Molecular Carcinogenesis and Chemoprevention


Leader: Steven Clinton, MD, PhD

Studies in carcinogenesis and ultimately in chemoprevention have been part of the OSUCCC – James research efforts since the National Cancer Institute designated Ohio State as a Comprehensive Cancer Center in 1976.

These studies are embodied in the Molecular Carcinogenesis and Chemoprevention (MCC) Program, one of five transdisciplinary and highly collaborative research programs at the OSUCCC – James. The MCC includes 41 investigators from eight colleges and 16 academic departments at Ohio State.

In the past 10 years, the MCC Program also has incorporated the discipline of nutritional sciences to contribute to one of the program’s major goals: translational research, or turning scientific discoveries into clinical applications.

Areas of strength are: groundbreaking research into the origin and progression of cancer in its many forms, and exploring strategies for preventing it; publishing study results in leading scientific journals, including some with impact factors of 10 or higher; National Cancer Institute (NCI) grant funding of $3.4 million in 2013, a total that constituted 47 percent of all grant funding for this program; a number of large, ongoing, collaborative research grants totaling millions of dollars (listed below).

Key Program Objectives

  • Carcinogenesis: To characterize molecular and cellular changes induced by chemical, physical and infectious agents that contribute to cell transformation, leading to malignancy

  • Chemoprevention: To develop and test novel chemopreventive agents and define their mechanisms, safety and efficiency in preclinical and human studies

  • Nutritional Sciences: To identify dietary components or patterns that impact carcinogenesis in experimental and human systems

  • Translation: To implement studies in human populations with an emphasis on those at risk due to exposure to carcinogenic agents, familial and genetic predisposition, or the presence of premalignant lesions, and to translate findings into clinical applications

Key Grants

Members in the MCC collaborate with members of other OSUCCC programs in studies relating to a number of large programmatic grants:  

Leukemia & Lymphoma Society Specialized Center of Research (SCOR): Experimental Therapeutics for Chronic Lymphocytic Leukemia (CLL) (7004-11)
PI: John C. Byrd, MD, co-leader of the Leukemia Research Program
Objectives: This grant supports the pursuit of preclinical and clinical investigational multi-targeted therapies for treating genetically high-risk CLL. Investigators in this group have contributed to clinical development of several drugs now approved or widely used for CLL treatment. Through the SCOR, they have continued to develop therapies for drug-resistant CLL.                                                                       

MicroRNAs and UCRs as BMs of Cancer Risk, Early Tumor Detection, Tumor Progression and Response to Treatment (U01 CA152758)                                                                                               
PI: Carlo Croce, MD, of the Molecular Biology and Cancer Genetics Program
Objectives: Develop microRNA and ultraconserved non-coding RNA (UCR) biomarkers for the assessment of cancer risk and for the early detection of five different epithelial cancers, including the four most common malignant tumors: lung, breast, prostate and colorectal cancer.                                         

Centers for Population Health and Health Disparities: Reducing Cervical Cancer in Appalachia (P50 CA105632)
Program Director: Electra Paskett, PhD, MSPH, leader of the Cancer Control Program
Objectives: A transdisciplinary team of investigators from Ohio State and the University of Michigan have collaborated in establishing this NCI-funded OSU Center for Population Health and Health Disparities to focus on cancer as an important health disparity among an underserved Appalachian population. The Center seeks to understand why cervical cancer incidence and mortality rates are higher in Appalachia Ohio and West Virginia. Christopher Weghorst, PhD, of the MCC Program, leads one of the four interrelated projects within this initiative.                                                                                                                          

Phase I Clinical Trials on Novel Anticancer Agents (U10 HL109322 – Phase I)                                       
PI: Michael Grever, MD, co-leader of the Leukemia Research Program
Objectives: This grant funds phase I clinical trials on novel anticancer agents (new drugs and drug combinations) as part of an NCI Experimental Therapeutics-Clinical Trials Network (ET-CTN) that supports the NCI’s new National Clinical Trials Network (NCTN). The OSUCCC – James works with other network members to define the drug development plan and conduct clinical trials for these novel anticancer agents. The trials are intended to provide the drug dose, schedule and early evidence of therapeutic activity.                                                                                                                                                

