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UNIVERSITY OF TEXAS, M.D. ANDERSON CANCER CENTER
Overall Abstract The goal of the M. D. Anderson Genitourinary Cancer SPORE is to facilitate innovative translational research in the prevention, detection, and treatment of urothelial cancer, leading eventually to the elimination of this disease, by assembling a team of dedicated collaborative researchers. We will accomplish this goal by effective integration of laboratory and clinical research, which will produce changes in clinical practice that will improve the outcome of patients with this disease. The complimentary translational projects of this SPORE will expand our understanding of the genesis, progression, and metastasis of bladder cancer and help develop novel therapeutic strategies for the prevention and treatment of this disease. The translational aims of the projects will be fostered through the support of the extensive infrastructure that exists at M. D. Anderson and further facilitated through interactions between the projects and cores of the SPORE. The Administrative and Biostatistics Cores will help design, implement, and manage the clinical trials. The Tissue Resource and Pathology Core with the support by the integrated data management system will provide evidence for unique mechanisms of action. The scientific leadership will adopt a flexible and collaborative research approach that will take advantage of research opportunities as they evolve, by reallocating resources when appropriate and by promoting substantive collaborations with investigators at other institutions and within other SPORES. SPORE PROJECTS The interactions between the SPORE projects follow several well developed themes whose development will be enhanced by the interactions between the SPORE investigators. Early Detection and Chemoprevention
Bladder Preservation
Novel Therapeutic Strategies for Advanced TCC
Project 1 Project 1 will test the hypothesis that genetic and protein alterations serve as signatures of bladder cancer and can be used for the early detection of bladder cancer and as indicators of progression. Novel markers will be defined and tested in a recently activated bladder cancer chemoprevention study. The studies in this project will (1) identify changes in protein expression patterns during the progression of urinary bladder cancer from clinically occult intraurothelial preneoplastic lesions using protein profiling and protein chip array technology, (2) identify changes in gene expression pattern during progression of urinary bladder cancer from clinically occult intraurothelial preneoplastic lesions using DNA microarray technology, (3) evaluate the applicability of altered proteins and genes identified in specific aims 1 and 2 as biomarkers for the early detection of occult urinary bladder cancer and its imminent progression to invasive disease, and (4) evaluate the potential value of upregulated and downregulated proteins and genes identified in specific aims 1 and 2 as surrogate endpoint biomarkers for bladder cancer chemoprevention in patients with superficial bladder cancer participating in a multi-institutional phase III chemoprevention trial. These studies will identify novel surrogate endpoint biomarkers for chemoprevention and indicators of progression in stage. Detecting patients with superficial TCC at high risk for recurrence will identify candidates for novel therapeutic strategies (i.e. gene therapy) detailed in Project 5.
Project 2 Project 2 will evaluate the epidemiological profiles and a panel of genotypic susceptibility markers related to tobacco carcinogen metabolism, DNA repair, disease progression, and nicotine addiction in the risk of recurrence in patients with superficial bladder cancer. These studies will (1) construct comprehensive epidemiologic profiles to test the hypothesis that continued exposure to tobacco and specific dietary patterns are associated with increased risk of recurrent bladder cancer; (2) determine the allele frequencies of genes related to DNA damage (MPO, NAT1, NAT2, GSTM1,GSTT1, and GSTP1) and/or repair (XRCC1, XPD, XRCC3, and p53), which will address the hypothesis that patients with adverse genotypes are at greater risk for developing tumor recurrence because of higher internal dose of tobacco carcinogens through increased activation or decreased detoxification or because of sub-optimal DNA repair capacity; (3) determine the allele frequencies of the cancer invasion/progression related genes E-cadherin, cyclin D1, MMP-1, MMP-9 and VEGF, to determine whether adverse genotypes of these genes are related to a greater risk of tumor recurrence; (4) determine the relationship between baseline and follow-up smoking status and potential genetic markers for nicotine-dependence (DRD2A1 and -B1 and SLC6A3-9). Studying the effect of genetic predisposition factors will provide further insights into the basic biology and therapeutic targets in bladder cancer (Projects 3 and 4). Risk factors may be identified that will identify patients with superficial TCC who are candidates for novel gene therapy strategies (Project 5).
Project 3 Project 3 will test the hypothesis that sensitivity to induction of apoptosis through "death receptors" (Fas, TNF receptor, and TRAIL receptors) participates substantially in IFN-induced tumor regression, and that loss of death receptor sensitivity occurs during tumor progression. In particular, the Project will (1) identify the molecular mechanisms underlying IFN and death receptor resistance in isogenic, orthotopically-selected non-metastatic and metastatic TCC variants, (2) Determine the importance of death receptor pathway(s) for tumor regression of human xenografts after systemic IFN-a therapy, and (3) characterize the effects of IFN therapy on death receptor signaling pathways, in patients with locally advanced bladder cancer treated with neoadjuvant chemotherapy followed by radical cystectomy. In Aims 2 and 3, effects of IFN therapy on death receptors will be compared with effects on markers of tumor invasion/angiogenesis (MMP-9, bFGF, Project 4) that were implicated in tumor regression in previous studies. Project 3 will also work with Project 5 to define the mechanisms of tumor cell killing following p53 gene therapy, focusing on the role of p53-mediated upregulation of death receptors.
