Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>ROCK1 is a multifunctional member of the AGC (protein kinase A/G/C) kinase family that has been implicated in the modulation of stress-fiber assembly, cell contraction, apoptosis, and in the migration and invasion of multiple cancer cell types. It has been reported that ROCK1 plays an important role in the activation and function of pancreatic stellate cells, including in the formation of desmoplasia in pancreatic ductal adenocarcinoma (PDAC)(Masamune, 2003, Br J Pharmacol, 140:1292). Desmoplasia and its effects are thought to contribute to poor drug delivery in PDAC treatment. We therefore hypothesized that ROCK1 inhibition may reduce desmoplasia and enhance drug efficacy in PDAC treatment. We previously reported that ROCK1 is overexpressed in human pancreatic tumor cells and amplified in a small subset of PDAC patient samples. In this study we report that the ROCK inhibitor, fasudil, reduced collagen mRNA levels by 3.9-fold in cultured pancreatic stellate cells derived from PDAC tissues treated at 100µM. We also observed a 3.0-fold reduction in collagen protein expression in co-cultured tumor and stellate cells at the same concentration of fasudil. Similar reductions were observed in immunofluorescence analysis of co-cultured tumor and stellate cells treated with fasudil. We next sought to determine if ROCK1 inhibition would result in a reduction in collagen expression in the the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model for PDAC. KPC mice were treated orally, b.i.d., with 100mg/kg fasudil and by i.p. with gemcitabine (q3dx4) at 80mg/kg. Tumors in KPC mice treated with the combination of fasudil and gemcitabine showed a marked reduction in overall tumor collagen content when compared to vehicle-treated mice as measured by a pentachrome staining. Histochemical analysis of tumors also showed reductions in the overall proliferation of the pancreatic stellate cell compartment. Ongoing efforts are being made to assess whether this treatment regimen may enhance gemcitabine efficacy in the KPC mice. These results indicate that ROCK1 is a potential therapeutic target in pancreatic cancer, and may provide an effective means to enhance current treatment regimens.</jats:p>
<jats:p>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 LB-239. doi:1538-7445.AM2012-LB-239</jats:p>