Abstract LB-380: Apo2L/TRAIL reduces interstitial fluid pressure and enhances gemicitabine uptake in patient pancreatic tumor xenografts

Abstract

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has promising anti-tumor therapeutic potential and is in clinical trials. It is known that microenvironmental factors such as elevated interstitial fluid pressure limits uptake and greatly inhibits anti-tumor efficacy of many therapeutics. We are investigating the role of interstitial fluid pressure in the anti-tumor effect of Apo2L/TRAIL alone and in combination with gemcitabine. We first carried out a histological analysis of Colo205 tumors treated with a single 1000 g dose of Apo2L/TRAIL. Apoptosis (ck18+ cells) and infiltration of macrophages (F4/80+ cells) peaks by 8 hrs; by 24 and 48 hours, apoptotic debris has been cleared and the lumen of tumor vessels is clearly apparent. This is in sharp contrast to untreated tumors in which cells are densely packed and vessels with an open lumen are seldom seen. Correspondingly, measurements of tumor interstitial fluid pressure (IFP) taken 48 hrs after a single treatment of Apo2L/TRAIL revealed a significant reduction in IFP compared to tumors in the untreated mice (n=5; 0.3 cm H2O vs. 3.4 cm H2O, P= 0.002). We have characterized the Apo2L/TRAIL sensitivity of a panel of patient pancreatic tumor xenografts and found a range of responses to Apo2L/TRAIL from actual regression (tumor growth inhibition, TGI, of 108%) to complete resistance (TGI of 0%). Histological analysis of a sensitive tumor showed that Apo2L/TRAIL induced both the physical changes seen in Colo205 as well as a similarly significant reduction in IFP (n=7; P= 0.003). Importantly, in these patient xenografts, combination therapy with Apo2L/TRAIL and chemotherapy has been shown to enhance the antitumor effect of gemcitabine. Therefore, we investigated the effect of Apo2L/TRAIL induced lowering of IFP on gemcitabine uptake. In these studies, a single dose of gemcitabine was administered 48 hrs after Apo2L/TRAIL administration. Pharmacological analysis reveals a 33% increase in gemcitabine uptake in tumors in the 6 hours following Apo2L/TRAIL administration; no such increase was observed in normal liver. These results support the idea that pretreatment of a tumor with Apo2L/TRAIL leads to “decompression” of the tumor and will selectively improve tumor uptake of chemotherapeutics. We are currently investigating different schedules of administration in order to maximize the uptake of gemcitabine and optimize the anti-tumor efficacy of this combination therapy. 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 LB-380.