Abstract 282: Minnelide improves the efficacy of the nab-paclitaxel plus gemcitabine plus cisplatin chemotherapy in mouse models of PDAC

Background: There have been some recently developed regimens which have improved the survival of patients with advanced pancreatic cancer. In a recent Phase Ib/II pilot trial in patients with advanced stage IV PDAC, nab-paclitaxel/gemcitabine/cisplatin regimen (triple combination, TC) exhibited promising clinical activity with a response rate of 71% and overall median survival of 16.5 months associated with manageable adverse effects (Jameson, et al., J. Clin. Oncol. 2017 35:4 suppl, 341). Minnelide (Min), a novel water soluble pro-drug of triptolide, a potent antitumor agent isolated from a Chinese medicinal herb, has demonstrated efficacy against several human cancers implanted in mouse models. Min is currently in Phase II trial in patients with refractory pancreatic cancer. In this study we evaluated the synergy between the TC and Min in various pancreatic cancer models (including the treatment sequence of the agents). Methods: The drug combination efficacy was evaluated in athymic nude mouse models generated with MIA PaCa-2 cells and patient derived xenografts (PDX) implanted subcutaneously. The mice were treated with vehicle control, Min (QDx21), TC (QWx3) or TC (QWx3) plus Min(QDx21). In the PDX models Min (QDx21) given before or after the TC (QWx3) was also evaluated. To evaluate the effects of the combination treatment on tumor immune microenvironment, the KPC transgenic mice (K-RasG12D/+, p53R172H/+) were also treated with same combinations. Tumor volumes were assessed by ultrasound and immune cell infiltration was assessed by immunohistochemistry (IHC). Results: The TC plus Min shows the greatest effect in tumor growth inhibition which remains persistent even after the treatment is discontinued in both the cell line xenograft model and the PDX models with several of the mice exhibiting complete remissions. In the MIA PaCa-2 cell line xenograft model, comparing to the vehicle control the tumor growth inhibition after drug treatment (21 days) was 97%, 93%, and 100% for Min, TC, and Min + TC, respectively. The animal survival at 45 days was 0%, 73%, 67%, and 90% for vehicle, Min, TC, and Min + TC, respectively. In the PDX model, the tumor growth inhibition after drug treatment was 86%, 84%, and 96% comparing to the vehicle, whereas the animal survival at 45 days was 0%, 89%, 100% and 100% for vehicle, Min, TC, and Min + TC, respectively. Min administered prior to or after the TC treatment also exhibited improved efficacy versus TC alone, with tumor growth inhibition similar to those treated with the agents concurrently. These results provide preclinical insights for the design of clinical trials that may further improve outcome in patients with advanced PDAC. (This work was supported by the SU2C-CRUK-Lustgarten Dream Team grant (Grant number: SU2C-AACR-DT-20-16)) Citation Format: Liang Ng, Pawan Noel, Stephanie Mou, Daniel D. Von Hoff, Haiyong Han. Minnelide improves the efficacy of the nab-paclitaxel plus gemcitabine plus cisplatin chemotherapy in mouse models of PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 282.