Abstract 3599: BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas
2019
Colorectal carcinoma (CRC) is the third most common malignancy in the US, being responsible for approximately 50,000 deaths per year. The overall 5-year survival rates are high for localized disease (~90%), but low for metastatic disease (~14%), thereby underlining the high unmet medical need for novel therapeutics for CRC patients. DHODH is a key enzyme in the de novo pyrimidine synthesis, converting dihydroorotate to orotate. We recently discovered its role in AML differentiation (Sykes et al 2016, Cell) and we are investigating BAY 2402234 in an ongoing phase I study in myeloid malignancies (NCT03404726). Since then, several publications have also described a role of DHODH in solid tumor indications. Herein we disclose the functional preclinical characterization of the novel DHODH inhibitor BAY 2402234 in CRC. BAY 2402234 is a selective low-nanomolar inhibitor of human DHODH enzymatic activity. In vitro it potently inhibits proliferation of CRC cell lines in the sub-nanomolar to low-nanomolar range. The anti-proliferative effects can be rescued by uridine supplementation which is known to bypass DHODH via the salvage pathway and demonstrates the on-target specificity of the inhibitor. Interestingly, not all CRC cell lines are sensitive to the inhibitor. Similar to the in vitro observations, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in some, but not all, subcutaneous CRC xenograft models. A large CRC PDX in vivo screen revealed tumor growth inhibition in over 60% of the models in response to BAY 2402234 treatment. To elucidate the mode of action of BAY 2402234 in CRC we analyzed transcriptomic changes in CRC PDX models in vivo after single treatment with BAY 2402234, and identified several hundred differentially regulated genes at early time points. These in vivo PDX models were also used to explore potential effects of BAY 2402234 treatment on a large panel of metabolites. These preclinical results support the clinical evaluation of BAY 2402234 in patients with CRC, and such a clinical study is planned for early in 2019. Citation Format: Claudia Merz, Sven Christian, Ashley Eheim, Henrik Seidel, Ralf Lesche, Merlin Luetke- Eversloh, Hanna Meyer, Steven Ferrara, Marcus Bauser, Andrea Haegebarth, Stefan Gradl, Andreas Janzer. BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3599.
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