American Cancer Research Center, Denver, Colorado                            cause13.jpg (3126 bytes)
Thomas J. Slaga, Ph.D., Center Chair
Dr. Slaga is determining the critical cellular and molecular mechanisms in epithelial tissues during carcinogenesis. These studies are primarily being investigated in mouse skin, a model where carcinogenesis can occur by a multistage process. Some emphasis is placed on elucidating the mechanism of action of potent inhibitors of skin tumor initiation, promotion and progression. Antioxidants and/or free radical scavenging agents plus suicide substrates and antisense molecules for H-ras oncogenes, polyamine synthesis, prostaglandin synthesis and telomerase genes, involved in chemical carcinogenesis are the major chemopreventive agents being studied. In addition, several phytochemicals with carcinogen detoxifying capability as well as antioxidizing activity are being investigated. Currently, he is focusing on the importance of specific protein changes, loss of the glucocorticoid receptor and/or function and the importance of genetic instability in this multistage process. He is currently determining the importance of GGT and glucocorticoid receptor in skin carcinogenesis by transfecting the genes into normal keratinocytes, papilloma cells and in carcinoma cells as well as developing transgenic and specific knock-out mice.
Rajesh Agarwal, Ph.D.
The major focus of the studies in Dr. Agarwal's lab is to search and identify novel and potent chemopreventive agents against skin, breast and prostate cancers. The emphasis is on both naturally occurring and synthetic chemicals. Based on the outcome of these studies identifying potentially effective agents in different animal tumor bioassay systems including multistage murine skin carcinogenesis protocols, studies are also being conducted to define the mechanisms of the cancer preventive effects at molecular level.
Irina Budunova, M.D., Ph.D.
The major direction of Dr. Budunova's research is to study the mechanisms of mouse skin carcinogenesis with the emphasis on the regulation of cell cycle in keratinocytes by glucocorticoid hormones, analysis of glucocorticoid resistance of transformed keratinocytes, role of NF-kB transcription factors in keratinocyte transformation and malignization, and alteration of gap junctional intercellular communication during mouse skin hyperplasia and skin carcinogenesis.
Rita Ghosh, Ph.D.
Dr. Ghosh's research interest is in ultraviolet (UV) radiation-induced DNA damage and repair mechanisms as they relate to skin cancer. UV radiation can damage DNA either directly, by dimerization of adjacent pyrimidine bases, or indirectly, by the generation of free radicals, which in turn cause oxidative DNA damage. Usually, damage to DNA is repaired at the cellular level, but unrepaired DNA can lead to mutations, one of the steps towards cancer development. Dr. Ghosh's laboratory is currently studying a protein isolated from a human fibroblast cell line that has a high affinity for UV-induced DNA damage. Dr. Ghosh is interested in the role of UV in the progression of normal melanocytes to metastatic melanoma. The involvement of DNA repair mechanisms in this process is being investigated in cultured cells.

Another project involves studying how DNA damage in the promoter elements of genes affects transcription. Gene transcription involves interactions between promoter elements of genes and proteins called transcription factors. DNA damage at gene promoters has the potential to alter gene expression either by preventing or facilitating binding of transcription factors to gene promoters. This could translate into inhibition or activation of gene expression, respectively. Such DNA damage associated alterations in gene expression could lead to cancer, depending on the function of that particular gene.

Margaret Hanausek, Ph.D.
Dr. Hanausek received her Ph.D. in immunology from the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw. Her research focuses on the mechanisms of altered gene expression during multistage chemical carcinogenesis with special emphasis on a new oncofetal protein (p65). She has identified the p65 gene as a novel member of the steroid receptor superfamilly of genes. The overall objective of her research is to identify the cellular origin of p65 and elucidate the mechanism of its expression in rat liver, skin, colon, prostate and mammary gland carcinogenesis and combine these basic studies with the translational research to provide a better understanding of the role of p65 gene and its product in cancer development.
Pratap Kumar, Ph.D.
