Drug Discovery News
PHILADELPHIA—Researchers at Jefferson Medical College have killed off pancreatic cancer cells by targeting them with a deadly diphtheria toxin gene, a finding they say could lead to a better way to detect the spread of pancreatic cancer to lymph nodes and enhance tumor immune therapy strategies against the fast-moving, deadly disease.
“Putting in a toxin gene into cancer cells should inhibit the protein synthesis machinery,” says Dr. Jonathan Brody, assistant professor of surgery at the university and a co-author of the study, published recently in Cancer Biology and Therapy. “By shutting down protein production in a pancreatic cancer cell…we effectively will kill the cell. This work, if fully realized, could help over 75 percent of patients with pancreatic cancer.”
Using a novel biodegradable nanoparticulate system, the team, comprised of scientists from Jefferson’s Kimmel Cancer Center, sought to target mesothelin-expressing pancreatic cancer cells with a potent suicide gene, diphtheria toxin-A (DT-A). Mesothelin is a candidate target protein shown by a number of laboratories to be specifically overexpressed in pancreatic cancers and not in the adjacent normal tissue. The researchers achieved dramatic inhibition of protein translation in mesothelin-expressing pancreatic cancer cell lines when DT-A DNA, driven by the mesothelin promoter, was delivered to pancreatic cancer cells.
“We show that this inhibition effectively targets the death of pancreatic cancer cells that overexpress mesothelin,” the researchers wrote. “The work presented here provides evidence that this strategy will work in pre-clinical mouse pancreatic cancer models, and suggests that such a strategy will work in the clinical setting against the majority of pancreatic tumors, most of which overexpress mesothelin.”
The scientists also found that the metastatic cancer cells in the lymph nodes of patients with pancreatic cancer produce enough of the protein, IDO, to essentially wall-off the immune system’s T-cells and recruit cells that suppress the immune system’s response to the tumor. The team analyzed IDO expression in 14 lymph nodes to which pancreatic cancer cells had spread and compared them to the primary tumors that had not spread in the same patients. In every case, they found greater expression of the IDO protein in the cancerous lymph nodes. They also looked at three cases of lymph node-negative pancreatic cancers, finding little IDO present.
Brody says the researchers are working to secure funding to test this treatment in pre-clinical animal models and then rapidly translate the work into a clinical trial.
“We are working on making sure only pancreatic cancer cells see this suicide gene,” Brody says. “By this, we are putting tighter regulation on the expression of this toxic gene. We hope to just help pancreatic cancer patients.”
The study, Nanoparticulate delivery of diphtheria toxin DNA effectively kills mesothelin expressing pancreatic cancer cells, was published online in the October 2008 issue of Cancer Biology and Therapy. DDN