Scientists on the cutting edge of biomedical research know that research is a process - a combination of successes and failures that inform the next step forward. However, for some researchers at The Ohio State University progress means taking a step back. Supported by the Ohio State University Center for Clinical and Translational Science (CCTS), these scientists are using failed and forgotten research to uncover future treatments for major health conditions as diverse as oral cancer and stroke.
In a recent editorial that detailed the goals of the soon-to-be launched National Center for Advancing Translational Science (NCATS), NIH Director Francis Collins, M.D. noted that the current research process for discovering new therapies is often slow, expensive and unsuccessful. He went on to describe several ways that translational medicine could revolutionize the system, including the idea of "repurposing and rescuing" drugs that could potentially have other uses - an idea being put into action at Ohio State.
"The translational science approach puts cross-functional teams and new technologies to work in more efficient ways, " says Rebecca Jackson, M.D., Associate Dean for Clinical Research in the College of Medicine and Principal Investigator of the Ohio State CCTS. "It allows our researchers to do innovative work - like resurrecting old data - that maintains a focus on answering questions that will make timely, positive impacts on the major health issues of today."
Rethinking fenretinide for prevention of oral cancer
For more than two decades, researchers have studied and used fenretinide, a synthetic vitamin A derivative. Fenretinide's capacity to induce both terminal differentiation and cell death yielded highly promising results with cultured human cancer cells. Likewise, studies in lung, breast skin, prostate and bladder animal cancer models re-enforced fenretinide's cancer-preventing effects at the in vivo level. However, when it came to prevention of oral cancer - a type of cancer that kills more than 7,000 people each year - fenretinide efficacy wasn't what scientists expected. After multiple studies with lackluster results, oral cancer researchers moved away from fentretinide to look elsewhere for an answer.
Oral pathologist Susan Mallery, DDS, Ph.D., and her colleague and co-investigator Peter E. Larsen, DDS are reminded daily of the need for an answer. Patients with pre-cancerous lesions returned time and time again for painful biopsies and surgical removal of cells that could turn deadly if left unchecked. Mallery knew there had to be something better she could offer her patients.
"I started thinking - maybe fenretinide wasn't working as well because systemic administration can reduce compound activity, and the need for fenretinide to get from the underlying vessels to the target epithelial cells. It seemed unlikely that a therapeutic amount was actually reaching the lesions," says Dr. Mallery, a professor of Oral Pathology at The Ohio State University College of Dentistry. "We needed to come up with a way to circumvent issues with poor systemic uptake by delivering the compound directly to the lesion. But, how do you deliver a water insoluble compound into a saliva filled mouth?
Mallery found the answer in partnering with two University of Michigan pharmaceutical chemists (Steven Schwendeman and Kashappa Goud Desai) to develop a first of its kind patch that sticks to the inside of the mouth, and delivers a continuous therapeutic dose of fenretinide directly to the precancerous lesion. The patch consists of three layers: a disk saturated with fenretinide and polymers that make the lipid soluble fenretinide better adsorbed in a water-rich environment, a secondary adhesive ring to hold the disk in place, and a final backing layer that ensures the medication stays inside the area of the patch. Patch formulation and in vitro and in vivo release kinetics were recently described in an article appearing in the journal Pharmaceutical Research (June 2011).
The research team has just completed a pharmacokinetic study in rabbits. Subsequent plans include an initial Phase zero study in humans, followed by a clinical trial to evaluate efficacy in patients with precancerous oral lesions. A companion formulation designed to prevent emergence of pre-cancerous cells within the entire mouth may also be used in the fenretinide patch clinical trial.
"At least one third of all patients with oral epithelial dysplasia will experience a recurrence of their lesions. While not all of these lesions progress to oral cancer, we cannot accurately predict which will be the "bad actors", which results in high anxiety in both our patients and clinicians. If the fenretinide patch can either induce regression or prevent progression of oral dysplastic lesions, we will have shifted the paradigm by which these lesions are managed," says Mallery.
Supplemental oxygen and stroke -
During stroke, blood vessels in the brain are blocked and vital blood-borne products, such as oxygen and glucose, are not able to reach the brain. In this hypoxic - or oxygen-starved - state, the brain releases excessive amounts of the neurotransmitter glutamate, which further damages brain tissue. Providing supplemental oxygen during a stroke seems to be a logical treatment course, and for years, researchers tried to reduce brain injury by doing just that. However, multiple clinical trials failed to show consistent success, and in some cases, the oxygen appeared to actually worsen the damage.
The idea of using oxygen during stroke lost steam. Researchers around the world turned their attention to pharmacological interventions that could mediate chemicals produced by the brain during hypoxia.
Dr. Savita Khanna, an assistant professor in the College of Medicine at The Ohio State University Medical Center, with an expertise in the pathophysiology of strokes, decided to go back to the basics - oxygen - to search for more clues.
"We wanted to know how important hypoxia is as an insult that contributes to stroke-induced neuronal death," Khanna says. "We thought that perhaps something more was happening on a molecular and even genetic level that could help explain why the results of oxygen supplementation during stroke have been so inconsistent."
In 2008, Khanna was awarded a pilot grant from the Ohio State CCTS to look at the role of glutamate in brain injury. Her research has revealed two key pieces of information that may help change the way strokes are treated in the future.
The data, published in the Journal of Cerebral Blood Flow and Metabolism (February 2010), gave a clue to why past research involving supplemental oxygen therapy hasn't yielded positive results - it's all about the timing. The research team discovered when oxygen therapy was given during stroke-induced hypoxia and before the introduction of clot-busting drugs, there was less brain damage. However, when oxygen therapy was applied after removing the blockage and blood flow was restored, damage was more severe.
"It appears that there may be a limited therapeutic window of opportunity for oxygen therapy - but if we can figure out what that window is - oxygen therapy can easily transition to a clinical setting without excessive cost to healthcare," Khanna says.
Her research is also the first to show that supplemental oxygen turns on a protective factor glutamate oxaloacetate transaminase (GOT) which helps metabolize glutamate to generate energy under low glucose conditions. Such metabolism lowers the levels of toxic glutamate and supplies energy to the affected tissue during stroke - turning the glutamate into a neuroprotectant. In recent years, researchers have noted the presence of GOT during ischemic events, and Khanna's data on GOT, published in Antioxidants and Redox Signaling (May 2011) helps further illuminate the potential for GOT as a therapeutic target.
Based on this research, Khanna is pursuing additional NIH funding to develop therapeutic oxygen strategies to reduce stroke-related brain damage.
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