Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) represents the most commonly diagnosed and lethal adult leukemia, with a 5-year survival of less than 15% in patients over the age of 60 (1, 2). AML originates from a leukemia-initiating hematopoietic stem cell and is characterized by uncontrolled proliferation of dysfunctional, immature hematopoietic myeloid cells (blasts). AML-initiating cells have features that resemble normal hematopoietic stem cells and are highly immune suppressive, making it quite challenging to treat with either targeted or immune-based therapies (outside of allogeneic stem cell transplant). Until recently, effective therapies for AML were limited to intensive chemotherapy followed by allogeneic stem cell transplant, which provided curative potential for a minority of patients. More recently, several therapies targeting select mutations, including IDH1 (ivosidenib) (3), IDH2 (enasidenib) (4), and FLT3 (gilteritinib) (5), have been approved for AML treatment and demonstrate a unique differentiating phenotype. By differentiating early AML progenitor cells, these therapies may further separate their phenotype from normal hematopoietic cells and in some cases can promote durable remissions. However, these targeted therapeutics are limited to AML patients with IDH1, IDH2, or FLT3 mutations, and resistance mechanisms have been reported (6, 7). Another example of mutation-specific, targeted differentiation therapy is all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) AML subtype. Despite the high response rate, there is a lack of durable response in most patients in the absence of combination therapy (8-10). This collective experience suggests that successful therapy will involve differentiation agents that can be used in a broader AML population and identifying combination strategies likely to result in durable remissions. The need for combination strategies is supported by murine model data of AML, where a combination of differentiation and targeted therapies is required to eliminate clonal AML stem cells (11). Broadly affecting AML with differentiation therapy will require a therapeutic target that is effective in AML subtypes independent of mutation subtype.One such target for broad differentiation of AML cells demonstrated by Sykes and Scadden et al. ( 12) and later corroborated by others is dihydroorotate dehydrogenase (DHODH) (13-15). DHODH is a mitochondrial membrane flavoprotein that catalyzes the rate-limiting step of the de novo pyrimidine nucleotide biosynthesis pathway (16,17). DHODH catalyzes the oxidation of dihydroorotate (DHO) to orotate, which is further converted downstream by uridine monophosphate synthetase to uridine monophosphate (18, 19), the biosynthetic precursor of thymidine and cytidine (20). Rapidly proliferating cells and most cancer cells rely predominantly on this de novo synthesis pathway (20) as opposed to the salvage pathway, which re-cycles degraded intracellular nucleic acids (17) or shuttles extracellular nucleosides using nucleoside transporters (12,17,20). Th...