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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor often with metastasis to distant sites including liver, lung and adjacent intestines. Diagnoses of PDAC carry a poor prognosis due to limited treatment options. Fatty acid synthase (FAS) has been shown to be a potential therapeutic target in breast carcinomas, mesothelioma and ovarian carcinoma. However, whether FAS could serve as a therapeutic target in pancreatic carcinoma is not known. We used a PDAC cell line, Colo357, which expresses abundant FAS in vitro and in mouse orthotopical tumor in vivo. Treatment of Colo357 with C75 resulted in increased apoptosis in a dose-dependent manner in vitro. To investigate the effect of C75 on growth and metastasis of PDAC, human PDAC xenograft tissue was surgically implanted with Matrigel synthetic basement membrane onto the pancreas of nude mice. Three weeks post implantation, mice were randomized into treatment groups, and C75 was administered at a dose of 25 mg/kg weekly for a total of six weeks. At week six, a 50% reduction in primary pancreatic tumor weight was observed in the C75-treated group compared to vehicle-treated mice. In addition, mice administered C75 had a significant reduction in liver weight compared to control mice. Gross examination revealed liver metastases in 1 of 5 (20%) C75-treated mice compared to 5 of 5 (100%) vehicle-treated mice, indicating that C75 inhibited tumor metastasis to the liver. Furthermore, none of the mice that received C75 developed peritoneal lymph node metastases or ascites, whereas 5 of 5 vehicle-treated mice showed such lesions. Collectively, these results suggest that FAS is a potentially important target for inhibiting PDAC growth and metastasis.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]

American Association for Cancer Research
2004