Thomas J.Slaga, PhD is the President of ACRCF. He is the former Deputy Director of the CTRC at the University of Texas Science Center at San Antonio, one of the National Cancer Institute’s designated cancer centers. He is also a professor is the Department of Pharmacology at the University of Texas Health Science Center at San Antonio.
Dr. Slaga received his PhD in physiology and biochemistry from the University of Arkansas Medical Center in 1969. From 1968 – 1971, he was a postdoctoral fellow at the McArdle Laboratory for Cancer Research at the University of Wisconsin Medical School. From 1971 – 1982, he worked in Seattle, where he held positions at the Pacific Northwest Research Foundation, the Fred Hutchinson Cancer Research Center, and the University of Washington Medical School. He also spent several years as a group leader at the Oak Ridge National Laboratory. From 1982 – 1997, Dr. Slaga served as Director of the Science Park-Research Division of the University of Texas, MD Anderson Cancer Center.
Under his direction, the Science Park – Research Division earned a reputation for research excellence in carcinogenesis and cancer prevention. Before joining the University of Texas Health Science Center at San Antonio, Dr. Slaga spent seven years as the Scientific Director of the AMC Cancer Research Center in Denver, Colorado and as Deputy Director of the University of Colorado Cancer Center.
Director Myeloma Institute for Research and Therapy
University of Arkansas for Medical Sciences
4301 W. Markham Street, Suite 816
Little Rock, AR 72205
From the inception of the myeloma program at UAMS in 1989, our physician-scientist team has been totally committed toward
• furthering insights in disease biology, genetics, gene expression profiling (GEP)
• refining diagnostic and staging tools (MRI and FDG-PET-CT);
• and advancing therapeutics through intense translational research
The structure of our comprehensive translational research program, “Growth Control in Multiple Myeloma,” has afforded discoveries that were critically dependent on
• a large patient referral base;
• tight, long-term follow-up;
• integrated basic–clinical investigation;
• and statistical power to interpret findings in the context of historical patients with comprehensive annotations of clinical course and therapeutic interventions as well as availability of samples and laboratory correlates in our database
The overall objective of our research is to understand myeloma (MM ) growth in the context of its interaction with the bone marrow microenvironment (ME) in order to translate this knowledge into smarter MM growth control in patients.
Unlike other myeloma research programs, the Arkansas approach is uniquely focused on the “total” treatment of patients, not just from the point of view of our Total Therapy strategy of applying all currently available agents upfront, but also in reference to our long-term follow-up of patients.
We have generated an unprecedented treasure of bone marrow samples annotated according to the phase of therapy at the time of procurement. We have GEP studies of MM and the bone marrow stroma from over 1000 cases and more than 70,000 metaphase karyotypes from more than 7000 individuals with MM. Additionally, MRI and PET-CT studies have been performed for almost all patients, leading to the recognition of focal lesion (FL) disease with unique biological and molecular characteristics. This wealth of data has allowed us to validate a GEP-based risk index and has provided evidence for a MM- bone marrow microenvironment (ME) interaction that is associated with both GEP-defined risk and molecular subgroup classification.
An adequately large sample size is critical for MM therapeutic trials to have a significant impact on clinical practice. The Myeloma Institute has maintained an annual referral of about 250 newly diagnosed, untreated patients, who are thus eligible for Total Therapy treatment protocol. Other trials have been available for patients presenting with renal failure, advanced age, or hematopoietic compromise.
Dr. Giuliano is an internationally recognized speaker and consultant who has served on a number of committees and investigative task forces of CARE International. Research interests include cancer epidemiology biomarkers; nutritional supplements and diet as chemopreventive agents; HPV and cervical cancer, breast cancer, and cancer screening. Dr. Giuliano is a member of ASPO, AACR, SER, and IEA, and has contributed significantly to the Institute of Medicine publication, The Unequal Burden of Cancer. The National Institutes of Health recently awarded $10 million to Dr. Giuliano for a study to determine men’s role in the spread of the human papillomavirus virus (HPV) that causes cervical cancer. The NIH grant is the largest ever to a cancer control and prevention researcher at the Moffitt Cancer Center.
Professor and Vice Chair for Research Development
Department of Pathology and Laboratory Medicine
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-7525
Cells are particularly vulnerable to the cancer causing effects of chemicals if the treatments occur when the cells start to synthesize DNA during the cell growth cycle. Studies are probing the mechanisms that cause this susceptibility including identifying genomic sites replicated early in the DNA synthesis phase. A separate area of study concerns the development of endometrial cancer. Human endometrium has been reconstructed in culture from its constituent cells and interactions between endometrial epithelial and stromal cells determine normal tissue structure and function. The reconstructed endometrium has been used to reproduce progressive steps of endometrial cancer development in translational studies.
Previous studies showed that cells are most susceptible to malignant transformation when they are treated with chemical carcinogens during the earliest part of the S phase. DNA is also preferentially damaged when it replicates, with elevated carcinogen binding to DNA at replication forks. It was hypothesized that susceptibility in early S phase occurs because DNA target sites critical for malignant transformation are replicated in the earliest part of the S phase. It was found that DNA replicates in a specific temporal order during S phase in normal human fibroblast cultures (NHF1 cells) and that DNA labeled as it replicated early in S phase was most prominent in six chromosomal bands in the next metaphase. DNA that replicated in the earliest part of the S phase was cloned and library clones were sequenced and mapped to the human genome. This revealed the location of early S phase DNA replication and found sites of early S phase replication in each of the early replicating chromosomal bands. The gene families overrepresented in the early replicating library are those for apoptosis, Wnt signaling and DNA base repair; abnormalities of these processes or pathway are commonly found in cancers. Recent studies have used new technology that stretches and aligns DNA fibers and permits examination of DNA replication through specific genomic regions. Results confirmed early S phase replication in an early replicating chromosomal band (1p36.1). These DNA fiber techniques have been shown to permit study of DNA repair at single DNA damage sites with the accuracy and precision of the best methods used for analysis of damage with large quantities of DNA. This DNA fiber technique is being evaluated in translational studies as a possible means of detecting the efficacy of therapeutic drugs in individual breast cancer patients.
Endometrial cancer is the most common invasive malignancy of the reproductive tract of American women. To study the origins of this disease we have reconstructed human endometrium from its constituent endometrial epithelial and stromal cells which preserves cell interactions that determine normal tissue structure and function. Functional endometrial glands form when these cells interface at a basement membrane-like matrix. Epithelial cells in glands have polarized structure, are interconnected by functional gap junctions, express estrogen and progesterone receptors, respond to estrogens and progestins, and produce hormone-dependent products. Many of these functions can be reproduced by substituting media conditioned by endometrial stromal cells in place of the stromal cells, which indicates that paracrine factors mediate many stromal cell functions. When preneoplastic or malignant human endometrial epithelial cells are substituted for normal epithelial cells, glandular structures form that resemble the abnormal structures seen in hyperplasias and cancers of the human endometrium in vivo. To maximize the reproducibility of co-cultures normal stromal and epithelial cells immortalized by constitutively-expressing telomerase reverse transcriptase have been substituted for normal cells with limited life-span and proliferative capacity. Ongoing studies focus on the separate functions of estrogen receptors alpha and beta, and signaling through the IGF-I pathway in endometrial tissue. Since abnormal ratios of epithelial to stromal cell numbers is a diagnostic feature of endometrial cancer and pre-malignant hyperplasia, co-cultures with abnormal ratios of stromal to epithelial cell numbers are being studied to determine how these abnormal cell ratios influence endometrial structure and function in reconstructed endometrium. These studies seek an abnormally expressed gene product in these co-cultures that may serve as a marker for diagnosis of endometrial cancer or pre-malignant hyperplasia.
Glucocorticoids (GC) are a class of steroid hormones that are used to treat several cancers and various other allergic, inflammatory, and autoimmune disorders. However, their use is often limited by the numerous side effects.
Separation of the anti-inflammatory effects of glucocorticoids from some of their side effects could be achieved by dissociated glucocorticoids, which are defined as those compounds that promote Glucocorticoid receptor (GR)-mediated transrepression of AP-1 or NFκB-dependent genes without increasing GR-mediated transcription, likely due to a lack of GR dimerization necessary for binding to the glucocorticoid-response elements (GRE). These dissociated glucocorticoids may serve as a better treatment strategy by potentially eliminating some of the negative side effects associated with transactivation by typical glucocorticoids, such as hyperglycemia, osteoporosis, and HPA axis suppression.
Our laboratory is studying the effects of glucocorticoids and various natural phytochemicals such as resveratrol from grapes, ursolic acid from rosemary, grape seed extract, ellagic acid from raspberries, calcium D-glucarate from broccoli, as well as Compound A and its derivatives from an African shrub, on skin cancer. Our laboratory utilizes mouse skin models such as in vitro model systems of transformed keratinocytes as well as in vivo models of multi-stage skin carcinogenesis to study the effect of different drug combinations on skin cancer initiation, promotion and full tumor development.
In addition, we plan to determine the mechanism(s) of synergistic action of some of the natural source compounds, known to inhibit one or more stages of skin carcinogenesiscancer, i.e., initiation and promotion/progression. Topical treatment with combinations of selected natural source inhibitors results in synergistic effects leading to more efficient prevention of skin cancer.
Tumor progression is a chain of cellular and molecular events that occur gradually during the development of neoplasia. We are studying the role of pro-protein convertases (PCs) such PACE-4 and furin during the early and late stages of tumor progression because these enzymes activate cancer related biomolecules. Over-expression of PCs correlates with aggressive tumor features both in mouse models and in human tumors. This has been demonstrated in our laboratory using tumor cells derived from lung, ovarian and oral malignant tumors. Inhibition of PCs can be obtained by using competitive inhibitors such as chloro-methyl-ketone (CMK). This inhibitor decreases and even abolishes the invasive/malignant phenotype of tumor cells by inhibiting the activation of invasion and metastasis-associated gene products such as MT1-MMP, stromelysin 3, TGF-β and IGFR1. CMK was also used in vivo by topical skin administration. Using this modality we were able to decrease 40% the number of chemically-induced mouse skin cancers as well as diminish 60% the respective tumor volumes.
Another unrelated gene, discovered during our PCs studies is Vsnl-1, a member of the neuronal Ca++ sensor protein family. Vsnl-1, also known as VILIP-1 is able to act as a tumor suppressor in mouse skin squamous carcinoma cells by inhibiting cell proliferation, adhesion and invasion. The effects are a consequence of VILIP-1 modulating cAMP levels as well as inactivating MMP-9 and RhoA activity. Recently, we have found that this gene is silenced in human tumors due to epigenetic changes including promoter hypermethylation and histone modification.
Professor of Pharmacology
Interim Director, Institute for Drug Development
Co-Leader, Experimental and Developmental Therapeutics Program
Cancer Therapy & Research Center
University of Texas Health Science Center at San Antonio
7703 Floyd Curl Drive
San Antonio, TX, 78229
Our research is dedicated to the discovery of more effective therapies for the treatment of cancer. There are several aspects to our work including drug discovery, identification of the mechanisms of drug action, the nature of drug resistance, identifying rational drug combinations and elucidation of the signaling pathways by which antimitotic agents prevent normal cell division and induce cancer cell death.
We conduct a drug discovery program to identify new anticancer agents from natural products and from small molecule chemical libraries. With collaborators all over the world we evaluate extracts and compounds from marine organisms and plants to identify new drug leads. We have an extensive library of plant extracts from Texas plants that have been evaluated for a variety of biological activities including cytotoxic actions against breast and prostate cancer cell lines. The active compounds are being isolated using bioassay-guided fractionation.
After discovering new agents we identify their molecular mechanisms of action. This includes identifying the cellular binding site and how they work to kill cancer cells. We are currently investigating new microtubule and vascular disrupting agents.
