Cancer Center Director Announces Pilot Project Grant Awards
Dr. Gary D. Kruh is pleased to announce that 10 pilot project grant applications were funded in this first Cancer Center Pilot Grant Program cycle.
A total of 35 applications were submitted. Forty-five faculty members participated in the review process. The Cancer Center program leadership team made final funding decisions.
Nine of the 10 projects were awarded at the level of $25,000 and one at $19,405. De-identified reviews have been shared with all grant applicants.
Congratulations to these 10 Cancer Center members!
“Enterotoxigenic Bacteroides fragilis in Colorectal Cancer Development”
Project Type: Individual Translational Research
PI: Richard Benya, MD, Professor, Section of Digestive and Liver Disease, Department of Medicine, College of Medicine. Co-I: Ki-Jong Rhee, PhD, Research Assistant Professor, Section of Digestive and Liver Disease, Department of Medicine, College of Medicine
Bacteroides fragilis are human gut commensal bacteria residing in the large intestine. Studies suggest that a toxin-producing (enterotoxigenic) strain of B. fragilis (ETBF) causes inflammatory diarrheal diseases in humans. Recent studies also suggest an association between ETBF colonization and colorectal cancer. In one study, ETBF was detected in stool of 38% of colorectal patients compared with 12% of healthy individuals. This study suggests that ETBF may be a contributing factor to colorectal cancer in humans. Using a mouse model of colorectal cancer (Min mice), we found that Min mice colonized with ETBF developed larger polyps more quickly compared to Min mice colonized with a non-toxigenic strain of B. fragilis. We further demonstrated that the toxin is necessary and sufficient to induce development of intestinal inflammation and polyp formation. ETBF activates the transcription factor STAT3 and beta-catenin which are critical in promotion of intestinal tumors. We propose that ETBF may be a risk factor for colorectal cancer in humans. In the proposed pilot study we will examine the prevalence of ETBF in healthy individuals and individuals with colorectal polyps. We will also use the Min mouse model to study how the toxin induces polyp development.
“Transformation of Ovarian Epithelium in Three Dimensions”
Project Type: New Investigator to UIC
PI: Joanna Burdette, PhD, Assistant Professor, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy
Epithelial ovarian cancer is the most lethal gynecological malignancy among U.S. women. If ovarian cancers are detected at Stage I, 93% of women survive 5 years; however, 67% of women are diagnosed after metastasis when only 31% survive 5 years. Ultimately, the etiology of ovarian cancer is unknown. The critical problem is the lack of models for studying the transformative process of the ovarian surface epithelium (OSE). If events linked with ovarian cancer could be modeled in a system that propagates normal cells in their proper microenvironment, then progress will be made in targeting early transformative events and biomarkers needed for early detection. Traditional experiments to study transformation fail to reflect microenvironmental changes, the influence of the extracellular matrix, and lack the tissue architecture that might improve our understanding of regulators of tumorogenesis. We have recently developed a 3D organ culture that might improve the progress towards characterizing factors critical to ovarian transformation. It is the hypothesis of this grant that ovarian surface cells grown in a 3D alginate organ culture can be transformed and will provide a model system for studying oncogenesis and prevention.
“Cervical Cancer Prevention Through Wide-Spread Human Papillomarvirus (HPV) Vaccination: A Survey of Chicago Parents”
Project Type: New Investigator to UIC
PI: Rachel Caskey, MD, MPP, Assistant Professor, Departments of Internal Medicine and Pediatrics, College of Medicine. Co-Is: Marian Fitzgibbon, PhD, Professor, Section of Health Promotion Research, Department of Medicine, College of Medicine; Elizabeth Calhoun, PhD, Associate Professor, Department of Health Policy and Administration, School of Public Health
Human Papillomavirus (HPV) is the most common sexually transmitted infection in the United States with an estimated 6.2 million new infections every year. Currently, universal HPV vaccination is recommended for all females 9 to 26 years of age. School-based HPV immunization is a novel approach for cervical cancer prevention as large numbers of adolescents can be vaccinated, especially those with limited access to health care resources. Our goal is to examine Chicago parents’ knowledge and behaviors surrounding cervical cancer screening; barriers and facilitators to adoption of the HPV vaccine; and attitudes surrounding school-based administration of the HPV vaccine. We will develop, validate and pilot a comprehensive survey instrument to survey a diverse population of Chicago parents who have a child between 9-18 years old. Decreasing mortality and morbidity due to cervical cancer depends on both prevention and early detection. The HPV vaccine provides a potential opportunity for cancer prevention. However, due to the enormous prevalence of HPV in the U.S. prevention can only be accomplished through widespread adoption of the vaccine. Our survey will provide essential information to guide efforts to increase vaccine availability through the school system and cervical cancer screening education targeted at high risk minority girls.