Phase II Clinical Trials to Test Novel Anticancer Agents in New Indications (N01 CM2011– Phase II)                
PI: Miguel Villalona, MD, of the Experimental Therapeutics Program
This grant enables the OSUCCC – James to conduct phase II studies on NCI-sponsored anticancer agents as the lead institution in a consortium that includes three other cancer centers as collaborators: Case Western Reserve Comprehensive Cancer Center/Cleveland Clinic; Georgetown University Lombardi Comprehensive Cancer Center; and Roswell Park Cancer Institute. These trials help scientists evaluate biologic effects of experimental agents and determine clinically relevant outcomes/correlates of drug efficacy and toxicity.                                                                                                                                         

Scientific Achievements

A review of the existing grading schemes and a proposal for a modified grading scheme for prostatic lesions in TRAMP mice. The transgenic adenocarcinoma of the mouse prostate (TRAMP) model is well established for studying chemopreventive agents, but there is no consensus on the grading of prostatic lesions in these mice. In this study, OSUCCC – James investigators, including Steven Clinton, MD, PhD, Ching-Shih Chen, PhD, Thomas Rosol, DVM, PhD, and Samuel Kulp, DVM, PhD, reviewed five currently available grading schemes and proposed a refined scheme that provides a useful definition of invasion for the differentiation of prostatic intraepithelial neoplasia (PIN) from well-differentiated adenocarcinoma and includes a numerical scoring system that accounts for both the most severe and most common histopathological lesions in each of the lobes of the prostate and their distributions. The study was published in the journal Toxicologic Pathology. (Toxicol Pathol. 2012;40(1):5-17)                                                                               
Senior author: Samuel Kulp, DVM, PhD

Ohio State and Malaysia Centre join forces in fight against cancer. The Ohio State University has signed an agreement with the Sarawak Biodiversity Centre in Malaysia to collaborate on the further development and commercialization of a promising anticancer agent called silvestrol that is derived from a tropical tree that grows on the island of Borneo. Researchers with Ohio State’s College of Pharmacy and the OSUCCC – James have worked together on silvestrol since 2004. The team’s early studies indicated that the agent might help treat acute and chronic leukemia, as well as mantle cell lymphoma and other currently incurable malignancies. Silvestrol kills cancer cells in an unusual way, by directly blocking the initial step in the process cells use to make proteins. A. Douglas Kinghorn, PhD, DSc, a researcher with the OSUCCC’s MCC Program, led the work that fully characterized the molecular structure of silvestrol and also named this compound. Michael Grever, MD, who co-leads the Leukemia Research Program at the OSUCCC – James, said Ohio State investigators will isolate and purify the agent and conduct the laboratory and animal studies that are needed to demonstrate its safety and effectiveness before using it in human clinical trials.

Medicated patch shows promise to prevent oral cancer. OSUCCC – James investigators hope soon to begin clinical testing of an adhesive medicated patch that releases a cancer-preventing drug directly into precancerous oral lesions to help prevent head and neck malignancies. The patch also keeps the medication from spreading, reducing potential side effects. Principal investigator Susan Mallery, DDS, PhD, of the MCC Program at the OSUCCC – James, says the team has successfully tested the patch in simulated saliva and laboratory models. Before that, she says, doctors couldn’t achieve a therapeutic dose of this drug because of its toxicity and clearance from the body. But the patch design enables direct drug uptake at the treatment site. Mallery says the patch—designed by the lab of her colleague, Dr. Steven Schwendeman at the University of Michigan—has three layers: a disk saturated with the drug and other substances that make it more soluble in saliva; an adhesive ring to hold the disk in place; and a backing to retain the medication.

Study shows how vitamin E can help prevent cancer. Researchers have identified an elusive anticancer property of vitamin E that has long been presumed to exist but difficult to find. Many animal studies have suggested that vitamin E could prevent cancer, but human clinical trials following up on those findings have not shown the same benefits. However, researchers at the OSUCCC – James showed in prostate cancer cells that one form of vitamin E inhibits the activation of an enzyme that is essential for cancer cell survival. The loss of the enzyme, called Akt, led to tumor cell death. The vitamin had no negative effect on normal cells. Lead author Ching-Shih Chen, PhD, of the MCC Program at the OSUCCC – James, says this was the first demonstration of a unique mechanism of how vitamin E can have some benefit in terms of cancer prevention and treatment. Chen cautioned that taking a typical vitamin E supplement won’t offer this benefit, but he said his team’s goal is to develop a safe pill at the right dose that people could take daily for cancer prevention. The study was published in the journal Science Signaling (Sci. Signal. 6 (267), ra19. [DOI: 10.1126/scisignal.2003816]).

