How pancreatic cancer able to defeat drugs

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Scientists at the Moores Cancer Center at the University of California, San Diego, have found one reason that pancreas cancer tumors are so difficult to treat with drugs. They have shown how a molecular switch steps up pancreas cancer cell survival as well as resistance to a standard chemotherapy drug, and have identified alternate routes cancer cells take to avoid the effects of the treatment.

The findings, by a group led by Andrew M. Lowy, MD, professor of surgery and chief of surgical oncology at the UCSD School of Medicine and the Moores UCSD Cancer Center, are reported online and will appear February 1 in the journal Cancer Research The study provides new insights into pancreas cancer development and new potential drug targets and therapy strategies against the disease.

"To understand how to treat pancreas cancer tumors, we need to better understand their circuitry and behavior," Lowy said.

Pancreas cancer is a especially deadly cancer, fast-moving and difficult to detect early. It's estimated that more than 35,000 people died from pancreas cancer last year in the United States.

RON is a signaling protein known as a tyrosine kinase, essentially a switch that turns on various activities in cells. Prior work in Lowy's lab showed that RON is overexpressed in a majority of premalignant and pancreas cancer cells, and could also help cells resist dying. The scientists wanted to find out what role, if any, RON played in pancreas cancer development and progression.

In a series of experiments, the scientists showed that RON sends signals that regulate the activity of genes that help tumors cells survive, "implying RON is a potent survival signal for pancreas cancer cells," Lowy said.

To see the effects of reducing or blocking RON activity, the team shut down RON expression in pancreas cancer cells using a molecular technique called "gene silencing," and then used those cells to establish tumors in mice. Those tumors were treated with gemcitabine, the most common chemotherapy drug used to treat pancreas cancer patients. Tumors in which RON was silenced were much more sensitive to the chemotherapy than the RON-expressing cancer cells.

"This is the first demonstration that RON-directed treatment in an animal model can sensitize tumors to chemotherapy," Lowy said. Yet, the researchers observed that the cancer cells and tumors were eventually able to bypass the silencing agent as well as the drug's effects, and continued to grow.

About 50 percent of the tumor cells re-expressed RON. The scientists also observed that the tumor cells activated other growth proteins, including epidermal growth factor receptor (EGFR), to enable them to continue to grow.

"This is what most tumors do," Lowy said, explaining that clinically, pancreas cancer tumors often respond to treatment at first, only to begin growing again. "We know that diseases such as pancreas cancer are too complex for one drug to be effective. If we can learn to predict the results of RON-directed treatment, maybe we can combine it with an EGFR-directed treatment, for example, to take away tumor escape routes".

Lowy explained that researchers still need far more information about RON's part in pancreas cancer development and progression. "We need to figure out which tumors are relying on RON," he said. "If we could develop biomarkers to identify which tumors are going to be susceptible to RON-targeted treatment, then we can begin to figure out what tumors do to escape such therapys".


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