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Organization of the Organ Systems Branch Current SPORE Programs Information for the Public PART Program Information for Applicants IntraSPORE Communications
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THE UNIVERSITY OF ALABAMA AT BIRMINGHAM
OVERALL ABSTRACT This SPORE in Ovarian Cancer will build on the programs and resources of the Comprehensive Cancer Center of The University of Alabama at Birmingham in the areas of Gene Therapy, Targeted Immunotherapy and Chemoprevention, all areas with nationally recognized research programs. The basic and clinical scientists in each of these areas have a well established translational research program that will be enhanced by this SPORE. The Gene Therapy Program will focus on the development of a new generation of vector systems capable of efficient and tumor cell-specific transduction and the application of novel noninvasive gene transfer imaging techniques; the Targeted Immunotherapy Program will focus on the development of novel genetically engineered monoclonal antibodies chelated to novel, more appropriate isotopes; and the Chemoprevention Program will develop appropriate animal models (avian and rodent), identify important biological markers for understanding the pathogenesis of this disease, and conduct secondary and primary chemoprevention studies in humans. The Programs will be supported by an Administrative/Biostatistical Core, a Tissue Resource and Immunopathology Core, a Vector Production Core, and an "In Vivo" Imaging Core. The SPORE will utilize a Career Development Program supplemented by a significant institutional commitment to attract junior and mid-level scientists with an interest in ovarian cancer research. In addition, a significant institutional commitment will also be added to the Developmental Research Program to enhance the ability of this program to remain on the "cutting edge" of research in the above areas. This institution and its Comprehensive Cancer Center are poised to build on the excellent translational research already established in this disease entity.
Research Program 1 Defining new therapeutic paradigms for patients with ovarian cancer is of critical importance, given that this is a uniformly fatal disease for the vast majority of women afflicted by it. Many human cancers, including ovarian cancer, are now recognized to be the result of accumulated genetic events, which culminate in the transformed malignant phenotype. Therefore, it is rationale to investigate the utility of various gene therapy strategies as a means to improve clinical outcome. Of note, distinct gene therapeutic initiatives have been rapidly translated into clinical trials for ovarian cancer, several of which have been conducted by the investigators of this proposal. The implementation of these trials, however, has revealed limitations that relate primarily to the inadequacy of current vector systems to achieve efficient and specific tumor cell targeting and to the logistics and morbidity associated with invasive assessment of in vivo gene transfer. It is our hypothesis that the therapeutic utility of cancer gene therapy approaches for ovarian cancer will be substantially improved by the employment of a new generation of vector systems capable of efficient and tumor cell-specific transduction and by the application of novel noninvasive gene transfer imaging techniques. To address this hypothesis, we propose: 1) To develop and validate a genetically modified adenovirus that augments tumor targeting and achieves an enhanced anti-tumor effect in the context of ovarian cancer, 2) To develop and validate, in the context of ovarian cancer, a gene transfer imaging methodology based on radionuclide imaging of genetically transferred receptors, 3) To prepare a Good Manufacturing Practice (GMP) adenoviral vector for a human clinical gene therapy trial in the context of ovary cancer that is genetically modified to augment tumor tropism and that encodes both a therapeutic gene and a receptor for gene transfer imaging, and 4) To conduct a Phase I/II trial in the context of ovary cancer utilizing a GMP adenoviral vector that is genetically modified to augment tumor tropism and that encodes both a therapeutic gene and a receptor for gene transfer imaging. Success in these endeavors will overcome the obstacles that are currently preventing gene therapy from reaching its potential as a clinically relevant option for ovarian cancer. Pursuant to this SPORE application, completion of these objectives will allow for establishment of gene therapy as a novel and effective treatment paradigm for ovarian cancer.
