Studies Reveal Potential Therapies for Pancreatic Cancer

Using a protein sponge to absorb most of a molecule responsible for angiogenesis or interfering with a signaling pathway that allows cancer cells to resist drugs are routes that may lead to improved treatment for pancreatic cancer, according to two studies from Dartmouth Medical School (DMS, Lebanon, NH, USA; www.darmouth.edu/dms/).

Pancreatic cancer is known for its ability to spread quickly, while becoming increasingly resistant to traditional chemotherapy. Generally diagnosed in an advanced state, it is frequently inoperable.

"By the time the disease is diagnosed, pancreatic cancer cells have a huge growth advantage over normal cells, which enables them to grow and metastasize very quickly,” said lead researcher Dr. Murray Korc, chair of the department of medicine at DMS. "Our research has focused on determining what factors enable the cells to grow at such a fast rate and then how to slow that rate down and actually suppress pancreatic tumor growth.”

Researchers focused on the overexpression of a molecule that hampers chemotherapeutic efforts, vascular endothelial growth factor (VEGF). VEGF is responsible for angiogenesis,, and in pancreatic cancer cells, there is a 90-fold higher level of VEGF than in normal cells, which enables the cancer cells to grow and metastasize quickly and efficiently.

In their study, the researchers injected a protein sponge, VEGF-Trap, into mice bearing pancreatic tumors derived from four different human pancreatic cancer cells. They predicted the sponge would absorb most of the angiogenic VEGF molecules, thereby slowing the blood vessel proliferation and suppressing tumor growth.

"The protein sponge completely suppressed pancreatic tumor growth,” said Dr. Korc. "In all the tumors tested, there was a marked decrease in blood vessel formation, which is very exciting.” The results of this study appeared in the May 15, 2004, issue of Clinical Cancer Research.

In the second study, published in the May 15, 2004, issue of Cancer Research, Dr. Korc and his team describe a mechanism for chemoresistance in pancreatic cancer. They identified the pathways responsible for giving the pancreatic cancer cells a growth advantage and making them resistant to chemotherapeutic drugs. They focused on two molecules, Smad7 and thioredoxin.

In future research, the team will introduce a molecular sponge to absorb certain overexpressed molecules that promote the expression of Smad7 and thioredoxin, in order to determine if this can render the cancer cells more responsive to therapy.

"The mortality rate virtually equals incidence,” said Dr. Korc, speaking of pancreatic cancer. "Of the 31,000 people in the United States that get it this year, 30,300 will die from it, and most patients will die within six months. That is why we are excited about this research and hope that it will lead to more advances in the treatment of pancreatic cancer.”





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