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U.S. National Institutes of Health
Last Updated: 11/29/11

UCLA SPORE in Prostate Cancer

To view UCLA Prostate SPORE activities, please visit http://urology.ucla.edu/body.cfm?id=229

Overall Abstract

Principal Investigator(s):
Robert Reiter, M.D.

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.

UCLA SPORE in Prostate Cancer: Main Projects

Project I: Imaging Prostate Cancer with Engineered PSCA Antibodies

R. Reiter,
A. Wu,
A. Raubitschek,
D. Colcher

Prostate Stem Cell Antigen (PSCA) is a cell surface protein expressed by a majority of prostate cancers. A fully human anti-PSCA antibody was developed in collaboration with industry and successfully translated into Phase 1 trials in men with metastatic prostate cancer. We propose to develop and test a radiolabeled PSCA antibody fragment to molecularly image prostate cancer with SPECT and PET scans. A PSCA-targeted molecular imaging probe has the potential to improve the ability to detect advanced and metastatic prostate cancer. It may be used to classify tumors with PTEN mutation or that respond to PSCA antibody therapy. Finally, a PSCA-targeted molecular imaging probe might be used to monitor response to therapy (e.g. PSCA antibody therapy or drugs that target the PI3 kinase-PTEN-Akt pathway). A humanized PSCA minibody has already been constructed and yields striking images of PSCA-positive xenografts with excellent pharmacokinetics (i.e. high tumor uptake and rapid clearance from normal tissues).

The Aims of this study are:

  1. to develop and test engineered antibody fragments in controlled biological systems,
  2. to assess PSCA antibody fragments to image transgenic models of prostate cancer, and
  3. to perform a pilot imaging trial in men with metastic prostate cancer. These studies have the potential to advance prostate cancer imaging in the age of targeted therapies and to link more closely the diagnosis and treatment of this disease.

This study proposes to develop a new test to identify metastatic prostate cancer and to classify tumors at the molecular level by a noninvasive means. We will develop an antibody that is radiolabeled and binds to the protein PSCA on the surface of prostate cancer cells. Mice and then men administered this antibody will be imaged with SPECT scans in order to detect localized or metastatic prostate cancer.

Project II: Exploiting PI3K Pathways Inhibitor Therapy in Prostate Cancer

H. Wu,
C. Sawyers,
H. Scher, R. Reiter

A rate-limiting step in the evaluation of molecularly targeted cancer therapeutics is the ability to match the right inhibitor with the right patient. Success requires molecular profiling of tumor tissue from patients and the discovery of biomarkers that predict sensitivity to specific agents. This project addresses this question in prostate cancer with the focus on inhibitors of the PI3-kinase (PI3K) pathway. The project builds on progress by Drs. Sawyers and Wu during the first 5 years of funding studying mTOR inhibitors and capitalizes on their expertise in developing genetically engineered prostate mouse models and using these models to evaluate signaling pathway inhibitors.

The project will use three well-characterized genetically engineered prostate cancer models (PTEN, MYC, AKT) to:

  1. define and measure pathway-specific, prostate cancer biomarker signatures in tumor tissue and serum using mouse models and human patients and
  2. evaluate PI3 kinase pathway inhibitor therapy alone and in combination using hormone refractory prostate cancer mouse models.

These findings will guide the design and execution of neoadjuvant clinical trials of PI3 kinase pathway inhibitors in prostate cancer, collaboratively at Memorial Sloan Kettering Cancer Center and UCLA, and assess the utility of circulating tumor cells (CTCs) as oncogenomic readouts in prostate cancer patients.

