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

Samuel Y. Ng, Noriaki Yoshida, Amanda L. Christie, Mahmoud Ghandi, Neekesh V. Dharia, Joshua Dempster, Mark Murakami, Kay Shigemori, Sara N. Morrow, Alexandria Scoyk, Nicolas A. Cordero, Kristen E. Stevenson, Maneka Puligandla, Brian Haas, Christopher Lo, Robin Meyers, Galen Gao, Andrew Cherniack, Abner Louissaint, Valentina Nardi, Aaron R. Thorner, Henry Long, Xintao Qiu, Elizabeth A. Morgan, David M. Dorfman, Danilo Fiore, Julie Jang, Alan L. Epstein, Ahmet Dogan, Yanming Zhang, Steven M. Horwitz, Eric D. Jacobsen, Solimar Santiago, Jian-Guo Ren, Vincent Guerlavais, D. Allen Annis, Manuel Aivado, Mansoor N. Saleh, Amitkumar Mehta, Aviad Tsherniak, David Root, Francisca Vazquez, William C. Hahn, Giorgio Inghirami, Jon C. Aster, David M. Weinstock () and Raphael Koch ()
Additional contact information
Samuel Y. Ng: Dana-Farber Cancer Institute
Noriaki Yoshida: Dana-Farber Cancer Institute
Amanda L. Christie: Dana-Farber Cancer Institute
Mahmoud Ghandi: Broad Institute of Harvard and MIT
Neekesh V. Dharia: Broad Institute of Harvard and MIT
Joshua Dempster: Broad Institute of Harvard and MIT
Mark Murakami: Dana-Farber Cancer Institute
Kay Shigemori: Dana-Farber Cancer Institute
Sara N. Morrow: Dana-Farber Cancer Institute
Alexandria Scoyk: Dana-Farber Cancer Institute
Nicolas A. Cordero: Dana-Farber Cancer Institute
Kristen E. Stevenson: Dana-Farber Cancer Institute
Maneka Puligandla: Dana-Farber Cancer Institute
Brian Haas: Broad Institute of Harvard and MIT
Christopher Lo: Broad Institute of Harvard and MIT
Robin Meyers: Broad Institute of Harvard and MIT
Galen Gao: Broad Institute of Harvard and MIT
Andrew Cherniack: Broad Institute of Harvard and MIT
Abner Louissaint: Harvard Medical School
Valentina Nardi: Harvard Medical School
Aaron R. Thorner: Dana-Farber Cancer Institute
Henry Long: Dana-Farber Cancer Institute
Xintao Qiu: Dana-Farber Cancer Institute
Elizabeth A. Morgan: Harvard Medical School
David M. Dorfman: Harvard Medical School
Danilo Fiore: Weill Cornell Medical College
Julie Jang: Keck School of Medicine, University of Southern California
Alan L. Epstein: Keck School of Medicine, University of Southern California
Ahmet Dogan: Memorial Sloan-Kettering Cancer Center
Yanming Zhang: Memorial Sloan-Kettering Cancer Center
Steven M. Horwitz: Memorial Sloan-Kettering Cancer Center
Eric D. Jacobsen: Dana-Farber Cancer Institute
Solimar Santiago: Aileron Therapeutics Inc
Jian-Guo Ren: Aileron Therapeutics Inc
Vincent Guerlavais: Aileron Therapeutics Inc
D. Allen Annis: Aileron Therapeutics Inc
Manuel Aivado: Aileron Therapeutics Inc
Mansoor N. Saleh: University of Alabama-Birmingham Comprehensive Cancer Center
Amitkumar Mehta: University of Alabama-Birmingham Comprehensive Cancer Center
Aviad Tsherniak: Broad Institute of Harvard and MIT
David Root: Broad Institute of Harvard and MIT
Francisca Vazquez: Broad Institute of Harvard and MIT
William C. Hahn: Dana-Farber Cancer Institute
Giorgio Inghirami: Weill Cornell Medical College
Jon C. Aster: Harvard Medical School
David M. Weinstock: Dana-Farber Cancer Institute
Raphael Koch: Dana-Farber Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04356-9

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