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
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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