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3 results on '"Andraos R"'

1. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia.

Author

Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, Christie AL, Liu H, Christodoulou A, van Bodegom D, van der Zwet J, Layer JV, Tivey T, Lane AA, Ryan JA, Ng SY, DeAngelo DJ, Stone RM, Steensma D, Wadleigh M, Harris M, Mandon E, Ebel N, Andraos R, Romanet V, Dölemeyer A, Sterker D, Zender M, Rodig SJ, Murakami M, Hofmann F, Kuo F, Eck MJ, Silverman LB, Sallan SE, Letai A, Baffert F, Vangrevelinghe E, Radimerski T, Gaul C, and Weinstock DM

Subjects
Aminopyridines pharmacology, Animals, Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Apoptosis, Benzimidazoles pharmacology, Cell Line, Tumor, Cytoprotection drug effects, Drug Synergism, Humans, Janus Kinase 2 chemistry, Janus Kinase 2 genetics, Mice, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Protein Kinase Inhibitors pharmacology, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Aminopyridines administration & dosage, Antineoplastic Agents administration & dosage, Benzimidazoles administration & dosage, Dexamethasone administration & dosage, Drug Resistance, Neoplasm drug effects, Janus Kinase 2 antagonists & inhibitors, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Protein Kinase Inhibitors administration & dosage
Abstract

A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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2. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.

Author

Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, Xu K, Manova K, Pankov D, O'Reilly RJ, Kleppe M, McKenney AS, Shih AH, Shank K, Ahn J, Papalexi E, Spitzer B, Socci N, Viale A, Mandon E, Ebel N, Andraos R, Rubert J, Dammassa E, Romanet V, Dölemeyer A, Zender M, Heinlein M, Rampal R, Weinberg RS, Hoffman R, Sellers WR, Hofmann F, Murakami M, Baffert F, Gaul C, Radimerski T, and Levine RL

Subjects
Animals, Antineoplastic Agents pharmacology, Benzamides administration & dosage, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Myeloproliferative Disorders genetics, Myeloproliferative Disorders metabolism, Protein Kinase Inhibitors pharmacology, Pyrimidines administration & dosage, Receptors, Thrombopoietin genetics, Receptors, Thrombopoietin metabolism, Sequence Analysis, RNA, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 genetics, Myeloproliferative Disorders drug therapy, Protein Kinase Inhibitors administration & dosage
Abstract

Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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3. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer.

Author

Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Müller U, Murakami M, Radimerski T, and Bentires-Alj M

Subjects
Animals, Breast Neoplasms drug therapy, Cell Death drug effects, Cell Line, Tumor, Female, Humans, Insulin Receptor Substrate Proteins metabolism, Interleukin-8 metabolism, Janus Kinase 2 metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Phosphatidylinositol 3-Kinases metabolism, Receptors, Interleukin-8A metabolism, STAT5 Transcription Factor metabolism, TOR Serine-Threonine Kinases metabolism, Breast Neoplasms metabolism, Janus Kinase 2 antagonists & inhibitors, Neoplasm Metastasis drug therapy, Phosphoinositide-3 Kinase Inhibitors, STAT5 Transcription Factor antagonists & inhibitors, Signal Transduction drug effects, TOR Serine-Threonine Kinases antagonists & inhibitors
Abstract

Hyperactive PI3K/mTOR signaling is prevalent in human malignancies and its inhibition has potent antitumor consequences. Unfortunately, single-agent targeted cancer therapy is usually short-lived. We have discovered a JAK2/STAT5-evoked positive feedback loop that dampens the efficacy of PI3K/mTOR inhibition. Mechanistically, PI3K/mTOR inhibition increased IRS1-dependent activation of JAK2/STAT5 and secretion of IL-8 in several cell lines and primary breast tumors. Genetic or pharmacological inhibition of JAK2 abrogated this feedback loop and combined PI3K/mTOR and JAK2 inhibition synergistically reduced cancer cell number and tumor growth, decreased tumor seeding and metastasis, and also increased overall survival of the animals. Our results provide a rationale for combined targeting of the PI3K/mTOR and JAK2/STAT5 pathways in triple-negative breast cancer, a particularly aggressive and currently incurable disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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