) to a cure rate >90%. Recently, Dihydroorotate Dehydrogenase (DHODH) inhibitors were found to induce myeloid differentiation in AML models. DHODH is an enzyme located in the inner mitochondrial membrane, which catalyses the oxidation of dihydroorotate to orotate and is a fundamental enzyme in the de novo pyrimidine biosynthesis (figure 1). 

Pyrimidines are crucial for the proliferation of living entities, as tumour cells. The current research focus is the characterization of new DHODH inhibitors and their preclinical study for the treatment of AML patients. This project starts from a fruitful collaboration, dedicated to the design and the biologically profiling of human DHODH inhibitors, that bond since 2017 the research group of the PI and of Medicinal Chemists at Department of Drug Science and Technology (DSTF) at the University of Turin. A novel class of DHODH inhibitors, with a strong differentiating and pro-apoptotic activity in vitro has been developed. We hypothesise that a therapy based on DHODH inhibitors could cause apoptosis and differentiation of leukemic cells and promote their sensitization to further drugs, leading to synthetic lethality. Moreover, we think that the evaluation of the molecular and metabolic profile of leukemic cells treated with DHODH inhibitors, and the correlation with response, will allow to identify specific predictive biomarkers.

• Understanding how DHODH inhibitors induce differentiation and apoptosis, investigating molecular and metabolic pathways influenced by these drugs. 

• Development of new, pharmacokinetically optimised, DHODH inhibitors with strong differentiating and pro-apoptotic activity on AML models. 

• Identification of drugs that, associated with DHODH inhibitors, could lead to synthetic lethality. 

• Identification of biomarkers predictive for response to DHODH inhibitors. 

• Prognostic stratification of patients according to metabolomic profiles 

• The team is able to cover all the skills necessary for the design of a preclinical candidate effective in haematological feld (Fig. 2). 

In particular: 

Medicinal Chemistry. Development and optimization of new DHODH inhibitors 

Biochemistry. Assaying the candidate on AML models both in vitro and in vivo. 

Clinic: This part of the project will be focused on the recruitment of patients to test new drugs on primary cells and to correlate in vitro response with clinical features. We collaborate with University Division of Hematology and Cell Therapy, Mauriziano Hospital, University of Turin. Thanks to excellent research experience in the field of medicinal chemistry, biological and clinical knowledge in 2020, the Spin Of of UniTo Drug Discovery and Clinic s.r.l. was funded.