“Development of a Gene Expression Signature for Predicting Hepatocellular Cancer Risk in Benign Liver Biopsies from Patients with Chronic Hepatitis C”
Project Type: Collaborative Translational Research
PI: Peter Gann, MD, ScD, Professor, Department of Pathology, College of Medicine. Co-Is: Scott Cotler, MD, Chief, Section of Hepatology, Department of Medicine, College of Medicine; Larisa Nonn, PhD, Assistant Professor, Department of Pathology, College of Medicine; Grace Guzman, MD, Associate Professor, Department of Pathology, College of Medicine; Yang Dai, PhD, Associate Professor, Department of Bioengineering, College of Engineering
Chronic hepatitis C (CHC) infection puts people at high risk for hepatocellular cancer (HCC), a disease that is typically fatal. Although most CHC patients undergo a needle biopsy to evaluate the extent of liver damage, that biopsy currently cannot be used to identify which patients are at highest risk for HCC. Our group has optimized methods for studying gene expression in small biopsy samples that have been archived in paraffin blocks. A recent study reported a 132-gene signature in benign liver that predicts the occurrence of a second liver tumor in patients after surgical removal of a primary tumor. Our main goal is to test whether this “late recurrence” gene signature, when used in liver biopsies, can also predict the initial occurrence of HCC. A secondary goal is to test whether gene expression related to epidermal growth factor and retinoic acid (vitamin A) signaling are also associated with HCC risk. We plan to compare benign biopsies from a group of patients who later developed HCC to matched control patients who remained free of HCC. This work could ultimately provide clinicians with a tool for identifying patients who need close monitoring, and provide a validated surrogate endpoint for chemoprevention trials.
“Molecular Characterization of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) and Associated Hepatocellular Carcinoma”
Project Type: Collaborative Translational Research
PI: Alan McLachlan, PhD, Professor, Department of Microbiology and Immunology, College of Medicine. Co-Is: Susan Uprichard, PhD, Assistant Professor, Section of Hepatology, Department of Medicine, College of Medicine; Eric Kallwitz, MD, Assistant Professor, Section of Hepatology, Department of Medicine, College of Medicine; Scott Cotler, MD, Chief, Section of Hepatology, Department of Medicine, College of Medicine
Obesity and diabetes are becoming increasingly more common in the United States and can result in the fatty liver diseases, nonalcoholic fatty liver diseases (NAFLD) and its more severe manifestation, nonalcoholic steatohepatitis (NASH). These disorders result in serious health problems, including cirrhosis and liver cancer in some cases. Understanding the underlying causes of NAFLD/NASH should permit its early diagnosis and offer potential treatment options, reducing the incidence and cost of this increasingly problematic condition. Transcriptional profiling will be used to characterize the gene expression patterns within the livers of patients at different stages of NAFLD/NASH. Analysis of the gene expression profiles will be used to identify the metabolic and regulatory pathways within the liver that are either activated or repressed as a consequence of the changing physiological states associated with disease development. Gene profiling of substantial numbers of patient samples may permit the identification and characterization of markers which could potentially serve as bio-indicators to distinguish NAFLD from NASH and as predictors of disease progression. Furthermore, understanding the metabolic pathways which are altered under the different physiological states associated with advancing disease may permit the identification of suitable molecular targets for pharmacological intervention.
“Examining the Use of Economic Subsidies to Support Healthy Eating Behavior in Low-income Families: Implications for Understanding the Role of Nutrition Policy in Cancer Prevention”
Project Type: New Investigator to UIC
PI: Angela Odoms-Young, PhD, Assistant Professor, Department of Kinesiology and Nutrition, College of Applied Health Sciences. Co-Is: Shannon Zenk, PhD, Assistant Professor, Department of Health Systems Science, College of Nursing; Marian Fitzgibbon, Professor, Section of Health Promotion Research, Department of Medicine, College of Medicine
Diet is an important modifiable risk factor in the development of cancer. Nevertheless, the diets of most Americans fall short of American Cancer Society/American Institute of Cancer Research cancer prevention recommendations. There is increasing recognition among researchers that population-based approaches have the greatest potential to address racial/ethnic and socioeconomic disparities in cancer-related risk factors. Drawing on lessons learned from policy approaches to reduce tobacco use, tax and subsidy instruments have been proposed as possible approaches to improve dietary quality by providing an economic incentive for individuals and families to purchase healthy foods.Consistent with this perspective, the United States Department of Agriculture published an interim rule revising the food packages provided in the Special Supplemental Nutrition Program for Women Infants and Children (WIC). These revisions include changes in the nutrient guidelines for WIC approved foods, specifically a reduction in fat (e.g., reduced fat milk) and increase in fiber content (e.g., whole grain bread) and the addition of a monthly cash-value voucher to purchase fruit and vegetables. The purpose of this pilot study is to evaluate the impact of the WIC food package revisions on dietary quality and weight status in 300 mother and children participating in WIC.