Project III: Lymphangiogenesis and Lymphatic Metastasis in Prostate Cancer

L. Wu,
M. Rettig

Metastasis is the main cause of prostate cancer mortality. The support of prostate cancer SPORE Development Program in the past two years has enabled Dr. Wu’s group to investigate the contribution of lymphangiogenesis to prostate cancer metastasis. It was discovered that elevated pro-lymphangiogenic factor (VEGF-C) in the prostate tumors induces the growth of lymphatic vessels, which in turn facilitates tumor cell dissemination to regional lymph nodes. Moreover, the lymphatic dissemination process also greatly impacts metastasis to distal organs, such as lung and liver. Hence, our current working hypothesis suggests that lymphatic circulation is a preferred route of dissemination and that regional lymph nodes provide a reservoir from which subsequent dissemination to distal sites occurs. This proposal will investigate this hypothesis further. In particular, this project will examine in detail the connection between lymphangiogenic pathways and metastasis in prostate cancer patients, focusing our molecular and histological analyses on the patients with node positive and recurrent disease. Using many relevant pre-clinical models developed at UCLA, efforts will be directed towards addressing two areas of great need, i.e. therapeutic intervention and diagnostic imaging of nodal metastasis. This project will investigate therapeutic effects of blockading the lymphangiogenic tyrosine kinase receptor by specific VEGFR3 antibody, and Sorafenib, a multi-kinase inhibitor known to target both VEGFR3. Molecular imaging technologies will be applied to monitor the impact of these interventions on the metastatic process. The ability of the prostate-specific imaging adenoviral vector to specifically detect nodal metastases in pre-clinical models will also be evaluated.  In addition, potential circulating surrogate markers for the lymphangiogenic pathways will be developed and assessed. The lack of such markers has halted progress in anti-metastatic treatment. The prostate cancer SPORE program at University of Washington is initiating a phase II neoadjuvant clinical trial of Sorafenib in patients with high-risk localized prostate cancer. In a collaborative effort with this study, blood and tissue samples will be obtained from the patients to analyze the molecular activity of Sorafenib again the VEGFR3 pathway and tumor lymphangiogenesis axis. The myriad of approaches taken in this project is directed towards improving the clinical management of metastasis stage of prostate cancer in the future.

Project IV: Development of IGFBP-3 Therapy in Men with Prostate Cancer

P. Cohen,
K-W. Lee,
A. Pantuck

In preliminary data derived with the initial SPORE grant, this group demonstrated interactions of IGFBP-3 with mitochondrial and nuclear apoptosis-related proteins and showed that IGFBP-3’s action requires rapid internalization, phosphorylation, and association with the multi-compartmental nuclear receptors RXRa and Nur77 leading to both rapid induction of apoptosis pathways. Particularly, it was found that the nucle-mitochondrial translocation of Nur77 in response to IGFBP-3 treatment is a key event in the IGFBP-3 cascade and could serve as a biomarker for IGFBP-3 responsiveness. Importantly, this group has also shown that the in vivo administration of IGFBP-3 to xenograft bearing mice results in substantial tumor suppression and inhibition of angiogenesis and that the effects of IGFBP in vivo are observed when given as a single therapy, and are enhanced in combination with other agents.

The specific aims are to

  1. develop histopathology assays for IGFBP-3 pathway molecules in prostate cancer and evaluate their role in determining disease prognosis and their ability to serve as surrogate tissue biomarkers of IGFBP-3 activity on prostate cancer in vivo, (e.g. Nur77 subcellular localization); and to determine, using the SPORE tissue array resource, if baseline intra - tumor staining levels of IGFBP-3, Nur77, and RXRa predict the clinical outcome of patients with prostate cancer,
  2. Conduct a Phase 1b dose response neoadjuvant trial of IGFBP-3 in men with CaP, and
  3. Optimize IGFBP-3 treatment of prostate cancer in in vivo mouse models, prior to initiating a larger phase 2 study.

The goals are to identify drugs that synergize with IGFBP-3, such as IGF receptor inhibitors, EGF receptor antagonists and nutritional agents including Pom X. Together, these efforts will serve to promote the development of rational IGFBP-3 related therapies and tools to assess its efficacy in prostate cancer. As the first clinical trials targeting other components of the IGF axis are already underway, we believe that IGFBP-3 will have additional tumor suppressive effects given its IGF-dependent and –independent apoptosis-promoting properties. If successful, findings from this project may provide new avenues for the treatment of this disease and pave the way towards larger clinical studies involving IGFBP-3.

