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

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Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma. / Mohlin, Sofie; Hansson, Karin; Radke, Katarzyna; Martinez, Sonia; Blanco-Apiricio, Carmen; Garcia-Ruiz, Cristian; Welinder, Charlotte; Esfandyari, Javanshir; O'Neill, Michael; Pastor, Joaquin; von Stedingk, Kristoffer; Bexell, Daniel.

In: EMBO Molecular Medicine, Vol. 11, No. 8, e10058, 01.08.2019.

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Mohlin, Sofie ; Hansson, Karin ; Radke, Katarzyna ; Martinez, Sonia ; Blanco-Apiricio, Carmen ; Garcia-Ruiz, Cristian ; Welinder, Charlotte ; Esfandyari, Javanshir ; O'Neill, Michael ; Pastor, Joaquin ; von Stedingk, Kristoffer ; Bexell, Daniel. / Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 8.

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TY - JOUR

T1 - Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma

AU - Mohlin, Sofie

AU - Hansson, Karin

AU - Radke, Katarzyna

AU - Martinez, Sonia

AU - Blanco-Apiricio, Carmen

AU - Garcia-Ruiz, Cristian

AU - Welinder, Charlotte

AU - Esfandyari, Javanshir

AU - O'Neill, Michael

AU - Pastor, Joaquin

AU - von Stedingk, Kristoffer

AU - Bexell, Daniel

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - cisplatin

KW - IBL-302

KW - multikinase inhibition

KW - neuroblastoma

KW - PI3K

UR - http://www.scopus.com/inward/record.url?scp=85069812158&partnerID=8YFLogxK

U2 - 10.15252/emmm.201810058

DO - 10.15252/emmm.201810058

M3 - Article

C2 - 31310053

AN - SCOPUS:85069812158

VL - 11

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4684

IS - 8

M1 - e10058

ER -