Crops to the Clinic Program promotes cancer prevention. In nutritional sciences, the MCC is a key player in Ohio State’s multidisciplinary Crops to the Clinic Program. Ohio State is ideally suited for such a program because the university has, on one campus: a College of Food, Agricultural and Environmental Sciences; a College of Medicine; a College of Public Health; a College of Dentistry; a College of Veterinary Medicine; Human Nutrition/Dietetics faculty; and an NCI-designated Comprehensive Cancer Center. The university also has a branch campus in Wooster, Ohio called the Ohio Agriculture Research and Development Center, and several farms around the state are part of Ohio State’s agricultural research system. MCC investigators have studied an array of foods that contain compounds with anticancer properties, including berries, tomatoes, cruciferous vegetables (broccoli, cauliflower, cabbage, etc.), avocados and soy. Studies led by Yael Vodovotz, PhD, Steven Clinton, MD, PhD, Steven Schwartz, PhD, and Mark Failla, PhD, have led to the development of soy breads and a soy-tomato drink that have appeared to be both promising and palatable in human clinical studies and may one day become available on the market.

Building a better bread to beat prostate cancer. Investigators in the MCC Program are developing a novel approach to providing soy in the diet for cancer-prevention studies. They have developed two functional foods—soy bread and soy-almond bread—–that are being tested in men with prostate cancer. Both breads were created by an MCC team led by Yael Vodovotz, PhD, a physical chemistry researcher and food scientist. Steven Clinton, MD, PhD, a medical oncologist and researcher who specializes in treating and preventing prostate cancer, directed the clinical trial involving 32 men with prostate cancer at The James. Gregory Lesinski, PhD, MPH, a cancer immunologist, has been evaluating how soy impacts the immune system in men on the trial. The researchers, who have completed their laboratory analysis and are in the final phases of statistical analysis, are focusing on isoflavones, which are among many compounds in soy that are studied for health-promoting properties. The researchers believe soy may also have benefits for various cancers, such as prostate cancer. Since soy is not commonly consumed in the Western world, the team developed breads that taste good and are easily incorporated into the diet. Almonds were added to improve the anticancer activity of the soy breads.

Strawberries for oral cancer prevention. Researchers in the MCC Program at the OSUCCC – James are finishing a clinical study of how natural compounds in strawberries may help prevent oral cancer. The team has applied a strawberry-based confection to the high-risk oral cavity of smokers, believing that anticancer compounds in the berries will cause genes altered by tobacco smoke to once again resemble the normal genes of never-smokers, thus preventing cancer development. Principal investigator Christopher Weghorst, PhD, says complex mixtures of bioactive compounds in various berries have been shown to possess cancer-preventing properties in animal models of cancer. With this in mind, researchers are applying a food-based approach that emphasizes the potential for mixtures of natural preventive agents in strawberries to modulate the molecular biomarkers of cancer risk in smokers. The two-year study enrolled 25 healthy individuals, including 13 who are smokers and 12 who are not. The team, which includes Steven Clinton, MD, PhD, Yael Vodovotz, PhD, and Steven Schwartz, PhD, is analyzing the activity of 41 cigarette smoke-associated genes in the oral cavities of the study participants. Because these genes have previously been shown to be altered in smokers, the researchers want to see how the genes respond to the strawberry confection.

NCI grant aids study of omega-3 fatty acids for breast cancer prevention. A $1.28 million, four-year grant from the National Cancer Institute is helping OSUCCC – James researchers test the ability of an omega-3 polyunsaturated fatty acid (PUFA)-rich fish oil supplement to reduce the risk of recurrence in women with aggressive subtypes of breast cancer. Principal investigator Lisa Yee, MD, of the MCC Program, says the team will randomize high-risk breast cancer survivors to either a placebo-low dose or a high-dose omega-3 PUFA capsule treatment. The researchers will use fine needle aspiration techniques to obtain breast cells and tissue for analysis. They hope to determine the ability of dietary omega-3 fatty acids to modulate breast epithelial and adipose tissue biomarkers of anti-carcinogenic activity in women at risk for recurrence of either ERPR(-)HER-2/neu(+)breast cancer or ERPR(-)HER-2/neu(-) breast cancer (also known as triple negative).

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