Obesity drug helps unlock clues about cancer

“Our discovery makes an exciting treatment target because theoretically you don't have to worry about harming nearby healthy tissue,” said senior researcher Steven J. Kridel, Ph.D., an assistant professor in the Department of Cancer Biology.

In the current issue of Cancer Research, Kridel and colleagues are the first to report that a tubular network within cells, known as the endoplasmic reticulum (ER), is regulated by an enzyme that is tightly linked to tumor growth and development.

“When the ER cannot do its job properly, there's a series of events that gets turned on that can lead to cell suicide or death,” said Kridel.

The research showed that an enzyme known as fatty acid synthase is vital for the ER to do its job. Blocking this enzyme, which makes fat in cells, has been shown to prevent tumor cell growth and to promote cell death.

“No one had made connection before between fatty acid synthase and the function of the ER in tumor cells,” said Kridel. “This is the first to show that fatty acid synthesis is important in maintaining ER function and keeping tumor cells alive.”

The researchers started the work five years ago when they analyzed prostate cancer cells to see which proteins and enzymes were expressed at high levels. Their hope was that treatments that reduced those levels could also stop tumor growth.

“We found that fatty acid synthase is expressed at high levels in tumor cells, but is fairly absent in normal cells,” said Kridel. “Other researchers had made similar findings in other types of cancer cells, so we decided to follow up because it looked promising.

“We then made the surprising finding that OrlistatTM, a drug approved by the FDA to treat obesity, can block the function of fatty acid synthase, prevent tumor cell growth and promote tumor cell death.”

Finding out exactly how the drug worked was the next step, so that better treatments could be developed. While effective in mice, Olistat's current formulation cannot be given to humans as a cancer treatment because it acts only in the digestive tract.

In the current study, Kridel and colleagues treated prostate, colon and cervical cancer cells in the laboratory with Olistat and two other agents to understand why blocking fatty acid synthase induces cell death.

“Our goal was to understand how fatty acid synthase contributes to tumor growth,” said Kridel. “This might provide an explanation for why this enzyme is expressed at high levels.”

Now that the scientists understand that the ER is involved — and that inhibiting fatty acid synthase can impair its function — they are working to develop new treatments for cancer therapy.

They are exploring the possibility of using existing FDA-approved drugs, as well as developing new drugs. They've already determined that the structure of Orlistat bound to fatty acid synthase, which is the first step in developing similar agents that could be used in humans.

“Our latest findings that connect fatty acid synthase and ER function gives us a better understanding about how the drug kills tumor cells and give us clues to make better drugs,” said Kridel. “For any drugs we develop, we'll need to show that they impair the function of the ER.”

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