Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models Journal Article

Authors: Ng, S. Y.; Yoshida, N.; Christie, A. L.; Ghandi, M.; Dharia, N. V.; Dempster, J.; Murakami, M.; Shigemori, K.; Morrow, S. N.; Van Scoyk, A.; Cordero, N. A.; Stevenson, K. E.; Puligandla, M.; Haas, B.; Lo, C.; Meyers, R.; Gao, G.; Cherniack, A.; Louissaint, A. Jr; Nardi, V.; Thorner, A. R.; Long, H.; Qiu, X.; Morgan, E. A.; Dorfman, D. M.; Fiore, D.; Jang, J.; Epstein, A. L.; Dogan, A.; Zhang, Y.; Horwitz, S. M.; Jacobsen, E. D.; Santiago, S.; Ren, J. G.; Guerlavais, V.; Annis, D. A.; Aivado, M.; Saleh, M. N.; Mehta, A.; Tsherniak, A.; Root, D.; Vazquez, F.; Hahn, W. C.; Inghirami, G.; Aster, J. C.; Weinstock, D. M.; Koch, R.
Article Title: Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models
Abstract: T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models. © 2018 The Author(s).
Keywords: unclassified drug; janus kinase 2; nonhuman; antineoplastic agent; mouse; animal tissue; stat3 protein; animal experiment; animal model; in vivo study; drug potency; in vitro study; tumor xenograft; enzyme activity; peptide; protein p53; protein mdmx; cancer regression; biomarker; bone; stat5 protein; romidepsin; protein mdm2; nk t cell lymphoma; cell; heterogeneity; angioimmunoblastic t cell lymphoma; vulnerability; human; article; alrn 6924; [2 (4 tert butyl 2 ethoxyphenyl) 4,5 bis(4 chlorophenyl) 4,5 dihydro 4,5 dimethyl 1h imidazol 1 yl][4 [3 (methylsulfonyl)propyl] 1 piperazinyl]methanone
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-05-22
Start Page: 2024
Language: English
DOI: 10.1038/s41467-018-04356-9
PROVIDER: scopus
PMCID: PMC5964252
PUBMED: 29789628
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Steven M Horwitz
    368 Horwitz
  2. Ahmet Dogan
    176 Dogan
  3. Yanming Zhang
    26 Zhang