Abstract 1060: Introducing a novel DHODH inhibitor with superior in vivo activity as monotherapy or in novel combination regimen with immunotherapy for hematological malignancies

Abstract

Acute myeloid leukemia (AML) is characterized by the uncontrolled expansion of un-differentiated hematopoietic progenitor myeloblasts. AML treatment is very challenging owing to its complex heterogeneity resulting in a dismal 5-year overall survival rate particularly in elderly patients unfit for standard induction chemotherapy. The expansion of AML requires the availability of sufficient nucleotides supporting the anabolic processes required for AML growth thus, targeting nucleotide biosynthesis can halt AML progression. Indeed, targeting dihydroorotate dehydrogenase (DHODH), a critical rate-limiting step in the de novo pyrimidine synthesis pathway not only induced cytotoxicity but has been shown to promote blast differentiation in a HOXA9/MEIS1 over-expressing model. We sought to develop a DHODH inhibitor that had superior properties to those reported for AML therapy. Compound 41 (cmpd 41) demonstrates sub-nanomolar 50% inhibitory concentration for DHODH biochemical activity and potent in vitro activity across several AML cell lines and primary AML cells independent of mutational subtype, including mutated TP53. Cmpd 41 also demonstrated superior in vivo anti-leukemic activity in multiple AML xenograft models as monotherapy and demonstrated synergy with a hypomethylating agent, decitabine in TP53 mutated AML. Given the heterogeneity of AML and frequent emergence of resistant clones, we aimed to investigate ways to enhance response to DHODH inhibitors through combination. After in vitro treatment of AML cell lines and primary patient samples with DHODH inhibitors, we observed an increase in CD38 surface expression suggesting synergy with CD38 targeting monoclonal antibody (mAb) immunotherapies. Indeed, we are the first to report synergy between DHODH inhibitors and anti-CD38 mAb in AML which emphasizes the synergy between this promising novel class of agents with immunotherapies via recruiting innate immunity. Consequently, given the relevance of CD38 mAb therapy to multiple myeloma (MM), we extended these studies to MM and remarkably found that cmpd 41 was highly efficacious as a monotherapy and in combination with CD38 mAb, resulted in complete tumor regression in a subcutaneous MM xenograft model. In summary, we introduce a best in class DHODH inhibitor with a data-driven combination strategy for both AML and MM. Our studies suggest a highly synergistic combination strategy involving immunotherapy for AML and other hematologic malignancies. Citation Format: Ola A. Elgamal, Sandip Vibhute, Sydney Fobare, Abeera Mehmood, Mariah L. Johnson, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Ramasamy Santhanam, Kasey Hill, Susheela Tridandapani, Christopher C. Coss, Alice S. Mims, Karilyn T. Larkin, Mitch A. Phelps, Sharyn D. Baker, Alex Sparreboom, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd. Introducing a novel DHODH inhibitor with superior in vivo activity as monotherapy or in novel combination regimen with immunotherapy for hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1060.