Project 4 Project 4 will delineate the cellular and molecular mechanisms by which EGF-R signal transduction regulates the expression of MMP-9 and thereby affects invasion, angiogenesis, and metastasis of bladder cancer. These studies will (1) determine the level and activity of metalloproteinases after EGF-R blockade, (2) determine whether EGF-R signaling causes MMP-9 production, (3) identify the molecular mechanisms underlying the regulation of MMP-9 by EGF-R signaling, (4) evaluate the efficacy of EGF-R directed therapy of bladder cancer and (5) characterize the effects of EGF-R therapy on the level of MMP-9 expression in patients with advanced bladder cancer.
Project 5 Project 5 will utilize preclinical models of intravesical gene therapy to investigate this treatment as a strategy for bladder salvage for patients whose superficial TCC has failed standard intravesical therapy and will also evaluate the feasibility of adenovirus p53 gene therapy with Syn3, a polyamide which enhances adenoviral-mediated gene transfer. These studies will (1) delineate the role of p53 in the pathogenesis of bladder cancer, (2) develop a relevant and reliable model for intravesical p53 gene therapy that can also be used to evaluate different intravesical therapeutic approaches, and (3) characterize the direct (downregulation of VEGF, upregulation of thrombospondin) and bystander (apoptosis, proliferation, angiogenesis) effects of adenovirus- mediated p53 gene therapy of superficial TCC.
CORE A The Administrative Core plays a critical role in enabling the success of the SPORE. Dr. Colin Dinney, the core director, will facilitate the functioning and interactions of all the projects and the cores. Dr. H. Barton Grossman as the Co-Director of the Administrative Core will co-chair the Executive Committee that is composed of all project Co-leaders and Core Directors. The Administrative Coordinator will work closely with Drs. Dinney and Grossman to schedule all meetings with investigators and provide timely and effective communication with investigators both within and outside MDACC. The Administrative Core will play a central role in coordinating the meetings of the Internal and External Advisory Committees. The specific responsibilities of the Administrative Core are: (1) to oversee all SPORE activities; (2) to provide administrative support for the Developmental Research and Career Development Programs; (3) to communicate and consult with the NCI project officer and program staff to assure the accurate and timely submission of all required reports and publications; (4) to coordinate quality assurance including data quality control in conjunction with the Internal Advisory Committee, Biostatistics Core, and Pathology Core; (5) to oversee all fiscal and budgetary issues; (6) to convene and provide administrative support for meetings of the Executive, Internal, and External Advisory Committees; (7) to assure compliance with all general, governmental, NCI, and institutional regulations and requirements; (8) to establish and implement policies for recruitment of women and minorities; (9) to coordinate research with other SPOREs through distribution of materials, electronic communications, progress reports, and participation in joint meetings; and (10) to establish a web site focused on bladder cancer translational research.
CORE B The Biostatistics and Data Management Core for the M. D. Anderson Genitourinary Cancer SPORE will serve multiple needs for the planning and conduct of the SPORE's translational research. This resource will be used for hypothesis refinement, experimental design, data management, quality control, result analysis and informative presentation of results, and will function across all projects of the SPORE. From a biostatistical perspective, design and analysis of laboratory and clinical projects will be performed in collaboration with Dr. Yu Shen, Dr. Dennis Johnston, Dr. Dorota Doherty and Mr. Mark Munsell. From a clinical and informatics perspective, Core services will be provided in collaboration with Dr. Randall Millikan. Data from SPORE clinical trials and laboratory projects that will be entered into a custom database application recently launched within the Center for Genitourinary Oncology. Among other advantages, this computerized database will facilitate continuous monitoring of clinical trial results and will allow for automated data audits. Thus, from inception to reporting, translational experiments will benefit from SPORE resource that will be used to augment existing M. D. Anderson biostatistics resources and to align these considerable resources with SPORE research objectives. The specific aims of the Biostatistics and Data Management Core are:
CORE C The projects of this SPORE will use human bladder cancer specimens for translational research directed toward improving the early detection, prevention, and therapy of human bladder cancer. The Tissue Resource and Pathology Core will provide the investigators at The University of Texas M. D. Anderson Cancer Center as well as other collaborating institutions with high-quality tissue samples from patients with bladder cancers diagnosed, treated, and followed at our institution. Standardized and centralized procedures for tissue procurement, quality control, processing, storage, and distribution of samples to individual investigators will ensure optimal utilization of the samples according to the guidelines established by the Tissue Acquisition and Distribution Committee. The tissue core facility will include tissue procurement, processing, storage, histopathological review, and management of both pathological and clinical databases, as well as distribution of well-characterized specimens to individual project investigators. The computerized database containing both pathological and clinical records of all samples both stored and distributed to individual investigators, including the results of individual SPORE projects, will facilitate the optimal responses of the core to requirements of investigators participating in this SPORE and in the collaborating institutions. The resources of this bank will also be available for future distribution through the NCI - sponsored tissue network. Two pathologists with expertise in urinary bladder cancer and in all aspects of the tissue core operations, including histopathological evaluation and quality control, will codirect the tissue core facility. This centralized comprehensive tissue core facility will provide support for the multidisciplinary and translational research projects outlined in this SPORE proposal. |
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