Dallas researchers, with VA funding, have established that GERD complications are not just caused by the release of stomach acids, which can be treated with PPIs, but also by bile salts, produced by the liver, stored in the gall bladder, and released into the intestine during digestion. Using cell lines developed from Dallas VAMC patients with Barrett’s esophagus – and then in studies performed during endoscopies with patients – these investigators revealed that Barrett’s cells treated separately with both gastric acid and bile salts (in concentrations that are found routinely in the esophagus of Barrett’s patient) developed DNA damage. Acid and bile salts also activated a protein complex, NF-kappaB, that stimulated the survival of these damaged cells.

Following on these results, a team of clinical researchers that included Souza’s longtime colleague Dr. Stuart Spechler, demonstrated that the application of a compound often used to treat patients with liver disease – ursodeoxycholic acid, or Urso – could prevent both the DNA damage and NF-kappaB activation that occurred with the application of bile salts. “So we thought: ‘Well, I wonder if we put our patients who are already on a PPI on Urso … could we actually prevent that DNA damage?’ So we did. We put them on eight weeks of Urso and brought them back to the endoscopy suite and once again perfused their esophagus with bile salts. We were pleased to find that after the eight weeks of Urso treatment the bile salts no longer induced DNA damage or NF-kappaB in the esophagus.”

“If you give a mouse chemotherapy or radiation therapy,” Travers said, “it will, in addition to killing the tumor, also produce this lipid mediator, which then induces regulatory T cells, which actually inhibit tumor immunity.”

The studies suggest that Urso might be used as a preventive measure, and ensuing investigations have helped explain just how it works on a molecular level. Souza and her colleagues are preparing for the next round of studies, designed to evaluate whether Urso could also be used to repair DNA damage in the esophagus.

 

Seeking New – and Improved – Treatments

The ability of researchers to alter variables at the molecular level is in the process of revolutionizing cancer medicine. In Los Angeles, for example, Rettig directs a prostate cancer drug screening program, evaluating the ability of an estimated 200,000 compounds to block the site on the prostate cell’s male hormone receptor that drives the development and proliferation of prostate adenocarcinoma.

In Indianapolis, Travers is studying the link between ultraviolet light exposure and the production of platelet-activating factor (PAF), a lipid activator that contributes to inflammation and suppresses immunity. The link, which he has demonstrated in mice, has significant implications for cancer treatment; PAF is also made in response to cancer treatments. “If you give a mouse chemotherapy or radiation therapy,” Travers said, “it will, in addition to killing the tumor, also produce this lipid mediator, which then induces regulatory T cells, which actually inhibit tumor immunity.” In VA-funded preclinical studies, his team has found that this immunosuppressive effect may be blocked with the use of a drug known as a COX-2 inhibitor, which targets a cellular enzyme responsible for inflammation.

The team’s study was recently accepted for publication in the Journal of Investigative Dermatology. “If we’re correct,” said Travers, “in the future when people get chemotherapy, radiation therapy, or photodynamic therapy, it’s going to affect the standard of care: Will they get a COX-2 inhibitor at the same time to block this untoward effect?”

Because intracellular increases in COX-2 enzyme are associated with many epithelial cancers – not just skin cancer – COX-2 inhibitors, such as celecoxib, have long been evaluated as possible therapies for these tumors. But according to Dr. Amy Fulton, a VA breast cancer researcher and associate director for basic research at the University of Maryland’s Greenebaum Cancer Center, clinical trials of COX inhibitors have found them, as did Travers’ team, to also inhibit the release of compounds that serve to protect the cell.

“We decided several years ago,” said Fulton, “to try to move downstream in that COX-2 pathway, and be more selective in inhibiting particular aspects of it instead of the entire pathway.” The Maryland team has found, for example, that older COX inhibitors inhibit the production of prostaglandin E2, a lipid that mediates many of the processes by which tumors grow and metastasize. Further analysis of cell receptors reveal that different receptors, on the same cell, respond differently when they bind to prostaglandin E2: one receptor will promote metastasis and induce immunosuppression, for example, while another will inhibit metastasis.

In follow-on studies, said Fulton, her laboratory revealed that a subset of malignant breast cells, the breast cancer stem cells, which are highly resistant to therapy, significantly increase the number of PGE2 receptors known to encourage tumor formation and metastasis – but the good news is that they’re also more sensitive to inhibition with PGE2 receptor antagonists than other tumor cells. “So we think what that’s going to mean, if this is relevant to human cancer, is that you probably would be able to inhibit the majority of tumor cells with conventional therapies,” she said. “But the tumor cells that are going to grow back and get you in the end, these cancer stem cells, will be exquisitely sensitive to antagonists at these receptors.”

Fulton and her team have designed a clinical trial of a drug to be tested against breast, prostate, and lung cancer, three cancers known to up-regulate the prostaglandin E2 receptors. While investigators believe the drug may be useful for all three types of cancer, results from the different groups may help broaden the knowledge base about effective treatments for cancer – and perhaps one day lead to a cure.

“Laboratory scientists like me,” said Fulton, “don’t often get to see the clinical application of their studies. They hope somebody’s going to take those findings and do something with them clinically to really help people, but it doesn’t always happen in their lifetimes. So I’m actually quite excited that not only do we have an agent we can test, but that we have the clinical collaborators in the VA system who are interested in going further to bring this solution to patients.”

This article first appeared in The Year in Veterans Affairs & Military Medicine 2014-2015 Edition.