Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma

Research output: Contribution to journalArticle

Abstract

The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor. Screening IBL-302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL-302 was more effective than single PI3K inhibition in vitro, and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels. IBL-302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho-proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL-302 treatment. While IBL-302 treatment alone reduced tumor growth in vivo, combination therapy with low-dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high-risk neuroblastoma.

Details

Authors
Organisations
External organisations
  • Spanish National Cancer Research Center (CNIO)
  • Academic Medical Center of University of Amsterdam (AMC)
  • Inflection Biosciences Ltd
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • cisplatin, IBL-302, multikinase inhibition, neuroblastoma, PI3K
Original languageEnglish
Article numbere10058
JournalEMBO Molecular Medicine
Volume11
Issue number8
Publication statusPublished - 2019 Aug 1
Publication categoryResearch
Peer-reviewedYes

Related research output

Karin Hansson, 2020, Lund: Lund University, Faculty of Medicine. 74 p.

Research output: ThesisDoctoral Thesis (compilation)

View all (1)