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

Fecha de publicación: 01/08/2019 Fecha Ahead of Print: 01/07/2019

Autores de IIS La Fe

Cristian García Ruiz

Autor

Participantes ajenos a IIS La Fe

Mohlin, S
Hansson, K
Radke, K
Martinez, S
Blanco-Apiricio, C
Welinder, C
Esfandyari, J
O'Neill, M
Pastor, J
von Stedingk, K
Bexell, D

Grupos

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

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.

Datos de la publicación

ISSN/ISSNe:: 1757-4676, 1757-4684
Tipo:: Article
Páginas:: -
DOI:: 10.15252/emmm.201810058
Factor de Impacto:: 4,816 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Mohlin, S:: Lund Univ, Dept Clin Sci, Div Pediat, Lund, Sweden
Hansson, K:: Lund Univ, Canc Ctr, Dept Lab Med, Translat Canc Res, Lund, Sweden
Radke, K:: Lund Univ, Canc Ctr, Dept Lab Med, Translat Canc Res, Lund, Sweden
Martinez, S:: Spanish Natl Canc Res Ctr CNIO, Expt Therapeut Programme, Madrid, Spain
Blanco-Apiricio, C:: Spanish Natl Canc Res Ctr CNIO, Expt Therapeut Programme, Madrid, Spain
Garcia-Ruiz, C:: Lund Univ, Canc Ctr, Dept Lab Med, Translat Canc Res, Lund, Sweden

Instituto de Investigación. IIS La Fe, Hematol & Hemotherapy Res Grp, Valencia, Spain
Welinder, C:: Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden
Esfandyari, J:: Lund Univ, Canc Ctr, Dept Lab Med, Translat Canc Res, Lund, Sweden
O'Neill, M:: Inflect Biosci Ltd, Blackrock, Ireland
Pastor, J:: Spanish Natl Canc Res Ctr CNIO, Expt Therapeut Programme, Madrid, Spain
von Stedingk, K:: Lund Univ, Dept Clin Sci, Div Pediat, Lund, Sweden

Univ Amsterdam, Univ Med Ctr, Dept Oncogen, Amsterdam, Netherlands
Bexell, D:: Lund Univ, Canc Ctr, Dept Lab Med, Translat Canc Res, Lund, Sweden

Keywords

cisplatin; IBL-302; multikinase inhibition; neuroblastoma; PI3K

Proyectos asociados

SPLICING Y EPIGENÉTICA EN SMD. Uso de modelos crispr/cas9 para estudiar el impacto de mutaciones genéticas y epigenéticas co-ocurrentes en los síndromes mielodisplásicos.

Investigador Principal: ALEJANDRA SANJUAN PLA

SAF2017-82171-R . MINISTERIO DE ECONOMIA Y COMPETITIVIDAD . 2018

In vivo models to approach functional genomics in myelodysplasic syndromes.

Investigador Principal: GUILLERMO SANZ SANTILLANA

2018_0246_CRC_AECC_GARCIA . FUNDACIÓN CIENTÍFICA AECC . 2018

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