In 2012, Pelotonia "Idea" Grants were awarded to the following thirteen research teams:
Chemotherapy-Induced Cognitive Deficits
Maryam Lustberg, MD, and Courtney DeVries, PhD
More than 30 percent of breast-cancer patients who receive chemotherapy report problems with memory, concentration, attention and understanding during and after treatment. Even though this is a common problem that significantly affects quality of life, the cause of these cognitive deficits is poorly understood, and there is no effective treatment. These researchers hypothesize that chemotherapy leads to inflammation of certain brain cells, altering their structure and function, which causes cognitive problems. This study will carry out four experiments to help establish the biological mechanism through which chemotherapy alters cognition. It will be the first study to test the idea that inflammation of neurons contributes to the development of cognitive impairment in chemotherapy patients.
The Role of Microvesicles in Multiple Myeloma: Elucidating Mechanisms of Disease Propagation and Immune Suppression and Novel Targets for Intervention
Don Benson, MD, PhD, and Flavia Pichiorri, PhD
Multiple myeloma (MM) is a cancer of white blood cells called plasma cells. MM cells require growth factors and other substances produced by normal bone-marrow cells for their growth and survival. The interactions between MM and cells could be important therapeutic targets, but little is known about how they occur. These researchers believe that microvesicles – tiny particles sometimes given off by cells – might serve as important messengers between MM and normal cells. This study will analyze the contents of microvesicles from MM patients and how the vesicles might function in MM-cell communication. It will also explore whether the vesicles play a role in suppressing the body’s immune response to MM. The findings will improve the understanding of the role of microvesicles in MM and could lead to new treatments for the malignancy.
Role of RAC1 GTPase in Astrocytoma Initiation
Chang-Hyuk Kwon, PhD, and Sung Ok Yoon, PhD
Malignant astrocytomas are highly fatal brain or spinal tumors that have no effective treatment. To find better therapies, scientists must understand how astrocytomas begin. Evidence suggests the regulation of oxygen radicals – unstable oxygen molecules that react with other molecules in the cell – is critical for tumor initiation, but how oxygen radical levels are regulated is unclear. Using an astrocytoma mouse model, this study will focus on genes called Rac1 and Prdx4, both of which are involved in regulating oxygen radicals in cells. It will explore whether the loss or suppression of these genes, and the resulting loss of oxygen radical formation, is involved in the initiation of astrocytomas. If so, small molecules that are known to induce oxygen radical production in cells might be useful for astrocytoma treatment.
Combined EGFR and BRAF Blockade in Patients With Advanced Malignancies and BRAF-Mutant Tumors
Miguel Villalona, MD
Metastatic melanoma often has mutations that overactivate a cancer-causing gene called BRAF. Drugs called BRAF inhibitors target the overactive gene and can help melanoma patients. Similar BRAF mutations are found in other cancers, including thyroid and colorectal cancers and non-small cell lung cancer. BRAF inhibitors might help these patients, too, except that these cancers often have high levels of a molecule called EGFR. Tumors with high EGFR are often resistant to BRAF inhibitors. This study tests the use of a BRAF inhibitor plus an EGFR inhibitor in patients with colorectal cancer, non-small cell lung cancer and other solid tumors with BRAF mutations. The study will demonstrate the feasibility of combining the two inhibitors in these patients and establish recommended doses. It will also evaluate EGFR activation in BRAF-mutant lung and colorectal tumors before and after the BRAF inhibitor is given, both in the presence and absence of the EGFR inhibitor.
Eicosanoids as Biomarkers of Dietary w-3 Fatty Acid Exposure and Response
Lisa Yee, MD
Evidence indicates that low levels of inflammation, which occur with metabolic diseases such as obesity and diabetes, can raise the risk for breast cancer. There is also evidence that omega-3 fatty acids, found in fish oil and fatty fish, can reduce such inflammation. This project analyzes biospecimens collected during two omega-3 fatty acid intervention studies in women at high risk for breast cancer. It will determine changes in levels of eicosanoids, molecules derived from the metabolism of omega-3 fatty acids. The findings will provide essential data regarding omega-3 fatty acid markers of exposure and response to support the initiation of a definitive breast-cancer prevention trial of omega-3 fatty acids in high-risk women.
