Giving Traction to Good Thinking
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.
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 theactivation 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."