Another blow to esophageal cancer

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Blair A. Jobe is working to clear the throat of all obstructions and maladies, save for a frog.

In 2011, his Archives of Surgery study warned that antacid medications -- popular proton pump inhibitors like Nexium and Prilosec used to control symptoms of gastroesophageal reflux disease or GERD -- may boost the risk of esophageal cancer.

The West Penn Allegheny Health System surgeon, then working at UPMC, performed groundbreaking surgery to rebuild the esophagi of patients with the early-stage cancer, adenocarcinoma. Removing the throat lining, he wallpapered the throat with animal-tissue scaffolding and successfully regrew a cancer-free lining. A human clinical trial is in the works to compare those results against the use of current methods to remove or destroy damaged tissue or remove the entire esophagus and replace it with a portion of the stomach.

Now, Dr. Jobe and his research team have published another study in the Annals of Surgery showing that an existing drug used in rats with GERD prevented development of Barrett's esophagus -- a precursor to cancer.

Barrett's esophagus occurs when GERD exposes the throat's swallowing tube -- the esophageal mucosal lining from the mouth to the stomach -- to gastric acid and bile. Those gastric fluids transform healthy squamous cells of the throat lining into gland cells -- similar to cells that line the stomach and small intestine. It's the body's method of protecting the sensitive throat lining from the gastric assault.

But protection can come at a deadly price.

Twenty-five to 40 percent of healthy adult Americans experience GERD symptoms each month with up to 10 percent experiencing symptoms on a daily basis, according to a Richter and a Gallup Organization National Survey.

The American Society for Gastrointestinal Endoscopy says the most common symptom of GERD is heartburn, which 20 percent of American adults experience at least twice a week. Most people with GERD never develop cancer, but 10 to 15 percent do develop Barrett's esophagus and "doctors believe most cases of adenocarcinoma of the esophagus begin in Barrett's tissue," ASGE reports, noting that 1 percent of people with Barrett's develop cancer.

From 1975 to 2001, adenocarcinoma rates rose from four people per million to 23 per million -- a sixfold increase, making it the fastest-growing cancer in the United States, according to the National Cancer Institute.

Jeffrey H. Peters of the University of Rochester Medical Center and School of Medicine and Dentistry said the rising rate is linked to obesity. Another factor is the use of an antibiotic to kill bacteria that cause stomach ulcers. But the bacteria also have an upside by protecting against cancer.

Dr. Jobe's rat study sheds new light on how Barrett's esophagus develops and, in some cases, leads to malignancy.

Development of the healthy cell lining of the esophagus is known as the hedgehog pathway. GERD occurs when a flaw in the sphincter muscle separating the esophagus and stomach allows gastric juices to enter the esophagus, where a smoothened protein known as "Smo" changes the cell lining to withstand the acidic assault. Healthy cells are turned into "an abnormal presence and proliferation" of gland cells, Dr. Jobe said, potentially leading to Barrett's.

But a drug produced by Bristol Meyers Squibb inhibits the Smo protein, preventing cell transformation and reducing the risk of Barrett's by 36 percent with a 62 percent relative risk reduction in esophageal cancer, when compared to the control group, the Jobe study found. "What we have shown in this study is that there may ultimately be a better way to prevent esophageal cancer using a targeted medical therapy that simply disables the molecular switch that puts the process of developing this condition into motion," he said.

Recognized for his expertise in esophageal diseases, Dr. Jobe left UPMC in July. The current study also was done mostly while he was with UPMC. Currently director of the WPAHS Institute for the Treatment of Esophageal and Thoracic Disease, he received the 2005 Outstanding Researcher of the Year Award from the Society of American Gastrointestinal and Endoscopic Surgeons and the 2010 Faculty of the Year Award within UPMC's Division of Thoracic and Foregut Surgery.

The current study also works to explain how the Smo protein participates in the cause of progression to Barrett's esophagus, revealing how the Smo-inhibiting drug works to prevent cancer. But some rats on the drug still developed cancer. In those cases, Dr. jobe said, other genes linked to esophageal cancer were triggered.

"We need to have a more cogent approach to prevention and treatment personalized for a given patient," he said. "In a person with reflux disease, we can take blood or tissue and show the genetic markers and use an agent to prevent the cancer, period. That's where the home run would be.

"This is the game we need to play -- a preventative scheme that will come through complex modeling and software development, linked to the genetic causes of cancer," Dr. Jobe said.

For now, the immediate goal is testing the safety and effectiveness of a low-dose regimen of the Bristol Meyers drug to prevent progression to cancer in highly selected, high-risk patients.

Dr. Peters said Dr. Jobe has done excellent work with his series of studies, with particular praise for rebuilding esophagi in patients suffering from early-stage cancer.

"He has a nice repertoire of interesting and new things concerning Barrett's and the esophagus, and he's emerging as one of the leading investigators, especially in thinking outside the box," Dr. Peters said, noting a growing focus on "unraveling the genesis of Barrett's."

"In the next 10 years, there should be enough knowledge to meaningfully prevent [Barrett's] disease, and Dr. Jobe is contributing significantly to that knowledge," he said.

David Templeton: dtempleton@post-gazette.com or 412-263-1578.

