Victor Jin, Tim Huang: Microenvironmental Influences on AKT1-regulated Transcriptome in Tumorigenesis
After the successful completion of the project, our computational tool will greatly benefit cancer researchers who utilize whole-genome-wide ChIP-seq technology, where it will speed up their progress. Our integrated genomic approach with high throughput screening and computational modeling will define a set of potential markers targeted by the AKT1 signaling pathway. Currently novel pharmacological drugs that target the AKT1 pathway are already being evaluated in early-phase clinical trials for other cancers. Therefore, our finding novel therapeutic markers will provide a new rationale for molecular targets in breast cancer. In addition, therapeutic targets discovered in this study may be used biomarkers for breast cancer therapy. Our long-term goal is a) to study the differences of binding patterns between various chromatin modifications data in different cancer cells, tissues and phenotypes, and (b) to identify cancer-cell-type (or cancer tissue-type) specific epigenetic signatures, preferentially located in euchromatin or heterochromatin domains. We anticipate that achieving these goals will help basic research in tissue-selective therapy of cancer.
Mark Bloomston, Lanchun Lu, Wendy Frankel, Zhilin Hu: Optical Coherence Tomography Imaging of Precancerous Pancreatic Lesions
Given the nearly universal fatality associated with pancreatic cancer, much research has focused on early detection and prevention. In recent years, some precancerous abnormalities of the pancreatic duct have been identified. Still, these lesions are difficult to detect due to the limitations in imaging. We have developed technology which will allow us to image the lining of the pancreatic duct at the microscopic level. Optical Coherence Tomography (OCT) utilizes a probe the size of a fiber that can be inserted non-invasively into the pancreatic duct and provide 3D images at the microscopic level. This allows for detection of abnormal cells that would not be visible to the naked eye using current technology. In this two-year project, we plan to build an OCT device at OSU in collaboration with Dr. Hu from Case Western University who first developed this technology nearly 10 years ago. We will then use the OCT device in the operating room to image the pancreas after it has been removed in patients with suspected precancerous lesions. The acquired images will then be compared to microscopic findings. Over the two years of the project, based upon the number of pancreas operations done at OSU, we expect to detect occult cancers in 6-8 of the 30-40 patients who will be having surgery. Once the reliability of the OCT device is confirmed, a larger project to image the pancreas of patients at high risk for pancreatic cancer prior to surgery will be undertaken. As well, the OCT device is designed to deliver radiation which opens the possibility for treatment of precancerous lesions without the need for radical surgery. Such an advance is potentially revolutionary in the early detection and prevention of pancreatic cancer.
Electra Paskett, Mira Katz, Scott Jewell: E-health Program to Reduce Obesity in Appalachia
Health disparities are associated with obesity and cancer among adults living in the Appalachian region of the U.S. The aims of this project are to develop an eHealth program to increase physical activity levels and change the diets to reduce obesity among members of churches in Ohio Appalachia. We will also explore the willingness of Appalachian community members to provide biomarkers and biospecimens to further understand the effects of the intervention on markers of obesity and to begin to establish a biospecimen bank within Appalachia. The proposed project uses a health disparities research team in partnership with churches throughout Ohio Appalachia.
Nancy Lill, Charlie Shapiro, Weiqiang (John) Zhao: CBL and EGFR in Triple Negative Breast Cancers
Triple-negative breast cancers (TNBC) are often basal-like and associated with a poor long-term prognosis. They lack the targets for trastuzumab and tamoxifen therapy, but many TNBCs express the epidermal growth factor receptor (EGFR). The presence of this cancer-linked protein raises several important questions. Could EGFR’s abnormal function in TNBCs be caused by a defect in an EGFR-regulating protein known as Cbl? And can the EGFR on TNBCs be exploited as a therapeutic target for new and effective combination anti-cancer therapies? The Pelotonia Idea Award project will investigate these questions in linked and complementary translational experiments by the study’s co-PIs. Our objective is to determine if TNBCs and other breast cancers retain or lack the EGFR-regulating function of Cbl and whether, therefore, the tumors are more likely to be killed using novel Cbl-dependent or -independent therapies. The results may suggest that certain therapies will more effective for different groups of breast cancer patients, based on their EGFR and Cbl status. Encouraging results could lead to in vivo studies of the combination therapies and clinical studies in breast cancer patients relatively soon.
