Evaluation of VTP-50469, a menin-MLL1 inhibitor, against Ewing sarcoma xenograft models by the pediatric preclinical testing consortium

Pediatr Blood Cancer. 2020 Jul;67(7):e28284. doi: 10.1002/pbc.28284. Epub 2020 Apr 25.

Abstract

Background: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1.

Procedure: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines.

Results: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 μM for EwS cell lines.

Conclusions: In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models.

Keywords: Ewing sarcoma; pediatric oncology; xenograft.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Female
  • Histone-Lysine N-Methyltransferase / drug effects*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / drug effects*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Pediatrics
  • Proto-Oncogene Proteins / drug effects*
  • Proto-Oncogene Proteins / metabolism
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • KMT2A protein, human
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase