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Memorial Sloan-Kettering Cancer Center
Overall Abstract MSKCC has made a major commitment to translational research in prostate cancer, recruited new faculty, constructed new facilities, and provided substantial pilot funding for translational research projects. MSKCC cares for a large population of patients (>1400/yr) with all stages of prostate cancer. While ethnic minorities are underrepresented, the large prostate cancer population assures sufficient minority patients eligible for SPORE investigations. Our strategy is to develop risk-adjusted therapies targeted to the characteristics of individual cancers. Translational research objectives are to: 1) develop predictive models of the natural history of localized cancer to improve patient decision-making and treatment selection, 2) determine critical molecular and genetic mechanisms of progression and metastasis; 3) develop risk-adjusted therapy for progression after local treatment using immunologic (PSMA-targeted vaccines) and other biologic agents; and 4) develop new mechanism-based therapy for advanced cancers. These goals will be addressed through 4 research projects (Population-based study of natural history, Molecular carcinogenesis, DNA vaccines, and Experimental therapeutics) supported by 6 cores (Pathology and tissue bank, Informatics, Animal models, Animal imaging, DNA arrays, and Administration), and Developmental Research (pilot projects) and Career Development components. The applied and basic scientists are organized into 3 multidisciplinary Translational Working Groups: Clinical Outcomes and Prognosis, Molecular Mechanisms and Markers, and Experimental Therapeutics. This SPORE addresses key research priorities of the NCI's Prostate Cancer Progress Review Group: new animal models, molecular mechanisms of carcinogenesis and invasion, validation of prognostic markers, and new targets for therapy. An MSKCC SPORE can provide NCI with a large patient population and frozen tissue bank, a history of active participation in clinical trials, a multidisciplinary team of clinicians and scientists successfully collaborating, an expanding basic research program, and advanced experimental therapeutics. The ultimate goal is to bring basic discoveries regarding mechanisms of prostate cancer development and progression to the clinic. With SPORE support, MSKCC can expand its approaches to the prevention, diagnosis, and treatment of prostate cancer to eventually reduce morbidity and mortality from this disease.
Project 1 Our objective is to further characterize the natural history of clinically localized prostate cancer managed conservatively. From standard prognostic factors, we will construct prognostic nomograms to compute for individual patients the probabilities of clinical progression (symptomatic local or distant) and of cancer-related death at a given time after diagnosis. Information from these "conservative management" nomograms and our prior aggressive therapy nomograms will be used to construct more robust decision-analysis models for men with clinically localized prostate cancer. Through a prospective clincial trial, we will test the hypothesis that men who choose treatment recommended by this model will be less likely to regret their decision. We will also use novel gene expression methods to identify and validate prognostically useful molecular markers that have the potential to increase the predictive accuracy of our nomograms. Our Specific Aims are: 1) To further define the natural history of clinically localized prostate cancer by identifying in an epidemiologic, population-based study in the United Kingdom a consecutive cohort of 2000 men diagnosed with prostate cancer in the PSA era but managed conservatively. In collaboration with the Imperial Cancer Research Fund, we will identify from regional tumor registries 2000 men diagnosed between 1990 and 1996 who had no treatment for at least 6 months after diagnosis and are eligible for a minimum follow-up of 5 years (maximum 10-16 years by completion of the SPORE in 2006). We will identify a second cohort of 2000 men treated with hormonal therapy alone within 6 months of diagnosis. Diagnostic biopsy specimens (mostly TURP) and clinical information will be retrieved and uniformly graded and staged with centralized review and the data computerized for further analyses. 2) To derive a nomogram that predicts the probability of progression (to symptomatic local or distant metastases), based on clinical prognostic factors (clinical stage, Gleason grade, and PSA level) for those cohorts of men managed conservatively (untreated or with hormonal therapy alone). 3) To construct a decision-analysis model which incorporates information from the conservative management nomograms and the aggressive-therapy nomograms previously developed and determine in a prospective clinical trial whether patients who chose treatment identified by the model as most beneficial (in quality-adjusted life years) are less likely to regret their choice. 4) To identify and validate expressed genes in prostate cancer that correlate with outcome and evaluate their ability to complement nomogram prediction of progression for clinically localized disease.