Project V: Dietary Fat Modulation and Targeted Therapies for Prostate Cancer Prevention

W. Aronson,
P. Cohen,
H. Herschman,
H. Wu,
D. Heber

Using pre-clinical models, this group has demonstrated that dietary fat reduction and decreasing the ratio of omega-6 to omega-3 fatty acids impacts on the development and progression of prostate cancer. This work has been translated into an ongoing clinical trial to determine if altering quantity and quality of dietary fat effects serum and prostate tissue nutrition-related, cancer-relevant biomarkers in men with prostate cancer. Based on data from the pre-clinical and clinical studies Dr. Aronson’s group postulates that the two main mechanisms underlying the anticancer effect of modulating dietary fat are through IGFBP-1 mediated inhibition of IGF signaling and through suppression of COX-2-dependent PGE-2 production. The primary aim of this project is to determine the contribution of the IGF/IGFBP and COX-2/PGE-2 pathways to the anticancer effect of dietary fat modulation. This will be accomplished through a series of experiments utilizing (1) serum and prostate tissue obtained from an ongoing dietary-fat intervention trial in men with prostate cancer, (2) pathway- and COX-2 pathways that will be examined for dietary fat-responsiveness, (3) and androgen-dependent xenograft models in SCID mice that will be treated with dietary fat optimization combined with targeted IGF or COX-2 pharmaceuticals. These proposed studies will be translated to a clinical trial testing the most promising combination of dietary fat modulation with a targeted molecular intervention, such as an antibody to the IGF-1R or a COX-2 inhibitor, to evaluate effects on defined serum and tissue biomarkers.  The overall goal for this project is that these studies will lead directly to large scale, prospective clinical trials combining targeted therapies with optimization of dietary fat to prevent the development and progression of prostate cancer.

UCLA SPORE in Prostate Cancer: Cores

The Administrative Core is responsible for the oversight and daily functions of the SPORE programs. It provides administrative support for grants and financial management; scheduling of meetings and seminars; and coordination of activities between the SPORE, the Jonsson Comprehensive Cancer Center, and other UCLA academic and administrative bodies. It has ultimate responsibility for the overall management of the budget and appropriate filing of budgetary information. It files progress reports and communicates with NCI, NIH, and outside agencies, as necessary, as well as the ULCA Office of Contracts and Grants. In addition, it ensures completion of necessary documents with regulatory agencies.

The Pathology Core provides essential services to all projects in the SPORE with major commitment to tissue acquisition and processing, tissue histology and analysis including specialized techniques, and pathology consultation. The core is fully committed to collaboration with other SPORE and NCI programs, including the National Biospecimen Network (NBN), the Inter-SPORE Prostate Biomarkers Study (IPBS) and the Detection Research Network (EDRN). The core will provide a full range of services including processing, fixation, embedding of human and murine tissues, routine histology, and specialized immunohistochemistry and in-situ hybridization studies. Particularly use will be made of high throughput techniques incorporating tissue arrays with samples related to outcome such as PSA recurrence metastasis. A computerized database will be maintained of well-characterized matched samples of normal and neoplastic tissues. This database is electronically linked to the clinical database maintained by the SPORE Biostatistics core and the Department of Urology. Core facilities include a histology laboratory, a fully automated immunohistochemistry laboratory, computerized instrumentation for quantitative immunohistochemistry, and a tissue array facility. One of the key contributions of this core is expert pathology consultative services. The Core’s leadership have demonstrated expertise with prostate pathology, both clinical and experimental, involving human and murine tissue. The investigators will continue to work closely with SPORE investigators in experimental design, use of human and murine tissues, and analysis and interpretation of results. Drs. Said and Thomas have co-authored over 30 prostate cancer publications during the five years of SPORE funding, reflecting their engagement in the program and contribution of this core to prostate cancer research at UCLA.

