Initial testing (stage 1) of the phosphatidylinositol 3' kinase inhibitor, SAR245408 (XL147) by the pediatric preclinical testing program

Abstract

Background: Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts.

Procedures: SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14.

Results: In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7-24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts.

Conclusions: Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered.

Figure 1

SAR245408 in vitro activity: The median rIC₅₀ ratio graph shows the relative rIC₅₀ values for the cell lines of the PPTP panel. Each bar represents the ratio of the panel rIC₅₀ to the rIC₅₀ value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity.

Figure 2

SAR245408 in vivo objective response activity. Left: The colored heat map depicts group response scores. 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. 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

SAR245408 activity in vivo against individual tumor xenografts. Rhabdomyosarcomas (Rh10, Rh18, Rh41): Kaplan-Meier curves for EFS (left), median relative tumor volume graphs (center), and individual tumor volume graphs (right) are shown for selected lines. ALL-7 (bottom panels): Kaplan-Meier curves showing the EFS (left), median leukemia engraftment (center) as detected in peripheral blood, and individual leukemia engraftment (right). Controls (gray lines); Treated (black lines), statistical significance (p values) of the difference between treated and control groups are included.

Figure 4

Characteristics of PI3K-Akt signaling in pediatric solid tumor xenografts. A. Expression levels of Class I PI3K isoforms from Affymetrix profiling (http://pptp.nchresearch.org/data.html); B. Protein levels for PTEN, Akt and phospho-Akt in solid tumor xenografts.