Project 2 Morphologically similar prostate tumors presenting in any assigned stage may behave in different fashions, hampering our ability to predict clinical behavior. Thus, it is critical to characterize and validate biological markers of clinical predictive significance. In addition, clinical advances on prostate cancer also depend on the development of animal models paralleling the human disease. The transgenic models we have engineered and those proposed, targeting prostate-specific functional inactivation of Pten, Rb or p53, will allow us to mechanistically test the working hypothesize that their inactivation plays a critical role in prostate cancer pathogenesis. Furthermore, work from our laboratory and others disclosed the clinical implications of detecting alterations of these genes in human prostate cancer. Due to their critical roles in proliferative and apoptotic programs, we are systematically analyzing these genes and their regulatory mechanisms in primary prostate tumors. The aims are: 1) To determine whether inactivation of Pten, Rb and p53 are required for prostate tumor development and progression by: 1A. Defining, in knock-out mice, the role of Pten in prostate cancer initiation, promotion and progression; 1B. Dissecting in the Pten+/- mouse the multistep process towards prostate cancer pathogenesis; 1C. Generating a mouse model of prostate cancer by conditional, prostate specific, Pten inactivation; 1D. identifying target genes and genetic events relevant for prostate tumorigenesis in genetically defined mouse models of prostate cancer. 2) To determine the predictive significance of PTEN, RB and p53 in human prostatic carcinoma by systematically characterizing mutations and aberrant patterns of expression affecting: 2A. PTEN; 2B. RB pathway (including cyclin D1-Cdk4-p16, as well as cyclin E-Cdk2-p27, and E2F proteins); 2C. p53 pathway (p21/WAF1, Mdm2 and p14ARF). In the context of this project, hypothesis-generating clinical studies will provide the statistical construct to determine whether an association exists between clinical endpoints and molecular events. Identification of such alterations may serve as predictive molecular markers to stratify patients into specific protocols. 3) To establish a protocol for marker development and clinical implementation through a strategy based on trial methodology and guided by statistical rigor. Programmatic interactions include those with RP1, taking advantage of the tumor banks and clinical research databases for correlative studies; RP4, providing mechanistic insights for biological therapeutic targets; and most of the cores (ie, CF3 Animal Models, CF5 DNA Array, CF1 Pathology, CF2 Informatics.) The main goal of this project is to translate basic and clinical research findings into clinical studies.
Project 3 Self antigens on cancers are commonly recognized by the immune system. These antigens are most frequently differentiation antigens, expressed by cancer cells and their normal cell counterparts. It has recently become clear that recognition of these antigens is relevant to immunity to cancer. Prostate-specific membrane antigen (PSMA) is a prostate differentiation antigen. It is a type II glycoprotein with restricted tissue distribution that can be recognized by autoantibodies and T cells of patients with prostate carcinoma. These observations support PSMA as a candidate target for vaccination. It is typically difficult to immunize against self glycoproteins, including differentiation antigens such as PSMA. However we have shown that tolerance against self can be broken by immunization with altered forms of antigen. We will investigate approaches for DNA immunization using self and altered forms of PSMA. Our goals are to: 1. Develop strategies using DNA immunization to induce immunity against PSMA, including immunization with syngeneic DNA, homologous xenogeneic DNA and mutated DNA libraries developed from syngeneic PSMA gene. 2. Investigate whether expansion of dendritic cells in tissue sites (GM-CSF) can enhance DNA immunization. 3. Assess both antibody and T cell responses to mouse PSMA in mouse models. 4. Develop mouse models for transplantable syngeneic tumors expressing mouse PSMA and models expressing mouse PSMA in endogenous prostate tumors. 5. Measure tumor immunity and tumor rejection in prevention and established tumor models. 6. Evaluate immunogenicity of DNA immunization with xenogeneic and syngeneic PSMA in a clinical trial in patients with prostate carcinoma.
