Abstract 322: Dual targeting of the PI3K/mTOR pathways by PF-04691502 or PF-05212384 exhibits therapeutic effects against the metastatic disease progression in the Ovcar 3 disseminated model.

Ovarian cancer has the highest mortality rate of all gynecological cancers primarily due to the high incidence of metastatic spread prior to diagnosis. Understanding the biology of this malignancy and developing models that reflect the patient disease phenotype will create better pre-clinical opportunities for testing targeted therapy. We used the Ovcar 3 cell line to establish a metastasis model through serial in vivo passage. The dual PI3K/mTOR inhibitors PF-04691502 and PF-05212384 were then investigated in this model for their therapeutic effect against metastatic disease progression. Notably, the stromal environment and tumor initiating subpopulation play critical roles on the Ovcar 3MET disease invasiveness and progression. Based on the molecular profile, these invasive Ovcar 3MET cells exhibited a more EMT phenotype when compared to parental cells. Impairing PI3K/mTOR pathway with the dual PI3K/mTOR inhibitors resulted in significant anti-metastatic activity and increased survival in the Ovcar 3MET model. Serum CA125 level, which is a validated clinical marker, correlated with anatomic measurement of tumor burdens via BLI and mouse survival time in these studies, providing means for longitudinal monitoring of disease progression and response to therapy. In addition, using ex vivo tumorsphere analysis under serum-free condition, both PF-04691502 and PF-05212384 demonstrated robust activity against the self-renewal ability of Ovcar 3 tumor cells. In summary, this translational tumor model may serve as a valuable tool for testing targeted therapies such as PI3K/mTOR inhibitors for their ability to impact progression of metastatic ovarian disease. Citation Format: Zhengming Yan, Douglas Fang, Brett Simmons, Jing Yuan, Julie Kan, Cathy C. Zhang. Dual targeting of the PI3K/mTOR pathways by PF-04691502 or PF-05212384 exhibits therapeutic effects against the metastatic disease progression in the Ovcar 3 disseminated model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 322. doi:10.1158/1538-7445.AM2013-322