James DeWille, Gustavo Leone: Genomic Analysis of Primary Tumor Lesions as an Approach to Early Chemoprevention
Certain types of cancer are more common in families or groups of related individuals compared to the general population. This suggests that heredity, i.e., the genes
you inherit from your parents, plays an important role in determining risk for developing cancer. One relatively common scenario in which heredity increases cancer risk occurs when an individual inherits one defective gene from one parent and one normal gene from the other parent. The presence of the defective gene increases the likelihood of developing cancer by a number of poorly understood mechanisms including losing the cancer preventing protective effect of the “normal” gene. How one broken gene leads to the break down of “normal” genes and predisposes to cancer development has remained an unanswered question in cancer research for decades. Major obstacles have been lack of an experimental model and lack of high throughput genome analysis instrumentation. This proposal will utilize a unique genetic model of cancer development
recently developed in the laboratory of Dr. Leone and state-of-the-art genetic analysis instrumentation available in the OSU Comprehensive Cancer Center’s Nucleic Acid Shared Resource to investigate this critical gap in our knowledge of cancer susceptibility. The results will provide new insights into how cancer develops and may open the door for new cancer prevention or cancer treatment strategies.
Denis Guttridge, Ching-Shih Chen: NF-ĸB Inhibition Cancer Therapy
NF-kappa B (NF-κB) is a protein that was first discovered in immune cells in 1986 in the laboratory of the Novel Prize Recipient, Dr. David Baltimore. After 25 years of intensive research into this molecule, we now know that NF-κB plays a critical role in cell survival and other cellular properties that tumor cells use to their benefit to form and metastasize. NF-κB is therefore considered a major therapeutic target in a wide spectrum of cancers. However, the pharmaceutical industry has lagged in their efforts to develop a drug that can potently and specifically inhibit NF-κB for cancer therapy. In this application, a team of experts will bring a new approach to the design of such a drug, which if successful in the pre-clinical phase I studies outlined in this proposal, can be further developed for treatment of breast and/or leukemia malignancies.
Christopher Weghorst, Steven Clinton, Yael Vodovotz, Steve Schwartz: Chemopreventive Effects of Strawberries on the Modulation of the Cigarette Smoke-Altered Transcriptome in Human Oral Mucosa
Numerous population studies have shown that consuming fresh fruits and vegetables results in a decreased risk of developing oral cancer. With this in mind, a food-based approach to prevention of oral cancer has been put forward by us that emphasizes the ability of whole foods to inhibit various stages of oral cancer. In support of this idea, our research team has successfully shown the capacity of strawberries and black raspberries to inhibit oral cancer in animal models and their various mechanisms of action in human cells in culture. In the current study, we wish to examine the activity of whole foods in the earliest stages of cancer in human subjects--to the “high risk” oral cavity of current smokers. We believe that exposure of the oral cavity to powdered strawberries in current smokers will result in favorable changes in the 41 reported cigarette smoke-altered genes that will result in them resembling the genes in never smokers and therefore favor cancer prevention. The results of this study will help us to recognize those important genes in oral cancer that are affected by whole foods and help us to identify those people who may be enrolled in future large scale national cooperative Phase III clinical studies that are concerned with prevention of oral cancer by whole foods.
Peter Houghton: Understanding Resistance Mechanisms to MEK Inhibitors in BRAF Activated Juvenile Pilocytic Astrocytomas (JPA)
Children with inoperable JPA, a form of brain cancer, die from the disease or have severe debilitating effects from current therapies. Recently it has been shown that a mutation in a gene known as BRAF is common in these tumors. We have shown that such tumors are very sensitive to a novel, non-toxic, therapy. However, from experience we know that drug resistance will occur. Here we propose to use non-clinical models to understand the mechanism(s) by which tumors become resistant. This knowledge will help us develop therapies that prevent resistance, or exploit the resistance mechanism to improve treatment outcome.
Don Benson, Steven Devine, Pierluigi Porcu, John Byrd, Robert Baiocchi:
PD-1 Blockade Enhance Natural Killer Cell Cytotoxicity Against Multiple Myeloma: Determining Molecular Mechanisms and in vivo Efficacy
Natural killer (NK) cells play a key role in the human immune system’s response to many cancers, including multiple myeloma, a form of blood cancer increasing in incidence and currently incurable with chemotherapy. A protein expressed on immune cells called “programmed death receptor-1” (PD-1) normally functions to limit the immune response to viruses and other infections, however, some forms of cancer, including multiple myeloma, exploit PD-1 as a way to hide from the immune system. We have shown that a blocking antibody against PD-1, either alone or in combination with lenalidomide (an immune modulating treatment for multiple myeloma) enhances NK cell function against the cancer cells. The present work seeks to characterize the mechanisms underlying this effect and will serve to justify a phase 2 clinical trial of these promising, novel treatments for patients with multiple myeloma.