|
|
||||
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
|
University of California, Los Angeles School of Medicine To view UCLA Prostate SPORE activities, please visit http://www.urology.medsch.ucla.edu/prost_spore-home.htm Overall Abstract The purpose of the UCLA SPORE in Urology is to contribute significantly to progress in the diagnosis, prevention, and treatment of prostate cancer. These goals will be accomplished through multiple and diverse research projects, both in basic science and population-based research, which can be rapidly translated into clinical applications. The organization of the SPORE reflects two major themes to accomplish its goals. Theme I is intended to apply research on gene expression and signaling pathways performed in our investigators' laboratories for the diagnosis, prognosis, and treatment of prostate cancer. Treatment will be directed at the specific molecular pheno types of the individual's tumors. Theme II investigates the relationship of dietary substances to prostate cancer growth. This study capitalizes on an observation by our investigators of a new bioassay for dietary effects on prostate cancer developed in a laboratory and then applied in future clinical trials. The over arching goal of the SPORE is to rapidly translate laboratory discoveries to clinical applications. A major objective of the SPORE is to develop new avenues of prostate cancer research through support of developmental research programs and to identify and cultivate young investigators seeking a career in prostate cancer research. Two major mechanisms will meet these objectives: The Career Development Program and The Developmental Research Program. Through these mechanisms, the field of prostate cancer research will be expanded and new avenues of translational clinical research will be developed. The goals of the SPORE will be supported by its major Cores: Administrative, Pathology, Biostatistics and Informatics, Mouse Models and Imaging. Each of these contributes uniquely to the planned research programs and the development of new research areas, and facilitates the rapid translation of basic research to clinical application. Project 1: The goal of this proposal is to examine the role of prostate stem cell antigen (PSCA) in the prognosis and therapy of prostate cancer. PSCA is a cell surface antigen, which is overexpressed in ~40% of primary prostate cancers and in as many as 100% of metastatic ones. PSCA is also overexpressed in a majority of transitional cell and pancreatic carcinomas. Overexpression of PSCA in prostate cancer correlates with adverse clinicopathologic features, including advanced tumor stage, grade and MYC amplification. A monoclonal antibody directed against PSCA inhibits tumorigenesis, slows tumor growth, prolongs survival and prevents metastasis in a preclinical zenograft model. These data suggest that PSCA may have utility as a prognostic marker and/or therapeutic target in prostate cancer. The overall goals of this project are to determine the prognostic utility of PSCA in patients with clinically localized prostate cancer and to understand and enhance the therapeutic utility of monoclonal antibodies directed against this target. Finally, we intend to translate the knowledge gained from preclinical evaluation of PSCA as a prognostic and therapeutic target into a pilot human clinical trial in which we ask whether PSCA monoclonal antibodies are safe and can localize to PSCA-overexpressing tumors in high-risk individuals undergoing radical prostatectomy. These studies are expected to lead to larger clinical trials examining the therapeutic efficacy of PSCA antibodies. The study has four aims:
Project 2: This project is based on research done in the investigator's laboratory demonstrating that prostate cancers lacking PTEN show a 400-fold increased sensitivity to drugs that inhibit mTOR, an enzyme downstream of Akt. Combining the mTOR inhibitor CCI-779 (Wyeth-Ayerst) with androgen ablation leads to decreased tumor size and apoptosis in animal models. The study will attempt to identify PTEN-null patients by prostate needle biopsy and selectively treat this population using an mTOR inhibitor. It is hypothesized that androgen activates an mTOR-independent survival signal protecting cells from cell death. This study will perform biochemical and microarray studies on tumor cells of defined PTEN status in the presence or absence of CCI-779 or androgen to define the nature of this survival pathway. This will provide insight into the use of mTOR inhibitors in androgen-independent prostate cancer. The project therefore adds to the information on prognosis through molecular marker status and develops a method for selectively treating patients with loss of the PTEN suppressor gene. The study has three aims:
Project 3: This study represents another translational research project targeting a signal transduction pathway important in prostate cancer. The principal investigator and associates have previously reported the importance of IGF and IGF-binding proteins in prostate cancer. They found that IGFBP-3 interacts with nuclear receptor RXR and these genes are potent regulators of prostate cancer growth. Ligands for these and related nuclear receptors may amplify growth suppression and apoptosis of prostate cancer, acting as a regulator of nuclear receptor transcription. These interactions are potential targets for therapy and could augment existing hormonal therapy and chemotherapy strategies. The project has four specific aims:
Because IGFBP3 protein and RXR agonists and antagonists are currently in clinical development for other indications, these results can be rapidly translated to a clinical trial. Furthermore, information regarding the prognostic implications of these receptors on tumor grade, stage and recurrence will be obtained, since the existing tissue samples and microarrays all have follow-up clinical data. This information may provide another molecular marker of prognosis.
