Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras(G12D) activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% ± 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogen-activated protein kinase pathway downstream of Kras(G12D) expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.
Highlights
The phosphatidylinositol 3-kinase (PI3K) pathway is an essential regulator of cellular proliferation, survival, metabolism, and growth acting through disparate downstream effectors including the AKT and mTOR pathways
We observed a reduction in FDG-uptake, indicating decreased glucose metabolism that correlates with the observed decrease in PI3K pathway activation
We present an in vivo efficacy study of the PI3K/ mTOR inhibitor, PF-04691502 in a genetically engineered mouse model of ovarian cancer driven by KrasG12D-activating mutation and Pten deletion
Summary
The phosphatidylinositol 3-kinase (PI3K) pathway is an essential regulator of cellular proliferation, survival, metabolism, and growth acting through disparate downstream effectors including the AKT and mTOR pathways. Receptor and ERBB2 are common in human cancers, making this pathway an attractive target for novel anticancer therapeutics [1]. Multiple small-molecule inhibitors have been targeted to different kinases throughout the pathway, including AKT inhibitors (MK-2206), mTOR inhibitors (everolimus, temsirolimus, AZD8055, OSI027), PI3K inhibitors (GDC-0941, PX866, BKM120), and dual PI3K/mTOR inhibitors [BEZ235; reviewed in [2, 3]]. PF-04691502, a novel dual PI3K/mTOR inhibitor, has been described [4] and has been entered in phase I clinical trials for the treatment of solid cancers. Minimal characterization of the preclinical predictors of the efficacy of this drug has been reported
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