Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy with a dismal prognosis. Developing novel strategies to prevent or delay pancreatic cancer is currently of intense interest. The chemopreventive efficacy of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, was evaluated against the progression of pancreatic intraepithelial neoplasms (PanIN) to PDAC in conditional LSL-Kras G12D/+ transgenic mice. LSL-Kras G12D/+ and p48 Cre/+ mice were bred, and offspring of activated Kras G12D/+ were generated. Six-week-old male Kras G12D/+ (20 per group) and C57BL/6 wild-type (12 per group) mice were fed (AIN-76A) diets containing 0, 100, and 200 ppm of gefitinib for 35 weeks. At termination, pancreases were evaluated histopathologically for PanINs and PDAC, and various biomarkers were measured by immunohistochemistry, immunofluorescence, immunoblotting, and/or reverse transcription-PCR. Dietary gefitinib at 100 and 200 ppm significantly suppressed PDAC incidence by 77% and 100%, respectively (P < 0.0001) when compared with control diet. Importantly, a significant inhibition of carcinoma and a dose-dependent suppression of PanINs [PanIN-1, 37-62% (P < 0.002); PanIN-2, 38-41 (P < 0.001); and PanIN-3, 7-34% (P < 0.0141)] were observed in mice treated with gefitinib. Furthermore, mice treated with 100 and 200 ppm of gefitinib exhibited 67.6% to 77.3% of the pancreas to be free from ductal lesions. Also, gefitinib reduced EGFR, proliferating cell nuclear antigen, cyclin D1, C 2 GNT, RhoA, β-catenin, p38, phospho-extracellular signal-regulated kinase, caveolin-1, and mucin and increased cyclin B1 in the pancreatic lesions/PDAC. In summary, these results show that gefitinib can prevent the progression of pancreatic cancer precursor lesions to PDAC in a preclinical model. The present study highlights the promise of chemoprevention and the potential usefulness of EGFR inhibitors in individuals at high risk for pancreatic cancer. Cancer Prev Res; 3(11); 1417-26. ©2010 AACR.
BACKGROUND Studies have shown telomerase activity to be present in some B‐cell non‐Hodgkin lymphomas (B‐NHLs). However, no large studies have assayed telomerase activity in a systematic and quantitative manner. Furthermore, the relation between telomerase and proliferation suggested by in vitro studies has not been adequately tested in B‐NHLs in vivo. This information is necessary to understand the relation between proliferation and telomerase and to predict the efficacy of antitelomerase drugs currently in development. METHODS Eighteen benign biopsies and 111 B‐NHLs of varying types were classified according to the revised European‐American classification of lymphoid neoplasms (REAL classification) and assayed for telomerase activity and proliferation index (PI). RESULTS All B‐NHLs contained telomerase activity except for low grade marginal zone B‐cell lymphomas (MZBCLs) (96 of 111, 86%) (χ2 95.90, P < 0.001). Telomerase activity correlated with PI (r = 0.7536, r2 = 0.5678, t = 10.51, P < 0.001) and showed a threshold whereby telomerase activity was not present below a PI of 9.2% (t = 4.875, P < 0.001). CONCLUSIONS The level of telomerase activity fell within characteristic ranges and generally correlated with the clinical aggressiveness of each B‐NHL category. Low grade MZBCLs of extranodal, nodal, and splenic types were unique among the categories of B‐NHL in lacking or containing very little telomerase activity. The association between telomerase activity and PI is evidence that telomerase is controlled in vivo along with the cell cycle and is not constitutively active in B‐NHL. These data provide evidence that antitelomerase drugs may be efficacious in most types of B‐NHL. Cancer 2000;89:445–52. © 2000 American Cancer Society.
Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes.
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