It is well established that mutations in, or deregulation of, growth promoting genes (oncogenes) or growth suppressing genes (tumor suppressor genes) are frequently associated with the development of cancer. Dr. Kumar's primary research interest is to understand the regulation of expression of such genes during carcinogenesis using an integrated research program that includes both in vitro cell culture models and in vivo animal models. Ornithine decarboxylase (odc) is a growth-associated enzyme and is a key regulator of the polyamine biosynthesis pathway. Dr. Kumar and his colleagues have found that the transcription factor Sp1 and its family members play an essential and critical role not only in the regulation of odc itself but also during tumorigenesis. Dr. Kumar's laboratory is currently developing transgenic mice overexpressing Sp1 and/or Sp3 (under the control of keratin K5 promoter) in order to investigate the in vivo role of Sp1 and its family members in epidermal carcinogenesis.

Dr. Kumar is also developing a research program to identify the molecular events associated with the development of androgen-independence during prostate carcinogenesis. In the initial stages of prostate cancer, the cancer is confined to the prostate gland and is androgen-dependent. At this point, androgen deprivation therapy has proven to be effective treatment. However, as the cancer progresses, it develops into a more fatal, metastatic, androgen-independent type, for which no treatment is currently available. The ultimate goal of the research is to identify the specific factor(s) that play a role in the progression of prostate carcinogenesis from androgen-dependent to androgen-independent in an effort to develop possible targets for chemoprevention.

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Michael LaBate, Ph.D.
Dr. LaBate has studied the induction and progression of tumorigenesis in mouse skin and breast tissue by dimethylbenzanthracene (DMBA). He has used the ras family of genes and p53 as biomarkers in assessing genetic damage in this process. This damage is correlated with histological evaluation of tumor progression. Following DMBA treatment, mutations in codon 61 of Ha-ras can be verified from developing tumors. He has also seen mutations in exons 5-8 of p53 in the hamster cheek pouch following DMBA treatment. These mutations have been shown to be good predictors of tumorigenesis in a variety of animal tissue models. In collaborative studies, he found p53 mutations in patients with metastatic prostate cancer of the bone that matched the mutation seen in the primary tumor.
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Johnny Lu, Ph.D.
Dr. Lu received his Ph.D. in nutritional sciences from Cornell University (Ithaca) with postdoctoral training in molecular biology also at Cornell. He has successfully adapted numerous molecular diagnostic approaches to studying the effects of various promotional and inhibitory agents on mammary tumor development. Dr. Lu is currently investigating the role of Ras-MAPK signal transduction pathways in mammary cancer promotion by high fat diets as well as the role of growth arrest and cell death-related genes as mediators of the cancer chemopreventive activity of selenium. Additional research focuses on the cloning and validating of gene expression markers of mammary carcinogenesis.
Jaime Modiano, Ph.D.
Dr. Jaime Modiano joined AMC in August of 1999. He received his veterinary degree from the University of Pennsylvania, where he also completed a Ph.D. in Immunology. Before coming to AMC, Dr. Modiano served as a resident in Clinical Pathology at Colorado State University in Fort Collins, CO. He also completed a post-doctoral fellowship at National Jewish Center for Immunology and Respiratory Medicine in Denver, CO and worked as Assistant Professor in the Departments of Pathobiology and Pathology and Laboratory Medicine at Texas A&M University. Through their research, Dr. Modiano and the members of his laboratory strive to enhance our understanding of how genes impact the development and progression of cancer.
Pepper Schedin, Ph.D.
Dr. Schedin received her Ph.D. in molecular, developmental and cellular biology from the University of Colorado, Boulder, and completed postdoctoral training in mammary carcinogenesis at AMC. She is studying the genesis and prevention of cancer from the perspective that carcinogenesis is a developmental disorder. Dr. Schedin has addressed this problem by isolating the extracellular matrix proteins. Breast cancer cells are then grown on this extracellular matrix material. Breast cells grown on the matrix organize into duct-like structures with a histology very similar to that observed in vivo. Her laboratory is currently using this system to address two questions: Can dietary modifications alter interactions between early stage tumor cells and their environment such that carcinogenesis is inhibited? And, is it possible to target these interactions with chemopreventive agents to suppress carcinogenesis? Another active research area in her lab is determining periods of mammary gland development such as puberty, pregnancy, post-lactational involution, peri-menopause and post-menopause. Targeting these stages with dietary and chemopreventive agents which alter cell-extracellular matrix interactions is anticipated to increase efficacy of treatment.
