Initial testing of the aurora kinase A inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP)

Abstract

Background: MLN8237 is a small molecule inhibitor of Aurora Kinase A (AURKA) that is currently in early phase clinical testing. AURKA plays a pivotal role in centrosome maturation and spindle formation during mitosis.

Procedures: MLN8237 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 microM and was tested against the PPTP in vivo panels at a dose of 20 mg/kg administered orally twice daily x 5 days. Treatment duration was 6 weeks for solid tumor xenografts and 3 weeks for ALL xenografts.

Results: MLN8237 had a median IC(50) of 61 nM against the PPTP in vitro panel. The ALL cell lines were more sensitive and the rhabdomyosarcoma cell lines less sensitive than the remaining PPTP cell lines. In vivo, MLN8237 induced significant differences in event-free survival (EFS) distributions compared to controls in 32/40 (80%) solid tumor models and all (6/6) ALL models. Maintained complete responses (CRs) were observed in 3 of 7 neuroblastoma xenografts, and all 6 evaluable ALL xenografts achieved CR (n = 4) or maintained CR (n = 2) status. Maintained CRs were observed among single xenografts in other panels, including the Wilms tumor, rhabdoid tumor, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, and medulloblastoma.

Conclusions: The in vivo activity observed against the neuroblastoma panel far exceeds that observed for standard agents evaluated against the panel by the PPTP. High levels of in vivo activity were also observed against the ALL xenograft panel. These data support expedited clinical development of MLN8237 in childhood cancer.

Figure 1

MLN8237 in vitro activity, figure 1A is a dot plot chart that illustrates the relative sensitivity of the cell lines using the IC₅₀ values displayed by histology. The black line indicates the median IC₅₀ (61 nM) for the panel. Figure 1B illustrates typical cytotxicity curves for CHLA-90 (multidrug resistant TP53-mutated neuroblastoma) and Molt-4 (T cell ALL). Error bars represent standard deviations for each concentration tested.

Figure 2

MLN8237 in vivo objective response activity. Left: A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥ 2 but < 6, and low activity by a score of < 2. The colored heat map depicts group response scores: MCR (red), CR (orange), PR (yellow), SD (gray), PD2 (light green), PD1 (dark Green). Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.

Figure 3

MLN8237 activity against individual solid tumor xenografts, Kaplan-Meier curves for EFS, median relative tumor volume graphs, and individual tumor volume graphs (controls, gray and treated, black lines) are shown for selected lines: (A) SK-NEP-1 (B) NB-1643, and (C) NB-EBc1.

Figure 4

MLN8237 activity against individual ALL xenografts, Kaplan-Meier curves for EFS and graphs of median and individual percentages of hCD45 cells (controls, gray and treated, black lines), are shown for selected lines: (A) ALL-2, (B) ALL-17, and (C) ALL-19.