Weill Cornell Scientists Discover Tumor Suppressor, Prostate Cancer Link

Finding Could Lead to Targeted Therapy

Jan 30, 2004

New York, NY

A snippet of protein that sits on top of healthy prostate cells is often lost as the cell morphs into a potentially life-threatening cancer. The protein, known as neutral endopeptidase (NEP), is inactive in about half of all prostate cancers.

Now, researchers at Weill Medical College of Cornell University in New York have discovered a major reason why NEP can curb prostate cell growth. And the finding may lead to targeted treatment for prostate cancer.

It appears that the protein interacts with a powerful tumor suppressor gene called PTEN, according to Dr. David M. Nanus and his team, who published their results in the journal Cancer Cell.

A lot of people are studying PTEN trying to figure how it works, and what our research has shown and it's the first time it's being reported is that NEP and PTEN interact, said Dr. Nanus, Associate Professor of Medicine and Urology at Weill Cornell Medical College. NEP stabilizes PTEN and allows it to localize in certain areas of the cell, which makes it more of an aggressive tumor suppressor. One of the consequences of NEP loss is that PTEN, even if it is present, is not going to function, or at least not as well as if NEP were present.

PTEN is also inactivated in other cancers, including tumors of the brain and uterus, and is one of the most common tumor suppressor genes missing in cancer cells.

The finding sheds light on the complex series of steps that cause a normal cell to become an aggressive invader. What's more, it could one day lead to new treatments for prostate cancer and possibly even lung cancer. Both NEP and PTEN are also missing in some types of lung cancer.

We are doing a number of studies trying to re-express NEP in prostate cancer cells to try to inhibit growth using a gene therapy approach, said Dr. Nanus, who is also the Medical Director of the Genitourinary Oncology Program at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. That's all in the lab right now, in animals, but we hope that if it's successful in animals to move it on to patients.

Historically, NEP was known to act as an enzyme, inactivating small growth factors known as peptide growth factors, said Dr. Nanus.

Our research has shown that in addition to acting as an enzyme, it has other functions that can also inhibit cell growth, he said. When you lose this enzyme, which occurs in prostate cancer, it can allow the cancer to be more aggressive and progress.

In particular, the loss of NEP allows one growth factor called endothelin-1 to keep churning out, unchecked.

Recent studies have shown that endothelin-1 is very important in bone metastasis in prostate cancer patients, Dr. Nanus said.

The researchers are now trying to determine if a test for NEP could help predict how a patient will fare.

If you lose PTEN and NEP, maybe it's worse than losing PTEN alone, or maybe if you lose PTEN or still have NEP it's not as bad; we don't know, those are the types of things that are being studied, he said.