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

Mohlin, Sofie LU orcid ; Hansson, Karin LU ; Radke, Katarzyna LU ; Martinez, Sonia ; Blanco-Apiricio, Carmen ; Garcia-Ruiz, Cristian LU ; Welinder, Charlotte LU ; Esfandyari, Javanshir LU ; O'Neill, Michael and Pastor, Joaquin , et al. (2019) In EMBO Molecular Medicine 11(8).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cisplatin, IBL-302, multikinase inhibition, neuroblastoma, PI3K
in
EMBO Molecular Medicine
volume
11
issue
8
article number
e10058
publisher
Wiley-Blackwell
external identifiers
  • pmid:31310053
  • scopus:85069812158
ISSN
1757-4676
DOI
10.15252/emmm.201810058
language
English
LU publication?
yes
id
49916c5f-7063-4ca0-9416-a9efb51a181b
date added to LUP
2019-08-26 09:05:52
date last changed
2024-01-16 08:50:26
@article{49916c5f-7063-4ca0-9416-a9efb51a181b,
  abstract     = {{<p>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.</p>}},
  author       = {{Mohlin, Sofie and Hansson, Karin and Radke, Katarzyna and Martinez, Sonia and Blanco-Apiricio, Carmen and Garcia-Ruiz, Cristian and Welinder, Charlotte and Esfandyari, Javanshir and O'Neill, Michael and Pastor, Joaquin and von Stedingk, Kristoffer and Bexell, Daniel}},
  issn         = {{1757-4676}},
  keywords     = {{cisplatin; IBL-302; multikinase inhibition; neuroblastoma; PI3K}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma}},
  url          = {{http://dx.doi.org/10.15252/emmm.201810058}},
  doi          = {{10.15252/emmm.201810058}},
  volume       = {{11}},
  year         = {{2019}},
}