New 'suicide gene' delivery approach may pave way for pancreatic cancer treatment

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Washington, Sept 24 : Scientists have developed a novel method to effectively kill pancreatic cancer cells - using nanoparticles to successfully deliver a deadly diphtheria toxin gene.

The study, led by researchers at the Department of Surgery at Jefferson Medical College of Thomas Jefferson University and the Kimmel Cancer Center at Jefferson, was the first one to test this unique strategy in pancreatic cancer cells

And the success of this method offers hope for future pre-clinical animal studies, and possibly, a new clinical approach.

It was found that delivery of a diphtheria toxin gene suppressed a basic function of pancreatic tumour cells by over 95 percent, which in turn caused significant cell death of pancreatic cancer cells six days after a single treatment.

The researchers also showed that the treatment targets only pancreatic cancer cells and leaves normal cells alone, thus providing a potential 'therapeutic window.'

Also, they are targeting a molecule that is found in over three-quarters of pancreatic cancer patients.

"For the pancreatic cancer world, this is very exciting. There are no effective targeted treatments for pancreatic cancer, aside from surgery for which only a minority of patients qualify. We are in great need of translating the plethora of molecular information we know about this disease to novel therapeutic ideas," said the study's lead author, molecular biologist Jonathan Brody, Ph.D.

The approach was originally developed in ovarian cancer cells by study co-author Janet Sawicki, Ph.D. The strategy is based on the fact that both ovarian and pancreatic cancer cells significantly over-express a protein found on the cell membrane, called mesothelin.

The function of mesothelin is unknown, but it is found in the majority of pancreatic tumors and ovarian cancer tumors. Other solid tumors also express mesothelin, but not at such a high rate.

"We don't know completely why cancer cells repeatedly turn on mesothelin genes to produce these membrane proteins, but it gives us a way to fool the cell and hijack its machinery, to trick it into making other more potent genes that will be detrimental to the cancer cells," said Brody.

For this, the researchers devised an agent that consists of a bit of mesothelin DNA connected to the gene that produces the toxin from diphtheria, a highly contagious and potentially deadly bacteria, which is now controlled through childhood DPT vaccination. Then, "naked" DNA is coated in a polymer to form nanoparticles which get transferred to the cancer cells.

Inside the cells, the nanoparticles biodegrade and the cell machinery senses genetic material from mesothelin. Brody said that it activates the diphtheria toxin gene, which then turns on production of the toxin which allows the toxin to then do its work on the cancer cells.

Before completing 24 hours of delivery, the toxin disrupted production of protein machinery by over 95 percent, and within six days, a number of cancer cells die or are arrested.

"The cancer thinks it is turning on mesothelin and once it gets started reading that genetic code, it can't stop. So it will read the bacteria's DNA and produce the toxin which shuts down protein production in the cancer cells," he said.

"It worked well in our cell culture models and now we are moving into pre-clinical experiments," said Brody.

The study will be published in the October issue of Cancer Biology and Therapy.

ANI

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