Project 4 This program is broadly directed toward establishing a paradigm within the SPORE program for the development of targeted, mechanism-based, molecular therapeutics for the treatment of prostate cancer. The specific goal of the proposal is the basic study and preclinical and clinical development of the ansamycin antibiotics as drugs which inhibit pathways important for the growth of advanced disease. The program involves chemists, cell and molecular biologist, pathologists and clinicians at the Center. Ansamycins are a novel class of antitumor antibiotics that bind hsp90 and cause the degradation of several key signaling molecules, including androgen receptor and HER2, and the inactivation of the Akt kinase signaling pathway. These properties suggest that ansamycins may be useful in the treatment of advanced prostate cancer. We have shown that ansamycins lead to the Rb-dependent G1 arrest of cancer cells, followed by apoptosis and that they have antitumor activity in animal models of prostate cancer at doses that are tolerable to the host. These findings led to an NCI-initiated phase I trial of 17-allylaminogeldanamycin (17-AAG) in which we are taking part. This grant proposes a phase II trial of 17-AAG based on our preclinical and phase I data, describes further in vitro and animal studies on the mechanism of action of 17-AAG alone and in combination with other agents, and phase I/II trials based on these preclinical studies. This work is the result of close, bidirectional interactions between the basic and clinical scientists at MSKCC which will serve as a model for the development of other modalities.
Core 1 The proper diagnosis, management, and overall control of prostate cancer are major challenges in clinical oncology. Response to therapy and survival are in great part dependent on morphological and clinical parameters. If these parameters are to be of any validity, they must be applied in a standardized and reproducible fashion. Nevertheless, we know that patients with similar clinical and pathologic features may respond differently to the same therapeutic modality and have radically diverse outcomes. Recent advances in molecular biology have increased our insight into the biology of prostate cancer and the molecular events, which may be associated with aggressive behavior, resistance to therapy, and poor survival. In addition, we now have novel therapeutic modalities that target tumor-specific molecules. Thus, one of our main goals is the identification of markers associated with disease progression within states, and across states, with an aim of improving outcomes for more patients. Nevertheless, alterations of biological markers of potential clinical significance await validation studies, which in turn requires the selection of well-characterized tumor material representing different points in the natural history of the disease, and the associated clinical information. The activities of this Core support four critical functions: 1) pathologic support for the conduct of retrospective and prospective clinical studies, 2) the characterization of cohorts of patients with respect to specific markers by means of immunohistochemistry and in situ hybridization, 3) acquisition and distribution of tumor tissue to be used by our investigators through our Tumor Procurement Service, and 4) aid in the construction of c-DNA and tissue arrays.
Core 2 The purpose of the Informatics Core Facility in the MSKCC SPORE in Prostate Cancer is to provide information technology and data modeling that will facilitate the translation of scientific discovery to clinical care. Although this process may occur in a variety of mechanisms, certain activities dominate. Because markers of disease may be discovered, this Core Facility would be needed in helping to define their clinical role. Groups of markers may need optimal assembly for the purposes of clinical prediction. Complex clinical decisions may require formal analysis. Large amounts of data may need thoughtful simplification and processing.. Limited resources may need rational allocation. Each of these activities may utilize the Informatics Core Facility; it is , there fore, important that this Facility provides a quality program of innovative collaborations supporting basic and clinical research. Moreover, members of the Core Facility will function as colleagues with SPORE scientists and clinicians throughout the research process. Specific Aims:
Core 3 The field of cancer modeling in the mouse has come a long way in the last two decades, and the pace of change is accelerating. With the recent commitments from the NIH and NCI to improve genomic tools for the mouse and to accelerate the sequencing of the mouse genome, the timing is right to scale-up cancer genetics in the mouse: with time, all major human tumor types should have one or more associated mouse models that accurately reflect the genetic and histopathological progression of the disease. The development of these mouse models requires the expert and efficient generation and analysis of genetically engineered mouse strains, as well as the generation and analysis of reagents derived from these animals. The general aim of the Core Facility CF3. Di Cristofano: Animal Models is to provide a facility in which this complex set of tasks will be optimized for 1) expert design and production; 2) efficiency; 3) cost reduction, with the following specific aims: 1) The Core Facility will generate and make available to SPORE investigators transgenic and knockout/knockin mouse strains of common interest; 2) it will assist individual components of the SPORE in the design and generation of targeting constructs as well as in the generation and characterization of the derived mouse strains; 3) it will serve as a centralized repository and breeding service for mouse strains of general use among SPORE investigators; 4) it will provide SPORE laboratories with dissected tissues, DNA, RNA and proteins from the various mouse mutants utilized by the investigators.
