Abstract 5685: Effects of sonic Hedgehog inhibitor combined with nanoparticulate drug delivery on vascular permeability and efficacy in a pancreatic cancer model

Abstract

Abstract Pancreatic cancer (PaCA) is lethal to the majority of patients, who present with unresectable disease and receive little benefit from chemotherapy. PaCA tumors are poorly perfused, which limits drug deposition. Inhibitors of the sonic hedgehog pathway (sHHI) promote tumor neovascularization and enhanced permeability to low molecular weight compounds in mouse PaCA models. Multiple sHHI are in early or advanced clinical trial. Here we tested the hypothesis that an inhibitor of Smoothened (NVP-LDE225) can enhance tumor deposition of sterically stabilized liposomes (SSL) and efficacy of SSL containing doxorubicin (SSL-DXR), a nanoparticulate carrier similar to Doxil®, an FDA-approved product. Forty mg/kg NVP-LDE225 was selected as a low but pharmacologically relevant dose; it is twice the dose that published reports show can sustain suppression of the downstream target Gli1 for 24 h in other tumor models. Ten daily treatments with the sHHI resulted in no significant inhibition of progression of low-passage, patient-derived pancreatic adenocarcinoma xenografts implanted subcutaneously in SCID mice, but markedly increased tumor deposition of 80 nm fluorescent SSL administered as a vascular permeability probe, for at least 4 days after discontinuation of the sHHI. Probe SSL diffused into regions of tumor cells after extravasation. Immunohistochemical staining revealed a slight trend toward higher microvessel density (CD31+) after sHHI treatment, but a significant increase in CD31+:pericyte (α-SMA+) and basement membrane (collagen IV+):CD31+ ratios, suggesting increased immature microvessels. SSL-DXR (15 mg/kg) administered after 10 days of sHHI treatment resulted in arrest of tumor volume progression, and 3-4 days after SSL-DXR treatment, tumor perfusion and permeability were reduced, suggesting initial vascular shutdown. With lower doses of SSL-DXR (6 mg/kg) that permit frequent and repeated administration, median time of tumor progression to protocol limits (TPPL) was extended by a single cycle of sHHI/SSL-DXR from 29 days for controls to 57 days for the combination, whereas SSL-DXR or sHHI alone was not effective. Three repeated cycles of sHHI pretreatment followed by SSL-DXR, with 10 days recovery between cycles, provided sustained suppression of tumor volume progression for up to 90 days in some animals. Median TPPL for the 3 cycle treatment was 29 d for controls, 41 d for SSL-DXR alone, 50 d for the sHHI alone, and 78 d for the sHHI/SSL-DXR sequence. We conclude that combination of sHHI in sequence with nanoparticulate drug carriers may take advantage of a ‘window of opportunity’ to exploit transient enhancement of tumor permeability/perfusion mediated by the sHHI to establish a persistent intra-tumor drug depot using nanoparticulate SSL drug formulations. This strategy has the potential to enhance efficacy of pancreatic cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5685. doi:1538-7445.AM2012-5685