The Impact of Stromal PTEN Status on Pathological Complete Response Rates to Neoadjuvant Dual HER2-Targeted Therapy
Charles Shapiro, MD, and Erin Olson, MD
Solid tumors contain both cancer cells and noncancer cells, called stromal cells. Evidence shows that genetic changes in stromal cells can influence the behavior of the cancer cells and vice versa. For example, mammary tumors in mice grow faster and more aggressively when certain stromal cells in them have low levels of a protein called PTEN. About 50 percent of human breast-cancer patients have low PTEN levels. This clinical trial will determine whether women with HER2-postive breast cancers that have higher versus lower PTEN levels in stromal cells have higher or lower remission rates after treatment with a combination of two drugs, trastuzumab and lapatinib, compared to breast tumors having normal stromal PTEN levels. If this proves correct, it will provide evidence that a tumor’s cancer cells and stromal cells should be considered together as a “treatment unit.” More importantly, it will be the first study to demonstrate that PTEN may be a predictive biomarker for women who are more (or less) likely to respond to dual therapy.
Decitabine Followed by NK-Cell Immunotherapy for Treatment of Elderly Patients With AML
Sumithira Vasu, MBBS, and Jianhua Yu, PhD
In patients older than age 60, acute myeloid leukemia (AML) is a devastating disease, with five-year survival rates below 10 percent. Allogeneic (from a donor) bone marrow transplantation extends life in many AML patients, but many elderly patients are ineligible for the therapy. This study tests whether treating older AML patients with a DNA hypomethylating agent called decitabine, plus infusions of cancer-fighting immune cells called NK-cells, might improve their therapy.
Testing the Feasibility of a Contingency Management Intervention to Encourage Medicaid-Enrolled Smokers to Quit
Amy Ferketich, PhD, and Eric Seiber, PhD
Contingency management (CM) interventions use an incentive, usually a reward, to encourage people to change a behavior. This pilot study tests the use of a CM intervention to promote tobacco abstinence among Medicaid-enrolled smokers in Appalachia Ohio. Ten study participants who form a control, or comparison, group receive counseling that encourages them to quit nicotine use and nicotine replacement therapy. Ten more participants form the intervention group; they receive counseling, nicotine replacement therapy and CM. The intervention participants create videos of themselves breathing into a carbon monoxide (CO) monitor and then show the result to the camera. For each CO reading that demonstrates tobacco abstinence, intervention participants receive escalating payments. All participants will receive $25 for completing a questionnaire at the study’s start and one after three months, the study’s end. The researchers will use data from this study to apply for National Institutes of Health funding to study a tobacco-dependence treatment intervention for Medicaid smokers that will include a CM component.
Pancreas-Specific microRNA Knockout for Tumorigenesis Study
Thomas Schmittgen, PhD, and Vincenzo Coppola, MD
Pancreatic cancer is one of the most lethal forms of cancer. Recent evidence suggests that noncoding microRNAs (miRNAs) might play an important role in initiating this disease. This study tests the idea that the loss of two miRNAs, miR-216 and miR-217, contributes to the development of pancreatic cancer (which would mean that they function as tumor suppressors in this disease). To test this hypothesis, the researchers will develop a strain of mice that lack these two miRNAs and cross them with a second strain of mice with that have a gene mutation that causes these animals to develop the most common form of pancreatic cancer. This study will evaluate the offspring of the cross to learn if the loss of miR-216 and miR-217 increases the development of pancreatic cancer. The findings will provide new fundamental information about the role of these two miRNAs in the development and progression of pancreatic cancer. The findings might also indicate that miRNA replacement could be a new form of pancreatic cancer treatment.