Project 4: Work in the investigators' laboratory supports a role for the Her-kinase axis in development of androgen independence, and suggests that various members of the axis can be individually targeted with differential results. This data forms a valuable background for the study of development of androgen independence and also potential translation to the treatment of patients to prevent emergence of androgen independence by co-treatment with androgen suppression. The final aim of translation will be based on study of treatments of various components in xenograft models and the physiologic role of various members of the axis. Since antibodies and other soluble inhibitor of targeted against Her2/neu and EGFR are currently in development for other indications, we anticipate translation to prostate cancer in the near future. Specific Aims:
Project 5: International incidence patterns and migration studies demonstrate that the environment plays an important role in determining the relatively high incidence of prostate cancer in the United States. Abundant epidemioligic data suggest that this environmental influence is mediated in whole or in large part through dietary factors. The nature of those dietary factors has not been conclusively established, although dietary fat appears to be involved. Moreover, the mechanisms through which dietary fat alters the biology of prostatic epithelium are incompletely understood thus complicating the identification of feasible intermediate markers of effective dietary intervention. The primary objective underlying studies of dietary modulation of the development of prostate cancer is to provide a scientifically sound foundation for large intervention studies aimed at preventing the disease, including identification and validation of intermediate markers of successful intervention which are feasible for application in intervention trials. The goal of this project is to better understand the mechanism(s) through which the quantity and composition of dietary fat may alter the risk of prostate cancer and develop a basis for both a feasible and effective diet and valid intermediate markers to be applied in future large intervention studies aimed at the prevention of prostate cancer. To pursue that objective, we have three specific aims: Specific Aims:
Administrative Core: The Administrative Core is responsible for overseeing the daily function of the SPORE programs. It provides administrative support, including support for grants and financial management; scheduling of meetings and seminars; coordination of activities between the SPORE, the Cancer Center, and other UCLA academic and administrative bodies; and assistance with manuscript preparation. It has ultimate responsibility for management of details of the budget and appropriate filing of budgetary information. It will file progress reports and communicate with NCI and outside agencies as necessary. It will assure completion of necessary documents with regulatory agencies. The Core will schedule meetings of all of the organizational committees and keep and distribute records of the proceedings and conclusions of these committees. The scheduling, dissemination of infon-nation, and organization of the annual UCLA Prostate Cancer SPORE Symposium, including the participation of the External Advisory Board, is the responsibility of the Administrative Core. The Core will be responsible for oversight of all the established policies for recruitment of women and minorities. It will also create and maintain the SPORE web page. Pathology Core: The Pathology Core will supply pathology support for the scientific community engaged in prostate research at UCLA. This will be accomplished through the following specific aims:
Imaging Core The Imaging Core will leverage the significant resources existing at UCLA focused on molecular imaging technologies in order to provide SPORE investigators with state-of-the-art imaging tools and assays for pre-clinical and clinical prostate cancer studies. The core includes the technologies of micro positron emission tomography (microPET), micro computed tomography (microCT), digital whole-body autoradiography (DWBA), and clinical PET. These tools when properly utilized should allow for the study of pre-clinical models of prostate cancer as well as human imaging of prostate cancer. Utilizing reporter gene technology developed at UCLA, it will be possible to mark prostate cells ex-vivo and track them in-vivo. Additionally, by utilizing reporter genes it will be possible to monitor gene therapy non-invasively. MicroCT will allow anatomical localization of metastases in small mouse models as well as longitudinal monitoring of these metastases. Several other tracers should also allow the study of prostate cancer in-vivo. The Imaging Core will help SPORE investigators to design, implement, archive, and analyze their imaging data. The Core will be jointly directed by Dr. Sam Gambhir and Mark Seltzer, both of whom have many years of experience in functional imaging. The imaging technologies all exist within the UCLA Medical Center for Health Sciences, and image review will be possible both at Imaging Core and remotely at any investigators desktop computer using imaging software developed at UCLA. The imaging Core will be dedicated to providing a user-friendly, easy access, and cutting-edge facility for advancing research in prostate cancer.
