<i>Fc</i>^<i>+</i><i>Pik3ca</i>^{<i>H1047R</i>} colon cancers develop through a non-canonical pathway.

<p>Histological examination demonstrates that these cancers are flat without a polypoid component. Low grade dysplasia (tubular adenoma) has not been identified in these or the <i>Fc</i>^<i>+</i> <i>Pik3c</i>a^<i>p110*</i> mice. At higher magnification, malignant glands above the muscularis mucosa can be identified which appear to be originating from the crypt bases without identification of surface low grade dysplasia. CTNNB1 staining demonstrates that nuclear CTNNB1 is absent in both of the <i>Pik3ca</i> mutant models, but is present in the <i>Apc</i>^<i>Min</i> controls. Scale bar for low magnification image = 1mm. High magnification H&E image is a 6x magnification of the area indicated in the image to the left. Scale bar for CTNNB1 images = 100μm.</p

The PI3K pathway is activated in <i>Apc</i>^<i>Min/+</i>, <i>Fc</i>^<i>+</i> <i>Pik3c</i>a^<i>p110*</i>, and <i>Fc</i>^<i>+</i> <i>Pik3ca</i>^{<i>H1047R</i>} mice.

<p>Immunoblotting demonstrates robust phosphorylation of AKT in <i>Apc</i>^<i>Min</i>, <i>Fc</i>^<i>+</i> <i>Pik3c</i>a^<i>p110*</i> and <i>Fc</i>^<i>+</i> <i>Pik3ca</i>^{<i>H1047R</i>} colon tumors (A). Increased phosphorylation of RPS6 and 4EBP1 beyond that seen in the <i>Apc</i>^<i>Min</i> lesions is observed in the <i>Fc</i>^<i>+</i> <i>Pik3ca</i>^{<i>H1047R</i>} and <i>Fc</i>^<i>+</i> <i>Pik3c</i>a^<i>p110*</i> colon tumors. The more aggressive phenotype seen in the <i>Fc</i>^<i>+</i> <i>Pik3c</i>a^<i>p110*</i> mice, with a greater number and decreased latency, is associated with an increased phosphorylation of 4EBP1 compared to <i>Fc</i>^<i>+</i> <i>Pik3ca</i>^{<i>H1047R</i>} tumors (B).</p

Mutant PI3K can lead to colon cancer development.

<p>Approximately 60% of <i>Fc</i>^<i>+</i> <i>Pik3ca</i>^{<i>H1047R</i>} mice develop tumors within the colon which can result in these mice becoming moribund. At necropsy large colon tumors are found extending through the colonic wall (A). Upon resection, multiple lesions can be identified within the colon and can be over 1 cm in size (A and B). Following histological sectioning, H&E staining demonstrates that these lesions are invasive mucinous adenocarcinomas of the colon without a predominant intra-luminal component (C). Higher magnification demonstrates an abundant desmoplastic reaction with surrounding mucin lakes lined with epithelial cancer cells (D). D size bar = 200 μm.</p

Dual PI3K/mTOR inhibition induces treatment responses in <i>Fc</i>^<i>+</i> <i>Pik3ca</i>^{<i>H1047R</i>} colon cancers.

<p><i>Fc</i>^<i>+</i><i>Pik3ca</i>^{<i>H1047R</i>} mice were treated with NVP-BEZ235 (35mg/kg/day) or control once daily by oral gavage for 14 days. These mice underwent dual hybrid 18F-FDG PET/CT imaging at baseline and then 24 hours following the last dose of study drug (A, arrows denote tumors pre- and post-treatment). A significant reduction in tumor volume, as measured on the CT images, was detected in the NVP-BEZ235 group (p = 0.008; B). In addition, there was a trend for a slight decrease in the median SUV for those cancers treated with the PI3K/mTOR inhibitor. In one control mouse, two tumors were observed on baseline imaging, but not detected on follow-up PET/CT imaging.</p