“c-Met: a Potentially New Therapeutic Target for Treatment of Human Melanoma”
Project Type: New Investigator to UIC
PI: Neelu Puri, Assistant Professor, Department of Biomedical Sciences, College of Medicine, Rockford
This year, 62,480 people will be diagnosed with melanoma in the US. c-Met, a receptor tyrosine kinase, plays an important role in tumor development and metastases. Preliminary studies indicate that a small molecule inhibitor of c-Met, SU11274, effectively induced apoptosis in melanoma cells up to 58% and inhibited cell proliferation up to 98%. A new missense mutation was identified in the JM domain of c-Met in melanoma tumors. We would like to further study c-Met mutations in a larger number of tumors from melanoma patients. Site-directed mutagenesis will also be used to study the effect of c-Met mutations on cell growth, signaling, motility and tumorigenicity in melanoma cells. Further studies will also be performed to determine the efficacy of small molecule inhibitors of c-Met in decreasing tumorigenicity and angiogenesis in mouse xenografts. Results from these studies can be used to develop small molecule inhibitors of c-Met into a therapeutic target against human melanoma.
“Advanced Image Analysis Tool for Detection of Brain Tumor Recurrence”
Project Type: Individual Translational Research
PI: Keith Thulborn, MD, Professor, Department of Radiology, College of Medicine, and Director of the Center for MR Research. Co-I: Ian Atkinson, PhD, Research Assistant Professor, Department of Radiology, College of Medicine, and the Center for MR Research
Patients with high-grade brain tumors have an unfavorable prognosis and undergo sequential treatment with surgery, radiation therapy and chemotherapy. The tumor response following radiation is monitored grossly by clinical evaluation and anatomically by magnetic resonance (MR) imaging. The current standard of practice in the United States does not superimpose radiation treatment over follow-up imaging to help distinguish radiation necrosis from recurrence. A PC-based software tool is to be produced that automatically superimposes the DICOM radiation treatment files derived from computed tomography (CT) over co-registered MR images across all follow-up studies. This tool is to be designed with a user-friendly interface for clinical use, with automated image retrieval, management and data archive. This tool will then be used to investigate the distribution of radiation dose with sites of tumor recurrence and radiation necrosis as distinguished by MR perfusion parameters.
“Signaling Mechanisms Contributing to Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease”
Project Type: Collaborative Translational Research
PI: Angela Tyner, PhD, Professor, Department of Biochemistry and Molecular Genetics. Co-Is: Nissim Hay, Professor, Department of Biochemistry and Molecular Genetics; Lester Lau, PhD, Professor, Biochemistry and Molecular Genetics; Pradip Raychaudhuri, PhD, Professor, Department of Biochemistry and Molecular Genetics
A wide range of diseases and conditions increase the risk for developing nonalcoholic fatty liver disease (NAFLD), including metabolic syndrome, high cholesterol, obesity, and type-2 diabetes. NAFLD is correlated with increased risk for developing hepatocellular carcinoma (HCC), and HCC is a major cause of mortality in patients with advanced NAFLD. A request for applications (RFA) entitled, "Etiology, Prevention, and Treatment of Hepatocellular Carcinoma," which supports studies directed at "Identification of molecular mechanisms and underlying etiology of HCC development in patients with nonalcoholic fatty liver disease and the metabolic syndrome," has been released by the NIH. We have requested funding to support acquisition of preliminary data for a new PO1 application in response to this RFA. Investigators from the Departments of Biochemistry and Molecular Genetics, Medicine, Pathology, and Microbiology and Immunology have rallied together to examine signaling pathways activated in NAFLD in patient samples and animal models. Factors playing a causative role in development and progression of NAFLD and NAFLD associated HCC will be targeted in animal models to determine their potential as therapeutic targets. These studies will provide important new information regarding how diet, obesity and metabolic syndrome impact the liver and promote development of liver cancer.
“Antioxidant Defense Gene Polymorphisms and Oxidative Stress Biomarkers in Women”
Project Type: Individual Translational Research
PI: Margaret E. Wright, PhD, Assistant Professor, Department of Pathology, College of Medicine
Superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX1) are the primary endogenous antioxidant defense enzymes that protect against oxidative damage within cells. The genes encoding these enzymes are polymorphic, and several variants have been linked to cancer incidence, either directly or indirectly through interactions with intakes of antioxidants and antioxidant-rich foods. In order to test our hypothesis that functional polymorphisms in these antioxidant defense genes are linked to cancer risk via alterations in oxidative stress levels, we will measure urinary concentrations of 8-isoprostane F2 (8-iso-PGF2) and 8-hydroxydeoxyguanosine (8-OHdG) – sensitive indicators of oxidative damage and lipid peroxidation, respectively – and determine whether these levels vary across selected MnSOD, CAT, and GPX1 genotypes. We will also investigate whether these associations are modified by antioxidative and prooxidative lifestyle exposures. Existing biological samples and data from 92 participants randomized to the control arm of the Diet and Hormone Study (DHS) – a one year dietary intervention trial aimed at reducing fat and increasing fruit and vegetable intake in healthy women ages 20-40 years old – will be utilized to address these aims. Assessment of relationships between polymorphisms in endogenous antioxidant defense genes and oxidative stress phenotypes will help to clarify the biological significance of oxidative damage to DNA and lipids in carcinogenesis. In addition, our study will yield critical information regarding the utility of these genotypes in separating responders from non-responders in antioxidant-rich dietary cancer prevention studies, including DHS.