Pelotonia Idea Grants jump-start insightful OSUCCC – James research that can lead to breakthroughs in cancer prevention and treatment.

The grants provide $100,000 of research funding spread over two years. Proposals are selected for funding through a peer-review process that considers the study’s potential for discovery and publication, whether it will lead to a clinical trial and the likelihood of subsequent funding from the National Cancer Institute.

Applicants also provide a “commitment to ridership” stating that they will participate in Pelotonia to help raise money for cancer research at the OSUCCC – James.

Here are three examples of Pelotonia Idea Grants that were awarded in 2012. For information on the remaining 10 projects, visit cancer.osu.edu/pelotonia.

By DARRELL E. WARD

CHEMOTHERAPY AND THE BRAIN
Nearly one-third of breast-cancer patients who receive chemotherapy report problems with memory, concentration, attention and understanding during and after treatment. Sometimes called “chemo brain,” chemotherapy induced cognitive deficits can also be a problem for patients treated for other malignancies, including ovarian and prostate cancers.

The cause of these cognitive problems is poorly understood, and currently there is no treatment for them. Through a Pelotonia Idea Grant, Maryam Lustberg,
MD, assistant professor of Medical Oncology and an OSUCCC – James breast-cancer specialist, and Courtney DeVries, PhD, professor of Neuroscience and Psychology, are investigating both a possible cause and a possible treatment in an animal model.

Lustberg and DeVries have evidence linking the cognitive difficulties to the overactivity of a particular type of immune cell in the brain. They also have identified an anti-inflammatory drug that might calm the overexcited cells and ease the symptoms.

“Our data from an animal model suggests that certain chemotherapy can overactivate brain cells called microglia, and that this contributes to localized inflammation and changes in brain cells,” Lustberg says.

She notes that microglia are involved in neurological disorders such as multiple sclerosis and other neuroinflammatory conditions.

“But we believe we are the first to tie them to chemotherapy-induced cognitive deficits,” Lustberg says.

Normally, microglia move through the brain to rid it of damaged neurons, infectious agents and debris from dead cells. “We believe that certain chemotherapy
regimens can lead to localized inflammation that involves the microglia and alters brain-cell structure and function, which in turn causes cognitive problems,”
DeVries says.

“The Pelotonia funding will help us tease out the biological mechanism,” she says. “We believe our research is the first to test the idea that inflamed neurons
contribute to the development of cognitive impairments in chemotherapy patients.”

Having a mechanistic explanation for the problem is essential for developing targeted therapies to treat it, she says. Until then, the Ohio State investigators have evidence that a widely available drug called minocycline might help control the inflammation and calm the overactivated microglia cells.

“The drug minocycline works well in our mouse model,” DeVries says. “With the help of Pelotonia funds, we will further define how it works and the best schedule for administering it.”

The researchers are using experimental conditions that closely mimic the therapy women receive, DeVries says. “We’re using the same chemotherapy drugs and similar doses, and we administer the treatment intravenously. A mouse model is not the same as a human, but we believe it is a good model that will be useful for testing additional agents for this problem.”

Next, the researchers want to evaluate minocycline in a clinical trial of women with breast cancer. “We could do this relatively quickly because this drug is already approved by the Food and Drug Administration and is available,” Lustberg says.

BLACK RASPBERRY CONFECTIONS TO INHIBIT ORAL CANCER
Cancer of the oral cavity is a devastating disease that can affect speech and swallowing, as well as often being fatal. In 2012, an estimated 42,250 Americans were expected to develop cancer of the mouth, and 7,850 were expected to die of the disease. The malignancy’s 50-percent five-year survival rate has remained largely unchanged for decades, so new ways to prevent and treat the disease are needed.

A Pelotonia Idea Grant awarded to Yael Vodovotz, PhD, professor of Food Science and Technology, and a multidisciplinary team of OSUCCC – James researchers might help meet both needs.

The scientists are developing a food-based approach for preventing oral cancer in people at high risk for the disease and for improving the treatment for people who have the disease. Their study uses highly concentrated black raspberries, which research has shown have significant anticancer activity.

The team’s Pelotonia grant will support a two-week clinical trial of 60 healthy adult volunteers who will consume black raspberry confections at two doses and in three forms. One form resembles a hard candy and releases the phytochemicals slowly; the other two forms have gummy consistencies that provide intermediate and fast release rates.

“The confections are a way to incorporate a substantial amount of black raspberry phytochemicals into the diet in a more directed way,” Vodovotz says.
The study will show which form most effectively releases the berries’ natural cancer-fighting phytochemicals into the mouth. To learn that, the researchers will take mouth swabs from each participant before, during and after the trial. This collects mouth cells that will be analyzed for certain phytochemicals or their metabolites and for the activation of certain genes.

Research by team member Christopher Weghorst, PhD, has found that black raspberry phytochemicals turn up the activity of certain genes and turn down the activity of others. “His evidence suggests that changes in these genes might improve the effectiveness of therapy for these cancers,” Vodovotz says.

The study should also reveal whether the phytochemicals are taken up better when released in the mouth slowly or quickly as a burst.

Team member Steven Schwartz, PhD, director of the OSUCCC – James Nutrient and Phytochemical Analytics Shared Resource, will oversee analysis of the biological samples, which include urine samples that are examined in part to monitor consumption levels of the confections by trial participants.

In the end, the phytochemical absorption information and gene expression data will determine which dose and form of confection best deliver the anticancer agents in black raspberries to cells that line the mouth. That knowledge, in turn, will guide the design of a future phase II study in people at high risk for oral cancer. That study will evaluate whether the confections can prevent oral cancer or improve therapy in cancer patients.

