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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Proteins
  • Depsipeptides / pharmacology
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Ikaros Transcription Factor / antagonists & inhibitors
  • Ikaros Transcription Factor / genetics
  • Ikaros Transcription Factor / metabolism
  • Imidazolines / pharmacology
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Lymphoma, Extranodal NK-T-Cell / drug therapy*
  • Lymphoma, Extranodal NK-T-Cell / genetics
  • Lymphoma, Extranodal NK-T-Cell / metabolism
  • Lymphoma, Extranodal NK-T-Cell / pathology
  • Lymphoma, T-Cell / drug therapy*
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology
  • Mice
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Peptides / pharmacology*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Remission Induction
  • Signal Transduction
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Whole Exome Sequencing
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Depsipeptides
  • IKZF1 protein, human
  • Imidazolines
  • MDM4 protein, human
  • Nuclear Proteins
  • Peptides
  • Proto-Oncogene Proteins
  • RG7112
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ikaros Transcription Factor
  • romidepsin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • JAK2 protein, human
  • Janus Kinase 2