Effective Use Of Pi3k/Mtor And Mek Inhibitors Prior To Hormone Ablative Therapy In Pten-Loss Driven Murine Prostate Cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The PTEN and p53 tumor suppressors are the most commonly altered genes in human cancer, including prostate cancer (PCa). Loss of PTEN is associated with increased Gleason score and clinical recurrence, and the majority of human metastatic PCas have PTEN loss via multiple mechanisms. Mice with prostate-specific homozygous deletion of PTEN develop invasive PCa albeit with prolonged latency of 6-8 months. Combined PTEN/p53 inactivation in mouse prostate elicits invasive cancer by 9 weeks of age and invariable lethality by 6 months of age. Since PTEN loss results in PI3K/mTOR pathway activation, we evaluated the impact of GSK458 (PI3K/mTOR inhibitor) and GSK418 (PI3K beta/delta isoform-specific inhibitor), singly and in combination with GSK212 (MEK inhibitor), in uncastrated, prostate-specific PTEN/p53 double knockout mice (4-6 months) and PTEN mice (11-14 months), respectively, harboring advanced PCa. The drugs were administered by daily oral gavage for 3 weeks with serial 18FDG-PET/MRI imaging at baseline, 2 days, 1 week, 2 weeks and 3 weeks post-treatment respectively. GSK458 treatment of PTEN/p53 and PTEN mice results in reduction in FDG-PET uptake as early as 24 h post-treatment, with 40% tumor shrinkage by 1 week post-treatment, but rapid regrowth of 18FDG-avid tumor by 2-3 weeks post-treatment. This acquired resistance was found to be mediated in part through upregulation of multiple receptor tyrosine kinases. In contrast, PTEN/p53 and PTEN mice did not respond to GSK418, by either FDG-PET or MRI analysis. We observed increased pERK/total ERK ratio by Western blot analysis and increased p-ERK staining by immunohistochemistry in GSK458 and GSK418-treated PTEN/53 mice, respectively. Treatment of PTEN/p53 and PTEN mice with GSK212 resulted in an approx. 40% reduction in tumor volume over 3 weeks. Treatment of PTEN/p53 mice with a combination of GSK458 plus GSK212 resulted in approx. 60% reduction of tumor volume at 3 week post-treatment. Strikingly, treatment of prostate-specific PTEN only mice with GSK458 plus GSK212 combination resulted in a >90% tumor regression at 3 weeks post-treatment. These results demonstrate the potential utlitity of PI3K/MEK-directed combination therapies in the neoadjuvant setting for locally advanced disease or hormone-sensitive phase in metastatic disease, thus delaying the need for hormone ablative therapy and its associated morbidity in advanced PCa. The data underscore the value of genetically engineered mouse models to co-clinically evaluate biomarkers of response and resistance to targeted therapies, and elucidate mechanisms of acquired resistance early in clinical development. The design of “personalized” combination therapies to overcome resistance to PI3K/MEK-directed therapies in the hormone-naive and castration-resistant contexts are currently underway in multiple GEMMs and Phase Ib co-clinical trials in advanced PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-365. doi:1538-7445.AM2012-LB-365