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Nat Commun. 2018 May 22;9(1):2024. doi: 10.1038/s41467-018-04356-9.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
2
Broad Institute of Harvard and MIT, 415 Main St, Cambridge, MA, 02142, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, 450 Brookline Ave, Boston, MA, 02215, USA.
4
Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
6
Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
7
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
8
Center for Functional Epigenetics, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
9
Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02215, USA.
10
Department of Pathology, Weill Cornell Medical College, 525 East 68th Street, New York, NY, 10065, USA.
11
Department of Pathology, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA, 90033, USA.
12
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
13
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
14
Aileron Therapeutics Inc, 281 Albany Street, Cambridge, MA, 02139, USA.
15
University of Alabama-Birmingham Comprehensive Cancer Center, 1824 6th Avenue South, Birmingham, AL, 3523, USA.
16
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. dweinstock@partners.org.
17
Broad Institute of Harvard and MIT, 415 Main St, Cambridge, MA, 02142, USA. dweinstock@partners.org.
18
Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA. dweinstock@partners.org.
19
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. raphael.koch@med.uni-goettingen.de.
20
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075, Göttingen, Germany. raphael.koch@med.uni-goettingen.de.

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.

PMID:
29789628
PMCID:
PMC5964252
DOI:
10.1038/s41467-018-04356-9
[Indexed for MEDLINE]
Free PMC Article

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