The Animal Models Core facility will support and centralize certain aspects of the work in each project proposed. It is our belief that prostate cancer biology is best studied in animal model systems that allow experimental monitoring of progression events such as metastasis and androgen-independent progression. This facility brings together expertise in mouse genetics and human tumor xenografs that will allow basic molecular biological questions to be addressed in state-of-the art model systems with direct relevance to the clinical situation. It also offers an opportunity for translational research questions to be addressed immediately in relevant pre-clinical models. The Core consists of five distinct components that will allow biologically based hypotheses to be tested in human prostate cancer xenografts. The Specific Aims of this Core are as follows:
Biostatistics Core The Biostatistics Core will meet demonstrated needs of the several project teams in SPORE with regard to biostatistical design and analysis, microarray gene expression analysis, data management, and computer support. The statistical and data management team assembled by the Core to carryout these activities has the required expertise and experience. List of investigators Jean B. deKernion, MD David Agus, M.D. William Aronson, M.D. Pinchas (Hassy) Cohen, M.D. Sanvij Gambhir, M.D., PhD. David Heber, M.D., Ph.D., F.A.C.P., F.A.C.N. Philip Koeffler, M.D. Diane Prager, M.D. Robert Reiter, M.D. Jonathan Said, M.D. Charles Sawyers, M.D. Marc Seltzer, M.D. Peter Tontonoz, M.D., PhD. Owen Witte, M.D. Hong Wu, M.D. PhD. Major accomplishments and reports of your overall SPORE program Project 2 - Targeted Therapy of PTEN Null Prostate Cancer We have optimized conditions for immunohistochemical detection of PTEN and phosphorylated Akt in paraffin sections from radical prostatectomy samples. We are currently applying these techniques to needle biopsies. Also, we are drafting a clinical protocol to treat men newly diagnosed with high risk prostate cancer with an mTOR inhibitor prior to radical prostatectomy. We expect this trial to begin within the next 4-6 months. Project 3 - Interactions between IGFBPs and Nuclear Receptors in Prostate Cancer Over the last decade, we have shown that the IGF axis in general and IGFBP-3 in particular, are important determinants of prostate cancer cell growth and death and represent epidemiological risk factors for this disease. Concurrently, we have characterized the role of nuclear retinoid-related receptors in cell function including neoplasia development. These two areas of research converged recently when we discovered that RXR serves as a nuclear receptor for IGFBP-3 and that ligands for RXR may co-operate with IGFBP-3 in inducing prostate cancer cell death. We are currently investigating the role of IGFBP-3 and of RXR agonists in the regulation of androgen-dependent and androgen-independent prostate cancer. Preliminary data indicate that IGFBP-3 and RXR ligands synergize to regulate expression of prostate target genes and to induce cell death. We have recently shown that in SCID mice, combination therapy of RXR ligands and IGFBP-3 result in suppression of prostate cancer xenograft growth. Treatment of CaP tumor-bearing SCID mice, and in the future, of humans with advanced prostate cancer, with combinations of RXR ligands and IGFBP-3 may result in synergistic effects on tumor suppression with reduced toxicity. Therefore, our objectives for this project over the next five years are: 1) To explore IGFBP-3 and retinoid receptor pathways as targets for CaP therapy using in vivo animal models. 2) To understand the molecular basis of the interaction between the RXR and IGFBP-3 signaling pathways. 3) To develop a clinical trial in men with high risk localized prostate cancer using RXR ligands and IGFBP-3. If successful, our findings may validate these targets for clinical development for use in men with CaP. These therapies may be particularly useful in men with androgen independent prostate cancer, where restoration of the suppressed IGFBP-3 - RXR - apoptosis pathway could prove important. Project 4 - The Role of the Her-Kinase Axis in Emergence of Androgen Independence in Human Prostate Cancer Aim 1 - Develop and use xenograft models of human prostate cancer in vivo to study therapy directed at the Her-kinase axis. We have established several xenograft models of andrigen dependent and independent prostate cancer in the laboratory and completed preliminary preclinical work with therapeutics that target the Her-kinase axis. These are the humanized monoclonal antibody Herceptin (targets the extracellular domain of Her-2, and causes an aberrant signaling event in prostate cancer cells), ZD1839 (targets the EGF receptor kinase), and 2C4 (a humanized monoclonal antibody which targets the extracellular domain of Her-2, and inhibits the heterodimerization of Her-2 with the EGF receptor and Her-3). In addition, we have developed two androgen independent models which have acquired resistance to Zd1839. Aim 2 - Investigate the physiologic role of members of the Her-kinase axis using using therapy targeted at the individual members of the axis. Initial data demonstrate varibale clinical activity with the Her-kinase directed therapies. The 2C4 monoclonal antibody has generated the most clinical activity to date in a number of xenograft models. In addition, 2C4 has shown activity in ZD1839-resistant androgen independent prostate tumors. Aim 3 -Develop clinical trials of therapy to prevent emergence of androgen-independence. A phase 1 clinical trial with 2C4 was completed by our group outside of the SPORE mechanism in preparation for the clinical trials described in the SPORE application. Project 5 - The Role of Quantity and Composition of Dietary Fat in the Prevention of Prostate Cancer We have made significant progress in regards to Aim 1. We are conducting a palatability study with SCID mice to make sure that they will take in adequate caloric intake of the low-fat omega-1 and high-fat omega-3 diets. We have demonstrated that they do have good caloric intake, and that the mice continue to gain weight on the diets. We are now growing human LAPC-4 tumors in SCID mice to be used for the upcoming feeding experiment. We have also made good progress with Aim 2. We anticipate starting the clinical trial in the early part of 2003. We are presently conducting a feeding study in men on watchful waiting for prostate cancer and have demonstrated that our patients are willing to be randomized, and are willing to make visits to the UCLA CRC to pickup their food, and are compliant with the diets made in the CRC. This preliminary study will also give important data on the use of the bioassay for evaluating the mitogenic effects of nutrition interventions. |
 |
|||
|
|