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IU Finding: Tumor Inhibitor Enhances Pancreatic Cancer

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December 16, 2013 — Indiana University says its cancer researchers have discovered that a protein that normally suppresses tumors actually promotes the growth and spread of pancreatic cancer.

It says Dr. Murray Korc and his colleagues have shown that the retinoblastoma protein, normally a tumor suppressor, often malfunctions in pancreatic cancer.  They say that dysfunction enables an inhibitory protein to promote pancreatic cancer growth.  The research was published today in the Journal of Clinical Investigation.

Korc says as a result of the dysfunctional retinoblastoma protein, pancreatic cancer cells lose their ability to be inhibited by transforming growth factor-beta, or TGF-β, which is a key negative regulator of cell proliferation.

He says that instead, the cells become stimulated by TGF-β due to activation of abnormal signals known as non-canonical pathways.

The researchers also showed that TGF-β induces the expression of a growth-stimulating molecule, Wnt7b, which is not usually found in a normal adult pancreas.

Dr. Korc explained how this combination allows TGF-β to directly enhance pancreatic cancer cell proliferation and survival with Wnt7b behavior, “You have a cancer in which the accelerator is stuck to the floor and the brake is broken, but because of the malfunctioning retinoblastoma protein, the combined actions of TGF-β and Wnt7b convert the broken brake into a second accelerator.”

Because the abnormal pathways activated by TGF-β and Wnt7b can be disrupted with drugs, Korc suggests the findings open options for exploring novel therapeutic combinations in pancreatic cancer.  However, he cautioned that more work remains to be done to determine how to best restore the regulatory functions of the retinoblastoma protein and prevent the harmful actions of TGF-β, “We have to figure out how to target these important pathways and to prevent bypass pathways from being activated,” he said.

Co-authors of the study were A. Jesse Gore, Samantha L. Deitz, Lakshmi Reddy Palam and Kelly E. Craven from the Department of Medicine at the IU School of Medicine. The study was made possible in part by a grant awarded by the National Cancer Institute of the National Institutes of Health.

For the past two decades, Dr. Korc’s work has focused on aberrant growth-factor signaling in pancreatic cancer, which only 6% of patients survive five years following diagnosis.  According to the National Cancer Institute, there will be an estimated 45,220 new cases of pancreatic cancer and 38,460 deaths from the disease in 2013.

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