Abstract LB-418: Targeting the PI3K/mTOR pathway in genetically engineered mouse models of prostate cancer
Authors: Patnaik Akash , Courtney Kevin , Bellinger Gary , Lunsford Elaine , Robichaud Kyle , Grant Aaron , Lenkinski Robert , Pedrosa Ivan , Signoretti Sabina , Wooster Richard , Cantley Lewis 
Published: August 2014

The PTEN and p53 tumor suppressors are among the most commonly inactivated or mutated genes in human cancer, including prostate cancer. Loss of PTEN is associated with increased pathologic Gleason score and risk of clinical recurrence, and 20-60% of human metastatic prostate cancers have loss of heterozygosity at the PTEN locus, resulting in hyperactivation of the PI3K/mTOR pathway. Mice with germline heterozygosity for PTEN have been shown to develop prostate intraepithelial neoplasia (PIN) at a high rate (&gt;60%) and mice with prostate specific homozygous deletion of PTEN develop invasive prostate cancer, albeit with prolonged latency of approx. 6 months. Combined inactivation of PTEN and p53 in mouse prostate elicits invasive cancer by 9 weeks of age and invariable lethality by 7 months of age.

There are several PI3K pathway-directed therapies currently in Phase I clinical trials, but the underlying tumor genetic signature of patients most likely to respond to these therapies is largely unknown. To understand the significance of targeting the PI3K/mTOR pathway in advanced prostate cancer driven by PTEN +/− p53 loss, we evaluated the impact of GSK458 (a dual PI3K/mTOR inhibitor) in prostate-specific PTEN/p53 double knockout mice and prostate-specific PTEN-knockout mice. The mice were imaged by synchronized 18FDG-PET and T2-weighted MRI, respectively, for baseline tumor metabolic and volumetric assessment prior to drug administration. GSK458 was administered at 3 mg/kg by daily oral gavage for 3 weeks with serial 18FDG-PET and T2-weighted MRI imaging at 2 days, 1 week, 2 weeks and 3 weeks after initiation of treatment, followed by sacrifice, prostate harvest and standard hisopathologic and immunohistochemical staining.

GSK458 treatment of PTEN/p53-deficient and PTEN-deficient mice results in target inhibition, based on pharmacodynamic assessment by 18FDG-PET uptake. MRI and histopathologic analysis demonstrate that there is a significant reduction, but not complete regression of tumor burden in both intraepithelial and poorly differentiated atypical components within stroma and partial stromal collapse following 3 weeks of GSK458 treatment. These data highlight the feasibility of monitoring dual pharmacodynamics/antitumor effects of PI3K-directed therapies using 18FDG-PET/MRI imaging and underscore the utility of genetically engineered mouse models to predict response to targeted therapies in genetically stratified human clinical trials. The evaluation of PI3K-isoform specific inhibitors and the design of rational combinations to overcome de novo and acquired resistance mechanisms to PI3K-directed therapies are currently being explored in multiple genetically engineered mouse model systems.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-418. doi:10.1158/1538-7445.AM2011-LB-418