The Biostatistics and Informatics Core will provide support in two related areas: a) biostatistical analyses, statistical consulting, and study design and b) research data collection, management, reporting, and data sharing. Each of the projects will utilize the tools, infrastructure, and expertise provided by this core. In addition, the biostatistics and bioinformatics core will provide support in the area of data sharing and communication for inter-SPORE collaborations similar to the Inter-SPORE Biomarkers Study (IPBS). Integrating biostatistics, data management, and bioinformatics within the same core ensures a seamless data analysis, and data sharing for each of the projects. The core members have a demonstrated track record of close collaboration and effective support of clinical investigators. The Biostatistics Core is organized to assist investigators in all aspects of the organization of their data flow and in the choice and setup of database management systems.

In particular, this core aims to

  1. assist in the biostatistical design of clinical, laboratory, and epidemiological studies;
  2. assist in the analysis of research data, i.e. general statistical consulting and to provide facilities to carry out cancer clinical trials, especially early phase studies Phase I, Phase II where both clinical and biomarker studies are assessed;
  3. provide a facility for analysis of tissue arrays including software and up-to-date statistical methodology;
  4. provide a facility to design and carry out data analyses of proteomics data;
  5. provide a facility to design and carry out data analyses of microarray gene expression;
  6. develop biostatistical methodology for statistical problems arising in the SPORE;
  7. build a web site and Intranet to support internal communications and dissemination of project accomplishments and data to the public;
  8. utilize a common set of software tools (the Central Codebook and Protocol Tracker) to support research and clinical data collection , management, and reporting and
  9. move data to caTissue and the Clinical Annotation Engine: caBIG tools.

The Animal Model Core supports and centralizes certain aspects of the work in each project proposed.  It is the UCLAProstate SPORE’s 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 xenografts 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 six distinct components that will allow biologically based hypotheses to be tested in suitable animal models or human prostate cancer xenografts.

The Specific Aims of this Core are as follows:

  1. To provide SCID mice to the research projects,
  2. To propagate four human prostate cancer xenografts: LAPC4, LAPC9, CWR22, and LUCAP on SCID mice for investigators in the SPORE,
  3. To maintain model mice, such as Pten and Cox-2 conditional knock-out, AKT and Myc transgenic mice as well as reporter lines needed for each project,
  4. To provide technical assistance for in-vivo experiments, such as harvest xenografts, measure PSA level, and inject pro-drugs for pre-clinical trials,
  5. To provide expertise/consultation on animal experimentation and surgical techniques required for the proposed studies, and
  6. To provide expertise/consultation for the general of new models.

The Imaging Core supports the in-vivo imaging needs of the projects of the UCLA SPORE in Prostate Cancer. The Imaging Core provides functional as well as anatomical imaging technologies to investigators to develop and implement new imaging tracers and technologies.

The goals of the Imaging Core are:

  1. to provide and support state-of-the-art small animal preclinical imaging research;
  2. to support innovative clinical imaging studies; and
  3. to provide scientific and administrative support to Prostate SPORE investigators.

Pre-clinical imaging studies are centralized in the Crump Institute imaging facility, which houses two microPET scanners, a microCT, three Xenogen IVIS optical imaging system, and a new Maestro multispectral fluorescence imager.  Ancillary facilities including radiolabeling lab and rodent housing, are adjacent.  In 2007 the preclinical Imaging Facility will relocate to new, spacious quarters in the California Nanosystems Institution building where it will continue to expand its offerings to investigators in oncologic molecular imaging. Clinical imaging and evaluation of novel radiolabeled tracers is supported by the Ahmanson Biological Imaging Clinic in the Geffen School of Medicine. Key aspects of the provision of imaging services are quality control and data acquisition/storage/analysis, which the Imaging Core provides in order to ensure reliable access to the instrumentation and data.

Molecular imaging will provide better ways to detect cancer, and smarter ways to understand its behavior and select the most effective therapy. The Imaging Core helps all SPORE investigators to integrate imaging into their basic investigations, and to develop new ways to detect prostate cancer in patients.

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