Core 4 Imaging studies offer the potential for noninvasive detection of key molecules that are important in cancer biology and critical to the advancement of medicine. The goal of the Core Facility CF4. Koutcher: Animal Imaging is to provide imaging research support to SPORE investigators who are involved in defining prostate cancer signature, often at the molecular level. Imaging studies may serve as a noninvasive phenotypic correlate of the molecular changes. The primary responsibility of CF4. Koutcher: Animal Imaging will be to provide PET, and magnetic resonance (MR) imaging/spectroscopy capability at the highest spatial resolution possible to monitor the effect of molecular changes. We will upgrade our MR equipment with stronger gradients (28 G/cm insert has just been delivered; 100 G/cm insert for higher spatial resolution is proposed); NIH funding has been obtained for a new spectrometer console to replace our antiquated system. A new vertical bore 500 MHz system with dedicated microscopy insert is being planned and will provide higher signal to noise and further improvements in image resolution. A new MicroPet has been ordered and delivery is expected shortly. This instrument will have isotropic 2-mm resolution (voxel = 8mm3). The MicroPET will be used to study 11C-choline, 11C-methionine, 18F-fluorodeoxyglucose, 18F-fluorodihydrotestosterone and 124I-iododeoxyuridine and the imaging studies will be correlated with pathologic data. Quantitative autoradiography equipment has also been upgraded and will complement the PET and MR. The upgrade to the QAR system will allow simultaneous imaging of three nuclei within the same sample. Further support, e.g., physiological monitoring, image correlation, will be necessary for the successful implementation of this project and will need to be developed. As a core facility, a main goal will be providing state-of-the-art imaging capability. This will include in vivo spatial resolution of between 50 to 100: in plane and 0.25-0.5 mm slice thickness for MR, < 8mm3 voxels for the MicroPET and 3 nuclide imaging in QAR. To increase MR spatial resolution further, more sensitive radiofrequency coils will be designed. Improvements in image processing and analysis to enhance the accuracy of multi-modality imaging will also be necessary. The lack of anatomical detail provided by PET necessitates the development of good software for correlating PET, MRI, and QAR data, in addition to histochemical/anatomic data.
Core 5 An essential need exists for microarray-based experimentation and expertise required by investigators of the SPORE. in Prostate Cancer. The SPORE in Prostate Cancer Core Facility for the DNA Array is designed to provide a comprehensive resource to meet this need. There are several critical issues that face investigators using microarrays for high-throughput nucleic acid analysis that this centralized resource will address including: satisfying the need for experienced technical support and specialized equipment; quality control and trouble shooting for critical procedures to maintain consistent and reproducible technique; cost effective, equitable and efficient use of shared equipment and supplies; expertise for experiment planning and data analysis; and facilitating interactions between projects and cores in the SPORE. This resource is the most efficient and cost effective means to provide these necessary research components to the multiple investigators in this SPORE that use microarray-based experiments. The overall objective of this core is to provide an efficient, high-quality, centralized DNA array resource supporting projects in this SPORE. The specific aims of this core facility are: 1) To provide consultation at all stages of project development and experimentation using microarray techniques; 2) to provide synthesis and labeling of nucleic acid target for microarray experiments; 3) to provide custom array production; 4) to provide microarray hybridization, washing, staining, image analysis and data management services for projects of the SPORE.
Core 6 The purpose of the SPORE in Prostate Cancer Core Facility CF6. Scardino: Administration is to support the translational research objectives of the SPORE by providing: 1) the management and coordination of the daily activities of the Program, 2) administrative direction and structure for the investigators, and 3) support for scientific activities of the SPORE investigators. The CF6. Scardino: Administration is responsible for the following: submission of reports and noncompeting renewal applications to the NIH, elective communication among SPORE investigators, organization of conferences and seminars, and sponsored travel of SPORE investigators to scientific meetings. In addition, this Core Facility will schedule and coordinate the SPORE investigators' attendance at the annual SPORE meeting and the meeting of the Internal Scientific Advisory Committee. They will also administer the annual competition for the External Advisory Board, Internal Scientific Advisory Committee and the Career Development Programall under the direction of the Principal Investigator, Peter T. Scardino, M.D. |
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