Abstract 3484: In vivo activity of combined PI3k/mTOR and MEK-inhibition in a K-RASG12D; PTEN deletion mouse model of ovarian cancer

Abstract

Abstract The PI3K/Akt pathway is commonly deregulated in human cancer, making it an attractive target for novel anti-cancer therapeutics. We have utilized a mouse model of ovarian cancer generated by K-RASG12D activation and PTEN deletion in the ovarian surface epithelium (Dinulescu, et al, 2005) for the pre-clinical assessment of a novel PI3K/mTOR inhibitor (PF-04691502, Pfizer). To enable high throughput studies, we have transplanted primary tumours from these mice orthotopically into the ovarian bursa. Tumour growth rates were monitored by small animal-Ultrasound, and when tumours reached an average of 200mm3, mice received vehicle or 10mg/kg PF-04691502 daily for 7 days. Ultrasound and FDG-PET scans were performed on day 0, day 2 and day 7 of therapy. PF-04691502 inhibited tumour growth at 7 days by 71.64%±8.93. Tumour weights measured post-mortem following 7 days treatment also showed a significant decrease in tumour mass in treated mice (0.78±0.13g in vehicle treated versus 0.38±0.06g in drug treated mice; p<0.05). FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically at 48 hours, and this reduction was maintained for the 7 day treatment duration, suggesting FDG-PET may be exploited as a biomarker of response to PF-04691502. To confirm that the PI3K/mTOR pathway is successfully inhibited with PF-04691502, western blots and immunohistochemistry were performed on tumour samples harvested at 7 days post-treatment. These show that pAKT(S473) and pS6(S240/244) were dramatically inhibited following PF-04691502 treatment. PF-04691502 was sufficient to inhibit PI3K/mTOR resulting in inhibition of tumour growth; however, we did not observe tumour regression in this model. Notably, tumours from PF-04691502 treated mice displayed activation of pERK, suggesting that activation of the MAPK pathway is a mechanism by which KRAS-mutant tumours can limit the efficacy of PI3K/mTOR inhibitors alone. To overcome the effects of RAS/MAPK signalling, we have performed studies evaluating PF-04691502 (7.5mg/kg, daily) in combination with an inhibitor of MEK (PD-0325901, Pfizer, 10mg/kg, daily). Ultrasound monitoring of tumour volume shows that over a 7 day treatment period, PF-04691502 led to tumour growth inhibition of 55%±10.27, PD-0325901 alone led to tumour regression (36.3%±20.45) and combined PD-0325901 and PF-04691502 led to a striking tumour regression of 80.7%±4.97. These data show that combined inhibition of PI3K/mTOR and MEK converts tumor growth delay with PI3K-inhibition alone to tumour regression in this KRAS and PTEN mutant mouse model of ovarian cancer. Therefore inhibition of MEK may enhance activity of PI3K/mTOR-inhibitors in tumours showing activation of the PI3K pathway by genomic changes such as mutation in KRAS combined with loss of PTEN. Dinulescu D. M., et al. (2005) Nat. Med. 11:63-70. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3484.