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 Van Scoyk, Nicolas A. Cordero, Kristen E. Stevenson, Maneka Puligandla, Brian Haas, Christopher Lo, Robin Meyers, Galen Gao, Andrew Cherniack, Abner Louissaint, Valentina NardiAaron 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, Raphael Koch

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

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.

Original languageEnglish
Article number2024
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

Fingerprint

Dive into the research topics of 'Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models'. Together they form a unique fingerprint.

Cite this