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Novel target for pancreatic cancer therapy identified
Novel pathways regulate tumor cell regulation in pancreatic ductal adenocarcinoma, and those pathways may represent targets for therapy, according to recent findings.
Researchers from the Mayo Clinic in Jacksonville, Fla., suggested that activation of the classical and alternative nuclear factor (NF)-kappaB pathways have played a role in pancreatic ductal adenocarcinoma.
Results of the current analysis indicated that activation of the alternative pathway may result in high basal NF-kappaB activity in the cell lines of this disease.
Stabilization and activation of the NF-kappaB-inducing kinase mediates increasing levels of activity of the p52/RelB NF-kappaB complex, according to the results.
The mechanism that causes active NF-kappaB-inducing kinase to increase in the cell lines of this cancer has been identified by the researchers as proteasomal downregulation of tumor necrosis factor (TNF) receptor-associated factor 2.
NF-kappaB-inducing kinase expression is upregulated, and the activity levels lead to increased proliferation and anchorage-independent growth. However, these factors are not linked to migration or survival of pancreatic ductal adenocarcinoma cells.
“Rapid growth is one characteristic of pancreatic cancer,” the researchers concluded. “Our data indicates that the [TNF receptor-associated factor 2]/[NF-kappaB-inducing kinase]/NF-kappaB2 pathway regulates [pancreatic ductal adenocarcinoma] cell tumorigenicity and could be a valuable target for therapy of this cancer.”
Perspective
Back to TopThis paper presented results of studies in human pancreatic adenocarcinoma samples and cell lines that indicate that down-regulation of TRAF2 — via ubiquitination and proteasomal degradation — is associated with increased levels of NIK, which is known to activate the NF-kappaB pathway, leading to cellular proliferation and apoptosis inhibition. These findings suggest that targeting TRAF2 by inhibiting proteasomal degradation may be an effective strategy in the treatment of pancreatic cancer.
The authors suggest a potential clinical approach using bortezomib (Velcade, Millennium) for proteasome inhibition in combination with gemcitabine (Gemzar, Eli Lilly) for apoptosis induction. It should be noted, however, that the combination of bortezomib and gemcitabine has been studied in metastatic pancreatic cancer patients in a randomized phase 2 study from the NCCTG. The combination, compared with gemcitabine alone, did not show improved OS or response rates. The combination of proteasomal and cIAP inhibitors may hopefully be of greater efficacy. That would be welcome news for advanced pancreatic cancer patients for whom current chemotherapy treatment options are rather limited.