Research Program 2 The purpose of this project is to optimize effective therapy for patients with peritoneal involvement of ovarian cancer using regional radioimmunotherapy. These studies will utilize a newly designed recombinant monoclonal antibody with a deleted CH2 region (HuCC49)CH2) radiolabeled with 188Re and administered by the intraperitoneal route (IP). Our prior phase I studies with 177Lu-CC49 have shown evidence of antitumor effects (objective responses and prolonged disease-free survival) but the trials were limited by the immunogenicity of the murine monoclonal antibody and dose-limiting marrow suppression. The newly designed molecule should have little or no immunogenicity allowing repeated courses of therapy. Also, animal studies have confirmed the predicted improved tumor penetration and short plasma half-life due to the small size of the antibody construct. The construct will be radiolabeled with 188Re which has shown superior results in animal studie3s and is predicted to reduce marrow radiation in analysis of clinical data. This new radiolabeled product 188 Re-HuCC49)CH2 will be possible due to availability of 188 Re from a generator and a stable trisuccin chelator synthesized and tested by our team. Our initial phase I trial will establish the maximum tolerated dose (MTD) of Re-HuCC49)CH2 administered by IP route and include studies of immune response, imaging, dosimetry, pharmacokinetics, tumor response, and tumor markers. Dr. Donald Buchsbaum will concurrently analyze repeat dose schedules and integration of radiosensitizing agents in animal models. The animal model results will be utilized in the details of designing two subsequent clinical trials aimed to further improve the tumor to normal tissue ratios of IP radioimmunotherapy with Re-HuCC49)CH2. These studies should provide effective new therapy for ovarian cancer patients who have relapsed after standard therapy or possibly as an adjuvant strategy in first-line therapy.
Research Program 3
Ovarian carcinoma represents the fourth leading cause of cancer death in the female population and is the most fatal gynecologic malignancy. Secondary to its presentation as advanced disease in the majority of cases and its low prevalence, strategies that center on therapeutics or screening are unlikely to impact the overall death rate. Therefore, when considering strategies to decrease the deaths attributable to ovarian carcinoma, prevention of disease represents the most rational approach. This approach to intervention is consistent with statements from the National Cancer Institute which have identified a need for development of primary and secondary chemoprevention strategies in ovarian carcinoma.
Administrative and Biostatistical Core The Administrative/Biostatistical Core supports the activities that are essential to the smooth functioning and interaction of the SPORE in Ovarian Cancer. This core functions to provide overall coordination of the three Research Programs and the Scientific Cores. In addition, this core is responsible for administration of the Career Development Program and the Developmental Research Program. The Internal and External Advisory Committees are coordinated through this core and, along with the Executive Committee of the SPORE are responsible for scientific planning and evaluation. This core is also responsible for the statistical planning, analysis and data management for each of the Research Programs and Developmental Projects. This core will also provide for maintenance and reconciliation of budgets and accounts, assist in acquisition of supplies and handle personnel management.
Tissue Resources and Immunopathology Core UAB has extensive experience in collecting, processing, storing, and supplying a wide range of human tissues to support research. Fresh, frozen, and paraffin preparations of tissues can be supplied as well as unstained tissue slides and other histology services. We will expand our current tissue resource services as part of the Ovarian SPORE to: 1) establish a bank of well characterized ovarian tumor specimens and matching normal specimens from patients who have given specific informed consent for their tissues to be used in genetic and other types of research so tissue can be supplied to investigators along with clinical data including outcome; 2) offer microdissected specimens for investigators wishing to use sensitive PCR based technologies on pure samples of ovarian neoplasia or normal ovarian tissue. This Core also will offer investigators access to methods of morphological analysis that are too complex for individual projects to support efficiently. Primarily the core will provide light microscopic and immunocytochemical interpretation of animal and human tissues and cytologic materials and will offer methods to detect gene products within tranfected cells and adjacent tissues. Investigators will have access to sophisticated techniques usually available only for human pathology, including tissue microdissection, immunoelectron microscopy, special histology services, in situ hybridization, and flow cytometry. Advantages are that the core will enable unified purchase, characterization and utilization of a shared set of reagents. Centrally performed procedures will free investigators from duplication of basic work, allowing more productive work with the available resources and acceleration of experimental timetables.
"In Vivo" Imaging Core
The In Vivo Imaging Core will support all 3 programs in the SPORE by providing a unique, non-invasive evaluation of (1) receptors important in the growth and spread of ovarian cancer, (2) tumor targeting via adenoviral vectors, and (3) apoptosis pathways in conjunction with therapy evaluation. In addition, the Core will conduct studies of organ function. The infrastructure for the core already exists, having been established by competitive funding through an internal mechanism. Radiotracers already developed over the past 2 years will be utilized for the proposed imaging evaluations. The majority of the imaging experiments will be conducted in animal models. However, it is anticipated that following validation of the reporter system of imaging gene transfer in the animal model, this capability will be translated to the Phase I clinical testing. The Core will support this part of the Phase I testing, which will be possible since the radiopharmaceutical is an approved human agent.
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