Blair A. Jobe is working to clear the throat of all obstructions and maladies, save for a frog.

In 2011, his Archives of Surgery study warned that antacid medications -- popular proton pump inhibitors such as Nexium and Prilosec used to control symptoms of gastroesophageal reflux disease or GERD -- may boost the risk of esophageal cancer.

The West Penn Allegheny Health System surgeon, then working at UPMC, performed groundbreaking surgery to rebuild the esophagi of patients with the early-stage cancer, adenocarcinoma. Removing the throat lining, he wallpapered the throat with animal-tissue scaffolding and successfully regrew a cancer-free lining. A human clinical trial is in the works to compare those results against the use of current methods to remove or destroy damaged tissue or remove the entire esophagus and replace it with a portion of the stomach.

Now, Dr. Jobe and his research team have published another study in the Annals of Surgery showing that an existing drug used in rats with GERD prevented development of Barrett's esophagus -- a precursor to cancer.

Barrett's esophagus occurs when GERD exposes the throat's swallowing tube -- the esophageal mucosal lining from the mouth to the stomach -- to gastric acid and bile. Those gastric fluids transform healthy squamous cells of the throat lining into gland cells -- similar to cells that line the stomach and small intestine. It's the body's method of protecting the sensitive throat lining from the gastric assault.

But protection can come at a deadly price.

Twenty-five to 40 percent of healthy adult Americans experience GERD symptoms each month with up to 10 percent experiencing symptoms on a daily basis, according to a Richter and a Gallup Organization National Survey.

The American Society for Gastrointestinal Endoscopy says the most common symptom of GERD is heartburn, which 20 percent of American adults experience at least twice a week. Most people with GERD never develop cancer, but 10 to 15 percent do develop Barrett's esophagus, and "doctors believe most cases of adenocarcinoma of the esophagus begin in Barrett's tissue," ASGE reports, noting that 1 percent of people with Barrett's develop cancer.

From 1975 to 2001, adenocarcinoma rates rose from four people per million to 23 per million -- a sixfold increase, making it the fastest-growing cancer in the United States, according to the National Cancer Institute.

Jeffrey H. Peters of the University of Rochester Medical Center and School of Medicine and Dentistry said the rising rate is linked to obesity. Another factor is the use of an antibiotic to kill bacteria that cause stomach ulcers. But the bacteria also have an upside by protecting against cancer.

Dr. Jobe's rat study sheds new light on how Barrett's esophagus develops and, in some cases, leads to malignancy.

Development of the healthy cell lining of the esophagus is known as the hedgehog pathway. GERD occurs when a flaw in the sphincter muscle separating the esophagus and stomach allows gastric juices to enter the esophagus, where a smoothened protein known as "Smo" changes the cell lining to withstand the acidic assault. Healthy cells are turned into "an abnormal presence and proliferation" of gland cells, Dr. Jobe said, potentially leading to Barrett's.

But a drug produced by Bristol Meyers Squibb inhibits the Smo protein, preventing cell transformation and reducing the risk of Barrett's by 36 percent with a 62 percent relative risk reduction in esophageal cancer when compared to the control group, the Jobe study found. "What we have shown in this study is that there may ultimately be a better way to prevent esophageal cancer using a targeted medical therapy that simply disables the molecular switch that puts the process of developing this condition into motion," he said.

Recognized for his expertise in esophageal diseases, Dr. Jobe left UPMC in July. The current study also was done mostly while he was with UPMC. Currently director of the WPAHS Institute for the Treatment of Esophageal and Thoracic Disease, he received the 2005 Outstanding Researcher of the Year Award from the Society of American Gastrointestinal and Endoscopic Surgeons and the 2010 Faculty of the Year Award within UPMC's Division of Thoracic and Foregut Surgery.

The current study also works to explain how the Smo protein participates in the cause of progression to Barrett's esophagus, revealing how the Smo-inhibiting drug works to prevent cancer. But some rats on the drug still developed cancer. In those cases, Dr. Jobe said, other genes linked to esophageal cancer were triggered.

"We need to have a more cogent approach to prevention and treatment personalized for a given patient," he said. "In a person with reflux disease, we can take blood or tissue and show the genetic markers and use an agent to prevent the cancer, period. That's where the home run would be.

"This is the game we need to play -- a preventative scheme that will come through complex modeling and software development, linked to the genetic causes of cancer," Dr. Jobe said.

For now, the immediate goal is testing the safety and effectiveness of a low-dose regimen of the Bristol Meyers drug to prevent progression to cancer in highly selected, high-risk patients.

Dr. Peters said Dr. Jobe has done excellent work with his series of studies, with particular praise for rebuilding esophagi in patients suffering from early-stage cancer.

"He has a nice repertoire of interesting and new things concerning Barrett's and the esophagus, and he's emerging as one of the leading investigators, especially in thinking outside the box," Dr. Peters said, noting a growing focus on "unraveling the genesis of Barrett's."

"In the next 10 years, there should be enough knowledge to meaningfully prevent [Barrett's] disease, and Dr. Jobe is contributing significantly to that knowledge," he said.

health

David Templeton: dtempleton@post-gazette.com or 412-263-1578.


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