PURPOSE : Concurrent gemcitabine and nab-paclitaxel treatment is one of the preferred chemotherapy regimens for metastatic and locally-advanced pancreatic ductal adenocarcinoma (PDAC). Previous studies demonstrate that caveolin-1 (Cav-1) expression is critical for nab-paclitaxel uptake into tumors and correlates with response. Gemcitabine increases nab-paclitaxel uptake by increasing Cav-1 expression. Thus, we hypothesized that pre-treatment with gemcitabine would further enhance the sensitivity of PDAC to nab-paclitaxel by increasing Cav-1 expression and nab-paclitaxel uptake.

EXPERIMENTAL DESIGN : We investigated the sensitivity of different gemcitabine and nab-paclitaxel treatment regimens in a panel of PDAC cell lines and orthotopic xenograft models. The sensitivity of different treatment regimens was compared to the standard concurrent treatment.

RESULTS : Pre-treatment with gemcitabine before nab-paclitaxel increased Cav-1 and albumin uptake and significantly decreased proliferation and clonogenicity compared to concurrent treatment, which correlated with increased levels of apoptosis. Cav-1 silencing reduced the uptake of albumin and therapeutic advantage observed when cells were pre-treated with gemcitabine prior to nab-paclitaxel. Additionally, we observed that pre-treatment with gemcitabine resulted in partial synchronization of cells in the G2/M phase at the time of nab-paclitaxel treatment, providing another mechanism for the benefit of altered scheduling. In heterotopic and orthotopic xenograft models, the altered schedule of gemcitabine prior to nab-paclitaxel significantly delayed tumor growth compared to concurrent delivery without added toxicity.

CONCLUSIONS : Pre-treatment with gemcitabine significantly increased nab-paclitaxel uptake and correlated with an increased treatment efficacy and survival benefit in preclinical models, compared to standard concurrent treatment. These results justify preclinical and clinical testing of this altered scheduling combination.