Pharmacodynamic (Pd) Endpoints And Cellular Proliferation Effects Of Nvp-Bez235, A Dual Pi3k/Mtor Inhibitor, In Breast Cancer Cells And Xenografts With Wild-Type (Wt) And Activating Pi3k Mutations

14508 Background: PI3K mutations are frequent in human cancer and play a role in the malignant phenotype and therapeutic resistance. NVP-BEZ235 is a small molecular mass compound in phase I clinical studies. NVP-BEZ235 reversibly blocks the ATP binding pocket on both the p110 catalytic subunit of PI3Ks and mTOR. Our aims were to study the activity and PD markers of NVP-BEZ235 in breast cancer cell lines with activating PI3K mutations. Methods: A panel of breast cancer cell lines with either WT, endogenous PI3K activating mutations or over- expressing oncogenic p110α mutants were treated with NVP-BEZ235. A xenograft breast cancer model was used to determine in vivo effects. Results: Target inhibition by NVP-BEZ235 was achieved as evidenced by a reduction in the level of the phosphorylated form of Akt, S6 and 4EBP-1, plus the nuclear re-localisation of FoxO3a. Cellular proliferation in all tested cancer cell lines was strongly inhibited in the nanomolar range as determined by the growth inhibitory 50 concentration values. NVP-BEZ235 induced G1 cell cycle arrest and apoptosis in the breast cancer cell lines tested as determined by fluorescence-activated cell sorting and the presence of cleaved PARP. There was a strong correlation between the concentrations that inhibited signalling and those that induced a growth inhibitory effect. Importantly, NVP-BEZ235 was significantly active in cell cultures harbouring oncogenic PI3K mutants and demonstrated activity in models of trastuzumab resistance. Statistically significant antitumor activity was observed upon oral administration of NVP-BEZ235 to mice bearing breast cancer xenografts at tolerated doses. PD endpoints (p-Akt, p-4EBP1 and p-S6) in tumour tissue were reduced after compound treatment. Conclusions: NVP- BEZ235 shows a rapid and profound inhibition of the PI3K pathway and results in tumor cell growth inhibition and apoptosis. Disease stasis and inhibition of PD biomarkers was observed in breast cancer xenograft models. The observed correlation between the in vivo antitumor activity and the selected PD endpoints suggests that these markers may be of assistance in the dose-finding studies in patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharma AG Novartis Pharma AG