Vladimir Spiegelman, M.D., Ph.D.
Dr. Spiegelman's research interest lies in the field of mouse skin carcinogenesis. His work is focussed on the role of glucocorticoid receptor in tumor promotion and progression, its function, interaction with other transcription factors and mechanisms involved in resistance to glucocorticoids acquired during carcinogenesis.
Rob Strange, Ph.D.
Dr. Strange received his Ph.D. in genetics from the University of California, Davis, and completed postdoctoral training at the University of Bern, Switzerland. His research areas are the molecular and cellular biology of normal and neoplastic mammary gland development. The focus of this research is on the process of apoptotic cell death that occurs during post-lactational mammary gland regression and how failure or incomplete apoptosis contributes to initiation of mammary neoplasia. His immediate goals are the identification and isolation of genes important in the initiation, regulation and execution of apoptotic cell death in mammary gland involution. The goal of this work is to identify intermediate biomarkers for evaluation of the relative risk of pre-malignant breast lesions. These should prove useful initially as a means of monitoring the efficacy of therapeutic treatment and ultimately as the means for preventive and therapeutic treatments of breast cancer.
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Henry Thompson, Ph.D.
Dr. Thompson received his Ph.D. in nutritional sciences from Rutgers University and completed postdoctoral training in molecular medicine at the Mayo Clinic, Rochester. His research focuses on efforts to reduce cancer morbidity and mortality via cancer prevention. These areas include regulation of apoptosis and its exploitation for cancer prevention using physiological, nutritional and pharmacological approaches, identification of misregulated genes in carcinogenesis and the development of pharmacological strategies to achieve gene-specific inhibition of cancer via chemopreventive agents, the modulation of biomarkers via lifestyle changes and/or pharmacological agents to reduce cancer risk and the identification of retinoids, polyamine antimetabolites, trace elements including iron and selenium, lipids including fish oil and conjugated linoleic acid, energy and exercise. The use of computer assisted image analysis to identify cellular markers of cancer promotion and progression is also being studied.
Zbigniew Walaszek, Ph.D.
Dr. Walaszek received his Ph.D. in bio-organic chemistry at Silesia Technical University. His research focuses on the control of the carcinogenic process by chemopreventive agents including glucuronidase inhibitors with an emphasis on D-glucaro-1, 4-lactone (GL) and its precursors. His approach is that potential toxins, carcinogens and tumor promoters are detoxified, in part, through coupling with D-glucuronic acid, and that by inhibiting b-glucuronidase, GL may control their levels in tissues and body fluids. The goal of the research is to determine the mechanism of GL-mediated control of disease and to demonstrate that cancer and possibly cardiovascular disease risk can be decreased by administering GL and its precursors such as D-glucarates or analogs, or by modifying metabolic pathways involved in its biosynthesis. A new gene therapy has been developed that apparently restore the regulator of cholesterogenesis and steroidogenesis. A new gene therapy has been developed that apparently restore the function of steroid hormone receptors in hormone-independent breast and prostate cancer cells and their responsiveness to treatment with aniestrogens and other hormonal agents. Mechanism-based inactivators of glucuronidase as well as new antioxidants have also been identified and will be tested as therapeutic and preventive agents.
Kim Westerlind, Ph.D.
Dr. Westerlind received her Ph.D. in Kinesiology and Research Design/Statistics from the University of Colorado in 1991 and completed an endocrine fellowship at the Mayo Clinic, Rochester. Her primary research focus is understanding the mechanism by which exercise may reduce a woman's risk for developing breast cancer. A number of hypotheses have been proposed, including alterations in ovarian steroids or other hormones, immune function, body composition and substrate availability/utilization. Using animal models to assess the exercise/carcinogenesis relationship, she will ultimately translate the findings to human-intervention trials aimed at reducing risk of primary cancers as well as prevention of metastases. Another focus is the role that estrogen metabolism may have in predicting a woman's risk for developing breast cancer, osteoporosis and/or other estrogen-related diseases.