Evidence for the importance of personalized molecular profiling in pancreatic cancer.

OBJECTIVES: There is a growing body of evidence that targeted gene therapy holds great promise for the future treatment of cancer. A crucial step in this therapy is the accurate identification of appropriate candidate genes/pathways for targeted treatment. One approach is to identify variant genes/pathways that are significantly enriched in groups of afflicted individuals relative to control subjects. However, if there are multiple molecular pathways to the same cancer, the molecular determinants of the disease may be heterogeneous among individuals and possibly go undetected by group analyses. METHODS: In an effort to explore this question in pancreatic cancer, we compared the most significantly differentially expressed genes/pathways between cancer and control patient samples as determined by group versus personalized analyses. RESULTS: We found little to no overlap between genes/pathways identified by gene expression profiling using group analyses relative to those identified by personalized analyses. CONCLUSIONS: Our results indicate that personalized and not group molecular profiling is the most appropriate approach for the identification of putative candidates for targeted gene therapy of pancreatic and perhaps other cancers with heterogeneous molecular etiology.

Molecular analysis of the inhibitory effect of N-acetyl-L-cysteine on the proliferation and invasiveness of pancreatic cancer cells.

Preliminary studies have suggested that the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) may be effective in inhibiting the growth of pancreatic cancer cells. In-depth cellular and molecular analyses were carried out to determine NAC's mode of action in inhibiting the growth of a well-characterized pancreatic cancer cell line (AsPC-1). Standardized assays were used to monitor cellular growth, apoptosis, levels of ROS, cellular senescence, migration, and invasiveness. Cell stiffness was measured using atomic force microscopy. Gene expression was monitored by quantitative PCR. NAC significantly inhibits the growth and metastatic potential of AsPC-1 cells by inducing cell-cycle arrest in G1 and subsequent cellular senescence and decreased invasiveness. These anticancer properties are associated with an unexpected increase in the intracellular concentrations of ROS. NAC does not decrease the susceptibility of AsPC-1 cells to the anticancer drugs gemcitabine, mitomycin C, and doxorubicin. NAC-induced changes in gene expression are consistent with the onset of mesenchymal-to-epithelial transition. In conclusion, our findings indicate that NAC induces an integrated series of responses in AsPC-1 cells that make it a highly promising candidate for development as a pancreatic cancer therapeutic.