Antimitotic drugs are some of the most effective used in cancer therapy, but the signaling pathways that lead from inhibition of mitotic spindle dynamics to initiation of apoptosis is not yet known. We are elucidating these pathways to identify new drug targets that can yield the efficacy of microtubule disrupting drugs without tubulin-related limiting toxicities.
Deaprtment of Pharmacology
Medical Research Division
Edinburg Regional Academic Health Center (E-RAHC)
1214 West Schunior Street
Edinburg, TX 78541
Skin cancer has become a worldwide public health problem, with nearly one million new cases of skin cancers yearly in the United States. It is well known that skin cancers including non-melanomas and melanomas are, most likely, the result of complex interactions between host risk factors (genetic aberrations and immunosuppression) and environmental exposures to ultraviolet irradiation and chemical carcinogens. The non-melanoma skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), account for approximately 80% and 16% of all skin cancers, respectively, whereas malignant melanomas account for only 4% of all skin cancers. BCC and SCC are both derived from the basal layer of the epidermis of the skin. BCC grows slowly and rarely metastasizes, whereas SCC is highly invasive and metastasized frequently. The majority of skin cancer related deaths are due to the metastasis. Through better understanding of molecular mechanisms underlying human skin carcinogenesis, we will be able to develop effective tools, such as specific gene chip and powerful drugs, to develop targeted molecular diagnosis and therapeutics in the clinic.
Much of our knowledge of multistage skin carcinogenesis, defined by initiation, promotion and progression to malignancy, is derived from the studies of mouse models, which have shown aberrations in oncogenes and tumor suppressor genes during neoplastic development. The molecular changes associated with the early stages of skin tumor formation have yet to be determined. The goals of our studies are to identify novel genes involved in early skin neoplastic development using a Tg.AC transgenic mouse model. This model possesses a v-Ha-ras transgene under the regulation of a fetal zeta-globin gene promotor which confers a unique phenotype of inducible skin papillomas with a high rate of progression to highly invasive squamous and spindle cell neoplasms. A body of evidence supports that keratinocyte stem cells (KSCs) residing in the hair follicle bulge region have long been thought to be a major carcinogen target which give rise to the latent neoplastic pool that clonally expand into cutaneous tumors. The candidate KSC population was isolated using fluorescence-activated cell sorting (FACS) from Tg.AC mice hyperplastic skin, which has been treated with a tumor promoter called 12-O-tetradecanoylphorbol-13-acetate (TPA), and their gene expression was analyzed using a mouse cDNA microarray technology. Interestingly, we have identified 11 genes whose expression changed significantly in the population of TPA-treated KSCs. Two up-regulated genes, DSS1 and nm-23/NDPK-B, have been identified and characterized as critical TPA-inducible genes expressed in KSCs, with possible involvement in early skin carcinogenesis.
More recently, our laboratory is also interested in identifying a role of the Deleted in Split hand/Split foot gene 1 (DSS1) in cancers. Our data indicates that DSS1 might play a critical role in regulating protein degradation functions through the ubiquitin-proteasome system (UPS). DSS1 is a gene associated with a human inherited heterogeneous limb developmental disorder called split hand/split foot malformation type 1 (SHFM1). This discovery is important since proteasome, besides being involved in basic biological processes leading to specific protein degradation and specific cellular pathway, has been implicated as playing a role in human disease states. Currently one proteasome specific inhibitor (Bortezomib or Velcade) has been developed by the Millennium pharmaceutical company and is in clinical use to treat patients with relapse multiple myeloma. The DSS1/proteasome interaction may provide an alternative mechanism to specifically inhibit proteasomal activity. It is anticipated that further exploitation of the DSS1/proteasome interaction could lead to the development of a new drug with important clinical potential for cancers, heart diseases, aging related and neurodegenerative disorders.
1. Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation. Sung-Jen Wei, Jason Williams, Hong Dang, Thomas A. Darden, Bryan L. Betz, Margaret M. Humble, Fang-Mei Chang, Carol S. Trempus, Katina Johnson, Ronald E. Cannon, and Raymond W. Tennant. Journal of Molecular Biology, 383: 693-712, 2008.
