Preclinical evaluation of the combination of AZD1775 and irinotecan against selected pediatric solid tumors: A Pediatric Preclinical Testing Consortium report.

Abstract

INTRODUCTION:

WEE1 is a serine kinase central to the G2 checkpoint. Inhibition of WEE1 can lead to cell death by permitting cell-cycle progression despite unrepaired DNA damage. AZD1775 is a WEE1 inhibitor that is in clinical development for children and adults with cancer.

METHODS:

AZD1775 was tested using a dose of 120 mg/kg administered orally for days 1 to 5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg for days 1 to 5 (one hour after AZD1775 when used in combination). AZD1775 and irinotecan were studied alone and in combination in neuroblastoma (n = 3), osteosarcoma (n = 4), and Wilms tumor (n = 3) xenografts.

RESULTS:

AZD1775 as a single agent showed little activity. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and two Wilms tumor models (CR and PR). The combination of AZD1775 + irinotecan-induced objective responses in two neuroblastoma lines (PR and CR) and all three Wilms tumor lines (CR and 2 PRs). The objective response measure improved compared with single-agent treatment for one neuroblastoma (PR to CR), two osteosarcoma (PD1 to PD2), and one Wilms tumor (PD2 to PR) xenograft lines. Of note, the combination yielded CR (n = 1) and PR (n = 2) in all the Wilms tumor lines. The event-free survival was significantly longer for the combination compared with single-agent irinotecan in all models tested. The magnitude of the increase was greatest in osteosarcoma and Wilms tumor xenografts.

CONCLUSIONS:

AZD1775 potentiates the effects of irinotecan across most of the xenograft lines tested, with effect size appearing to vary across tumor panels.

• Authors: E Anders Kolb, Peter J Houghton, Raushan T Kurmasheva, Yael P Mosse, John M Maris, Stephen W Erickson, Yuelong Guo, Beverly A Teicher, Malcolm A Smith, Richard Gorlick
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 67 Issue 5 Pg. e28098 (05 2020) ISSN: 1545-5017 [Electronic] United States
• PMID: 31975571 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 Wiley Periodicals, Inc.

Chemical References

• Pyrazoles
• Pyrimidinones
• Irinotecan
• adavosertib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Child
• Female
• Humans
• Irinotecan (pharmacology)
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, SCID
• Neoplasms, Experimental (drug therapy, metabolism)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Pyrazoles (pharmacology)
• Pyrimidinones (pharmacology)
• Wilms Tumor (drug therapy, metabolism, pathology)
• Xenograft Model Antitumor Assays