“This crops-to-clinic initiative is a marriage of food science and medicine,” Vodovotz says. “To my knowledge, our collaborative team is unique in the way we approach functional food to fight cancer, and Pelotonia will have played an important role in making it happen.”

Other OSUCCC – James investigators involved in this study are Steven Clinton, MD, PhD, and Dennis Pearl, PhD.

TARGETING MICRO MESSENGERS
Multiple myeloma (MM) is currently an incurable cancer of the blood that affects 21,700 people in the United States and kills about 10,700 Americans annually. The malignant cells survive and grow in part by triggering the release of growth factors and other substances from normal cells in the bone marrow.

How the cancer cells cause the normal cells to release those factors isn’t understood, but OSUCCC –James researchers Don Benson, MD, PhD, and Flavia Pichiorri, PhD, have evidence that an unusual mechanism is involved, and they have been awarded a Pelotonia Idea Grant to pursue their suspicions. If they are correct, it would lead to a better understanding of the disease and perhaps to new ways to diagnose and treat it.

Their evidence indicates that myeloma cells shed tiny spheres called microvesicles into the blood. The spheres are packed with regulatory molecules called microRNA. Bone marrow cells take up the spheres and respond to the regulatory molecules by producing factors that help the cancer cells grow and proliferate. In addition, the spheres influence the behavior of immune cells called natural killer cells.

“It was first believed that microvesicles were bits of cell membrane or pieces of dead cells floating around in the bloodstream,” Pichiorri says. “Then we looked at them more closely in blood from myeloma patients and found that they contain a rich repertoire of signals that other cells can take up.”

Preliminary work by the investigators has shown that MM microvesicles include microRNAs that can influence cancer development and immune responses.
“Microvesicles have been reported in a number of cancers, but MM seems to make a lot of microvesicles relative to other cancers, and they are jam-packed
with potential cell signals,” Benson says.

Their Pelotonia-funded research will analyze the contents of microvesicles from MM patients and explore how the vesicles might communicate with other cells and whether the vesicles help suppress the body’s immune response to the disease.

The findings could lead to a novel form of therapy.

“If we knew more about how microvesicles facilitate the disease, we might make synthetic microvesicles and pack them with signals that help control the
disease,” Benson says. The project is emblematic of the concept behind Idea Grants: a neat idea that no one has yet explored very deeply. “If what we expect is true, it will put us in a competitive position for obtaining larger grants,” Benson says. “It’s high-risk and high-reward research. It’s the kind of idea that would be sitting on the shelf without the Idea Grant mechanism.”

RIDING FOR THE HEALTH OF IT JOEL MAYERSON, MD Joel Mayerson, MD, director of Musculoskeletal Oncology at the OSUCCC – James, had ridden a bike as a teenager, and every so often after that. He made the decision to ride when the first Pelotonia ride was announced in 2009. “I got out the mountain bike that I’d had as a teenager and rode the 50-mile route,” Mayerson says. “It was fantastic being out there and seeing colleagues, staff and even patients riding,” he says. But Mayerson is a big guy, and he was bigger then, weighing some 325 lbs. “I completed the 50 miles, but I about died. It was really challenging.” Mayerson had another reason for getting his bike out and riding, too. His son, Drew, 13, had been diagnosed with type I diabetes earlier that year. “I wanted to set a good example for him,” Mayerson says. He resolved to get into shape. He went on a lowcarbohydrate diet, and, after trading his mountain bike for a hybrid model, he began training and trimming down for his son and for Pelotonia 2010. He rode about 1,500 miles in training rides and lost 80 pounds. The 50-mile Pelotonia route was no problem in 2010. He also organized a sarcoma peloton, or riding group, of four or five people. Looking ahead to Pelotonia 11, he set out to tackle the 100-mile ride. He clocked about 3,000 miles in training rides in preparation. When the time came, he succeeded with little problem and repeated the ride for Pelotonia 12. But his 2011 century ride was especially memorable, Mayerson says. “It was fantastic. It was the first time in my life I’d ridden a hundred miles. I was 42 years old, I’d trained for it, and I kept up with my partner who was eight years younger.” His sarcoma peloton had grown to 18 members and included two patients and a cancer survivor. The community support was energizing, he says. “The ride is amazing. Sixty and seventy miles out, you pass people along the road with signs that say things like ‘Thanks for riding’ and ‘Thanks for making a difference.’ “It’s a six-and-a-half or seven-hour ride, and when you’re tired, it’s pretty cool to see those signs and the people cheering you on.” Pelotonia is meaningful in many ways for Mayerson. From a personal standpoint, it helped him adopt a healthy lifestyle. “I’ve ridden close to 8,000 miles since I began training,” he says. “It’s gotten many people involved in a healthier lifestyle and gotten corporations involved in getting their employees out and exercising.” And it brings the community together to fight cancer. “One of every two or three of us is going to get cancer. Pelotonia raises cancer awareness – thousands of people may have learned about sarcoma who otherwise might not have – and it raises dollars to cure cancer so that maybe someday we won’t have to worry about it.” It’s good for the city’s economy, he says, and it raises awareness about the city of Columbus. “People who pass through Port Columbus see the Pelotonia banners and want to know more about it. They will learn something about the city that might bring them back.” Even the word “Pelotonia” stirs curiosity. “I’ve worn my Pelotonia shirt to scientific meetings in San Francisco and elsewhere, and I can be at Starbucks and someone will ask me what it means. It’s an interesting word,” he says. “I think what’s most amazing is the community spirit that in four years has created the largest charity bicycle event in terms of riders in the United States. We’ve gone from 2,250 riders to 6,200 riders in four short years. It shows how wonderful our community is.”