Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo
Autor: | Damian Stichel, M M Araujo-Cruz, Lara Klett, Amar Deep Sharma, Stefan Kaulfuss, Luisella Toschi, A. von Deimling, Anuhar Chaturvedi, A Bakkali, Ramya Goparaju, Robert Geffers, Stefan Pusch, Razif Gabdoulline, Eduard A. Struys, Anthony D. Ho, Arnold Ganser, Katja Zimmermann, Tilmann Bochtler, Felicitas Thol, Hartmut Rehwinkel, Alwin Krämer, Lena Herbst, Andrea Haegebarth, Roland Neuhaus, Karsten Rippe, Markus Bauser, Olaf Panknin, Michael Heuser, Holger Hess-Stumpp |
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Přispěvatelé: | Laboratory Medicine, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition |
Jazyk: | angličtina |
Předmět: |
0301 basic medicine
Cancer Research Myeloid Mutant medicine.disease_cause Biochemistry Mice 0302 clinical medicine hemic and lymphatic diseases CEBPA Myeloid Cells Molecular Targeted Therapy Enzyme Inhibitors Tumor Stem Cell Assay Myelopoiesis Mutation Aniline Compounds Myeloid leukemia Hematology Isocitrate Dehydrogenase 3. Good health Neoplasm Proteins Histone Code Haematopoiesis Leukemia Leukemia Myeloid Acute Isocitrate dehydrogenase medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Neoplastic Stem Cells Original Article Stem cell Immunology Mutation Missense Antineoplastic Agents Biology Methylation Glutarates 03 medical and health sciences Pan-Mutant-IDH1 Inhibitor Bay-1436032 Cell Line Tumor medicine Animals Humans Point Mutation business.industry Cell Biology DNA Methylation medicine.disease Xenograft Model Antitumor Assays Transplantation 030104 developmental biology Cancer research Benzimidazoles business Protein Processing Post-Translational Ex vivo |
Zdroj: | Leukemia, 31(10), 2020-2028. Nature Publishing Group Chaturvedi, A, Herbst, L, Pusch, S, Klett, L, Goparaju, R, Stichel, D, Kaulfuss, S, Panknin, O, Zimmermann, K, Toschi, L, Neuhaus, R, Haegebarth, A, Rehwinkel, H, Hess-Stumpp, H, Bauser, M, Bochtler, T, Struys, E A, Sharma, A, Bakkali, A, Geffers, R, Araujo-Cruz, M M, Thol, F, Gabdoulline, R, Ganser, A, Ho, A D, Von Deimling, A, Rippe, K, Heuser, M & Krämer, A 2017, ' Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo ', Leukemia, vol. 31, no. 10, pp. 2020-2028 . https://doi.org/10.1038/leu.2017.46 Leukemia |
ISSN: | 1476-5551 0887-6924 |
DOI: | 10.1038/leu.2017.46 |
Popis: | Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are frequently found in patients with acute myeloid leukemia (AML) and several other tumors. Mutant IDH1 produces R-2-hydroxyglutarate (R-2HG), which induces histone and DNA hypermethylation through inhibition of epigenetic regulators, and leads to a block in differentiation to promote tumorigenesis. Methods: We developed a novel, highly active oral pan-IDH1 inhibitor, BAY-1436032, for clinical evaluation. Its inhibitory potency was evaluated in primary human AML cells in vitro for the five major IDH1R132 mutation types and in two patient derived AML xenograft (PDX) models in vivo, in which BAY-1436032 cleared leukemic blasts in peripheral blood and prolonged survival by induction of differentiation and inhibition of leukemia stem cell self-renewal. Results: R-2HG production by mutant IDH1 was effectively inhibited in patient derived AML cells with all reported IDH1R132 mutations ex vivo by BAY-1436032 with an IC50 between 3 to 16 nM. AML cells cultured ex vivo showed morphologic differentiation and marked upregulation of the myeloid differentiation markers CD14 and CD15. For in vivo experiments, human AML cells from two patients were transplanted into sublethally irradiated NSG mice. After stable engraftment at 17 (PDX1) or 90 (PDX2) days post transplantation, mice were treated with BAY-1436032 orally every day at a dose of 150 mg/kg or vehicle for 100-150 days (n=10 per group). The R/S-2HG ratio in serum was reduced to near normal levels by BAY-1436032. Leukemic cell counts in peripheral blood constantly increased in control mice, while leukemic cells declined from day 30 of BAY-1436032 treatment onwards with morphologic and immunophenotypic evidence of differentiation (Figure). Importantly, all BAY-1436032 treated PDX1 mice survived until the end of treatment at 150 days. In contrast, vehicle-treated mice died with a median latency of 91 days (range 70-95, P To assess the effect of BAY-1436032 on leukemic stem cell self-renewal we treated PDX1 mice with 150 mg/kg BAY-1436032 or vehicle for 4 weeks and performed a limiting dilution transplantation experiment in secondary recipient mice. LSC frequency was 100-fold lower in BAY-1436032 treated compared to control mice. Gene expression profiling showed that stemness associated genes were downregulated, while genes associated with myeloid differentiation like PU.1 and CEBPA were upregulated upon treatment with BAY-1436032. In addition, cell cycle progression was slowed and E2F transcription factors concomitantly inhibited. In accordance with gene expression profiling results, methylation of the PU.1 promoter decreased, while E2F1 promoter methylation increased upon treatment with BAY-1436032. Finally, histone trimethylation levels at residues H3K4, H3K9, H3K27, and H3K36 decreased in both IDH1R132C and IDH1R132H mutant AML cells but not in IDH1 wildtype cells upon BAY-1436032 treatment. Conclusion: In summary, the novel oral pan-mutant IDH1 inhibitor BAY-1436032 is active against all IDH1R132 mutation types and shows strong anti-leukemic activity in two independent AML PDX mouse models. Clinical development is ongoing with a first in man study with BAY-1436032 in IDH1 mutant solid tumors. * M. Heuser and L. Herbst contributed equally to this article #A. Krämer and A. Chaturvedi share senior authorship Figure Human leukemic cells in peripheral blood of mice treated with BAY-1436032. ** P Disclosures Heuser: Tetralogic: Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Bayer Pharma AG: Research Funding; Celgene: Honoraria; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Pusch:German Cancer Research Center: Patents & Royalties: WO2013/127997A1. Kaulfuss:Bayer Pharma AG: Employment. Panknin:Bayer Pharma AG: Employment. Zimmermann:Bayer Pharma AG: Employment, Patents & Royalties: WO2015/121210 . Toschi:Bayer Pharma AG: Employment. Neuhaus:Bayer Pharma AG: Employment, Patents & Royalties: WO2015/121210. Haegebarth:Bayer Pharma AG: Employment, Equity Ownership. Rehwinkel:Bayer Pharma AG: Employment, Equity Ownership, Patents & Royalties: WO2015/121210. Hess-Stumpp:Bayer Pharma AG: Employment. Bauser:Bayer Pharma AG: Employment. Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. von Deimling:German Cancer Research Center: Patents & Royalties: IDH1R132H mutant specific antibody H09; BRAF V600E mutant specific antibody VE1; BAY-1436032 patent. |
Databáze: | OpenAIRE |
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