Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201810058
Keywords
cisplatin; IBL-302; multikinase inhibition; neuroblastoma; PI3K
Categories
Funding
- Swedish Cancer Society
- Swedish Research Council
- Swedish Childhood Cancer Fund
- Region Skane
- Skane University Hospital
- Mary Beve Foundation
- Magnus Bergvalls stiftelse
- Thelma Zoega Foundation
- Hans von Kantzow Foundation
- Crafoord Foundation
- Ake Wiberg Foundation
- Ollie och Elof Ericssons stiftelser
- Berth von Kantzows stiftelse
- Royal Physiographic Society of Lund
- Spanish Ministry of Health and Social Policy [ADE08/90038]
- Spanish Ministry of Science and Innovation [CIT-090000-2008-14]
- RFI/VR
- Jeanssons Stiftelser
- Science for Life Laboratory, Sweden
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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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