2. Comprehensive microarray transcriptome profiling of CD34-enriched mouse keratinocyte stem cells. Trempus, CS, Dang H, Humble MM, Wei SJ, Gerdes M, Morris RJ, Bortner CD, Cotsarelis G, and Tennant RW. Journal of Investigative Dermatology, 127: 2904-2907, 2007.
3. Identification of genes and gene ontology processes critical to skin papilloma development in Tg.AC transgenic mice. Hong Dang, Carol S. Trempus, David E. Malarkey, Sung-Jen Wei, Margaret M. Humble, Rebecca J. Morris, and Raymond W. Tennant. Molecular Carcinogenesis, 45: 126-140, 2006.
4. The Ins (1, 3, 4) P 3 5/6-kinase/Ins (3, 4, 5, 6) P 4 1-kinase is not a protein kinase. Qian X, Mitchell J, Wei SJ, Williams J, Petrovich RM, Shears SB. Biochemical Journal, 389: 389-395, 2005.
5. 12-O-tetradecanoylphorbol-13-acetate and UV radiation-induced nucleoside diphosphate protein kinase B mediates neoplastic transformation of epidermal cells. Sung-Jen Wei, Carol S. Trempus, Robin C. Ali, Laura A. Hansen, and Raymond W. Tennant. Journal of Biological Chemistry, 279:5993-6004, 2004.
6. IFN-beta induces caspase-mediated apoptosis by disrupting mitochondria in human advanced stage colon cancer cell lines. Juang SH, Wei SJ, Hung YM, Hsu CY, Yang DM, Liu KJ, Chen WS, Yang WK. Journal of Interferon and Cytokine Research, 24: 231-243, 2004.
7. Colon cancer cells with high invasive potential are susceptible to induction of apoptosis by a selective COX-2 inhibitor. Chen WS, Liu JH, Wei SJ, Liu JM, Hong CY, Yang WK. Cancer Sciences, 94: 253-258, 2003.
8. Identification of Dss1 as a 12-O-tetradecanoylphorbol-13-acetate-responsive gene expressed in keratinocyte progenitor cells, with possible involvement in early skin tumorigenesis. Sung-Jen Wei, Carol S. Trempus, Ronald E. Cannon, Carl D. Botner, and Raymond W. Tennant. Journal of Biological Chemistry, 278: 1758-1768, 2003.
9. Combination gene therapy of cancer: granulocyte-macrophage colony stimulating factor enhances tumor regression induced by herpes simplex virus thymidine kinase/ganciclovir “suicidal” treatment in a mouse tumor model. Wei SJ, Yang WK, Ch’ang LY, Yang DM, Hung YM, Lin WC. Journal of Genetics and Molecular Biology, 13: 194-208, 2002.
10. Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 expression and inhibited by a COX-2-selective inhibitor, etodolac. Chen WS, Wei SJ, Liu JM, Hsiao M, Lin JK, Yang WK. International Journal of Cancer, 91: 894-899, 2001.
11. PIK3CA as an oncogene in cervical cancer. Wei SJ, Ma YY, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY. Oncogene, 19: 2739-2744, 2000.
12. Involvement of Fas (CD95/APO-1) and Fas ligand in apoptosis induced by ganciclovir treatment of tumor cells transduced with herpes simplex virus thymidine kinase. S-J Wei, Y Chao, Y-L Shih, D-M Yang, Y-M Hung, and W K. Yang. Gene Therapy, 6: 420-431, 1999.
13. S- and G2-phase cell cycle arrests and apoptosis induced by ganciclovir in murine melanoma cells transduced with herpes simplex virus thymidine kinase. Sung-Jen Wei, Yee Chao, Yi-Mei Hung, Wen-chang Lin, Den-Mei Yang, Yung-Luen Shih, Lan-Yang Ch’ang, Jacqueline Whang-Peng, and Wen K. Yang. Experimental Cell Research, 241: 66-75, 1998.