Pharmacodynamically directed targeted therapy for leukemia - PROJECT SUMMARY Acute Myeloid Leukemia (AML) is both the most common and deadliest adult leukemia. Even with the best therapeutic approaches the majority of AML patients relapse and die of their disease. Our central hypothesis is that the inability to therapeutically impact AML outcome is derived from the similarity of these tumor cells to normal hematopoietic stem cells and that both the disease and current therapies utilized to treat it are profoundly immunosuppressive. As a team (Ohio State and the University of Cincinnati), we have moved toward developing therapeutics that differentiate AML cells further from normal hematopoietic stem cells while at the same time enhance immune activation. We have chosen to therapeutically target DHODH, a mitochondrial localized enzyme that performs a rate limiting step in pyrimidine synthesis. Inhibition of DHODH with small molecules has been shown to promote AML differentiation via induction of replicative stress and to activate the innate immune system. Recent data generated by our group demonstrates DHODHi also mediates death in AML cells via induction of ferroptosis. Using multiple in vivo models of AML, we have demonstrated DHODHi synergizes with a wide range of currently used targeted therapies. Notably, we demonstrate significant synergy of DHODHi with decitabine in TP53 mutated AML, the most lethal subset of this disease for which overall survival is poor. We recognize prior limitations of potent DHODH inhibitor trials including 1) lack of patent protection to enable effective drug development, 2) treatment related toxicity 3) ineffective pharmacodynamic (PD) markers to predict adverse events, and 4) no strategy to mitigate adverse events. We have systemically addressed each limitation with the pre-clinical development of our lead compound, HOSU-53. Improvements with our program include 1) world-wide composition of matter patent protection, 2) optimization of a PD blood marker (dihydroorotate, DHO) that defines tolerable versus toxic levels of DHODH inhibition, 3) delineation of a mechanism of cell death (ferroptosis) that can be monitored in vivo and 4) strong pre-clinical data to support development of combination approaches of HOSU-53 with decitabine. Having completed IND enabling studies with HOSU-53, we anticipate this molecule will enter phase 1 testing as early as the 1st quarter of 2025. This proposal seeks support for implementation of the first in human clinical trial with HOSU-53 in AML utilizing corresponding pharmacokinetic and pharmacodynamic monitoring along with novel single cell DNA sequencing to monitor for elimination of specific clones of AML eradicated by this treatment. Following completion of this phase 1 trial, we seek to perform a phase 1b/2 study of HOSU-53 given together with decitabine in previously untreated TP53 mutated AML. At completion of this project, we will have transitioned the potent DHODH inhibitor HOSU-53 to the clinic and established a pharmacodynamically-informed dose. By utilizing single cell DNA sequencing to examine efficacy in intra-patient clones of AML, we will also enable targeting specific molecular subsets of AML in future studies. Finally, we will have completed a phase 1b/2 trial of HOSU-53 in previously untreated TP53 mutated AML.
