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Supplementary Materials from JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease

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posted on 2023-03-31, 17:54 authored by Emeline Evrot, Nicolas Ebel, Vincent Romanet, Claudia Roelli, Rita Andraos, Zhiyan Qian, Arno Dölemeyer, Ernesta Dammassa, Dario Sterker, Robert Cozens, Francesco Hofmann, Masato Murakami, Fabienne Baffert, Thomas Radimerski

- PDF file 1093K, Supplementary Table S1. Activity and tolerability of ruxolitinib (RUX) and panobinostat (PAN), alone and in combination, in a mouse model of Ba/F3 JAK2V617F cells-driven leukemic disease. Supplementary Table S2. Levels of panobinostat (PAN) and ruxolitinib (RUX) in blood and tissues post-final dose in a mouse model of Ba/F3 JAK2V617F cells-driven leukemic disease. Supplementary Table S3. Exposure to panobinostat (PAN) and ruxolitinib (RUX) in blood and tissues in a mouse model of Ba/F3 JAK2V617F cells-driven leukemic disease. Supplementary Table S4. Levels of panobinostat (PAN) and ruxolitinib (RUX) in blood and tissues post-final dose in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Table S5. Exposure to panobinostat (PAN) and ruxolitinib (RUX) in blood and tissues in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S1. Tolerability of ruxolitinib (RUX) and panobinostat (PAN), alone and in combination, in a mouse model of Ba/F3 JAK2V617F cellsdriven leukemic disease. Supplementary Figure S2. Modulation of aberrant JAK2/STAT5 signaling in vitro and in vivo following treatment with ruxolitinib (RUX) and panobinostat (PAN), alone and in combination. Supplementary Figure S3. Efficacy and tolerability of ruxolitinib (RUX) in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S4. Modulation of STAT5 phosphorylation in spleen and bone marrow following treatment with ruxolitinib (RUX) in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S5. Histological analysis following treatment with ruxolitinib (RUX) in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S6. Efficacy and tolerability of panobinostat (PAN) in a mouse model of JAK2V617F-driven MPN-like disease Supplementary Figure S7. Modulation of protein acetylation and acetylated histone H3 in spleen and bone marrow, respectively, following treatment with 21 panobinostat (PAN) in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S8. Histological analysis following treatment with panobinostat (PAN) in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S9. Efficacy and tolerability of ruxolitinib (RUX) and panobinostat (PAN), alone and in combination, in a mouse model of JAK2V617Fdriven MPN-like disease. Supplementary Figure S10. Impact of ruxolitinib (RUX) and panobinostat (PAN), alone and in combination, on relative levels of retrovirally transduced JAK2V617F in a mouse model of JAK2V617F-driven MPN-like disease. Supplementary Figure S11. Histological analysis following treatment with ruxolitinib (RUX) and panobinostat (PAN), alone and in combination, in a mouse model of JAK2V617F-driven MPN-like disease

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ARTICLE ABSTRACT

Purpose: The myeloproliferative neoplasm myelofibrosis is characterized by frequent deregulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, and JAK inhibitors were shown to reduce splenomegaly and ameliorate disease-related symptoms. However, the mutant clone and bone marrow fibrosis persist in the majority of patients. Using preclinical models, we explored whether JAK and pan-deacetylase inhibitor combination yielded additional benefits.Experimental Design: The combination of the JAK1/2 inhibitor ruxolitinib and panobinostat was investigated using two different mouse models of JAK2V617F-driven disease. A Ba/F3 JAK2V617F cell–driven leukemic disease model was used to identify tolerated and efficacious doses. The drugs were then evaluated alone and in combination in a mouse model of myeloproliferative neoplasm–like disease based on transplantation of bone marrow transduced with a retrovirus expressing JAK2V617F. Exposures were determined in blood and tissues, and phosphorylated STAT5 and acetylated histone H3 pharmacodynamic readouts were assessed in spleen and bone marrow. Histologic analysis was conducted on spleen and bone marrow, including staining of reticulin fibers in the latter organ.Results: The combination of ruxolitinib and panobinostat was found to have a more profound effect on splenomegaly, as well as on bone marrow and spleen histology, compared with either agent alone, and the analysis of pharmacodynamic readouts showed that ruxolitinib and panobinostat have nonoverlapping and complementary effects.Conclusion: Combining JAK1/2 and pan-deacetylase inhibitors was fairly well tolerated and resulted in improved efficacy in mouse models of JAK2V617F-driven disease compared with the single agents. Thus, the combination of ruxolitinib and panobinostat may represent a promising novel therapeutic modality for myeloproliferative neoplasms. Clin Cancer Res; 19(22); 6230–41. ©2013 AACR.

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