Pan-Cancer MRI Agents That Self-Assemble in Malignant Tumors
Michael Tweedle, PhD, and Josh Goldberger, PhD
Getting anticancer drugs and imaging agents selectively into tumors and not healthy tissue remains a challenge. Many drugs target receptors on the cancer-cell surface, but cancer cells mutate rapidly, altering receptor structure and allowing tumors to escape receptor-targeted drugs. These investigators have developed a vehicle for delivering imaging agents and anticancer drugs to tumors that does not rely on specific receptors. The molecule, called a peptide amphiphile (PA), is composed of amino acids and lipids. The PA is a sphere at normal serum pH (7.3-7.4), but at the lower pH of a tumor (6.6-7.0), it transforms into larger nanofibers. This transformation would release anticancer drugs packaged within the spheres and trap imaging agents built into the PA. In this study, the researchers will refine the PA structure so that the transition occurs at pH 6.6-7.0 inside a living animal and demonstrate for the first time that the vehicle will be selectively retained in tumors in an animal model using the proposed mechanism.
Phytochemical Release Rate From Black Raspberry Confections Alters Gene Expression and Chemical Profiles Relevant to Inhibition of Oral Carcinogenesis
Yael Vodovotz, PhD (PI); Steven Clinton, MD, PhD; Steven Schwartz, PhD; Christopher Weghorst, PhD; and Dennis Pearl, PhD
Oral cancer is a devastating, global disease. These investigators are developing a strategy for preventing oral cancer in people at high risk for the disease by using formulations of black raspberries, which have been shown to have anticancer activity. The researchers have developed a series of confections that release black raspberry phytochemicals in the mouth at varying rates. This study will support a clinical trial involving 60 healthy adults who will use the confections over two weeks at two doses of black raspberry phytochemicals released at three different rates. Data such as phytochemical profiles and gene expression profiles in biological samples will be collected to determine optimal dose and release rates. This information will be used for a future phase II study in high-risk populations to evaluate the confections for oral cancer prevention or therapy.
Impact of Androgen Deprivation Therapy on Cardiac Function in Prostate Cancer Patients
Steven Clinton, MD, PhD (PI); Subha Raman, MD; Orlando Simonetti, PhD; and Brian Focht, PhD
Androgen deprivation therapy (ADT) is the most significant treatment ever developed for men with prostate cancer. It is often a component of therapy intended to cure men with high-risk localized prostate cancer or to limit the progression of metastatic disease. But ADT is also linked to loss of skeletal muscle mass, lower bone mineral density, greater risk of metabolic syndrome, and a fatigue syndrome – effects that cause declines in performance status and in quality of life. These researchers are currently doing NIH-funded research to quantify these declines in performance and quality of life in men on ADT, and to identify a diet and exercise program that will prevent the declines. This cardiac-function study complements that work. It will quantify changes in cardiac performance in men on ADT using the novel non-magnetic treadmill stress test and cardiac MRI system developed at Ohio State. The findings will help determine dietary and exercise interventions that will prevent or reduce the deleterious consequences of ADT on cardiovascular health, physical performance and quality of life.
Developing a Combination Therapy Using ATM Inhibitor and γδ T Cells for Breast Cancer
Hiranmoy Das, PhD, and Charles Shapiro, MD
Laboratory studies by these researchers have shown that a subtype of immune cell, called γδ T cells, limits the growth of multiple subtypes of breast-cancer cells by causing many of the cells to die by triggering apoptosis, a natural form of cell death. The researchers have also shown that γδ T cells can strongly inhibit tumor growth in at least one type of breast-cancer in an animal model and learned the mechanism by which γδ T cells trigger the death of breast-cancer cells. In this study, they will examine whether drugs called ATM inhibitors, combined with γδ T cells, can more efficiently control tumor growth in an animal model than current treatments.