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SPOREs : Organ-Specific SPORE Programs : Prostate

Pacific Northwest Prostate Cancer SPORE

Principle Investigator(s): Peter S. Nelson, M.D.
Co-Investigator(s): Janet L. Stanford, Ph.D., Paul Lange, M.D.

Fred Hutchinson Cancer Research Center /
University of Washington

 

Overall Program Description

The Pacific Northwest (PNW) Prostate Cancer SPORE continuation grant represents a coordinated effort of four institutions with established programs and strengths in translational prostate cancer research and career development: 1) the Fred Hutchinson Cancer Research Center (FHCRC); 2) the University of Washington (UW) and its affiliated institutions; 3) the University of British Columbia and the Prostate Centre of Vancouver General Hospital (UBC); and, 4) Oregon Health and Sciences University (OHSU). These Seattle-, British Columbia- and Portland-based institutions have large multidisciplinary teams of investigators and laboratories dedicated to prostate cancer research and a history of working closely together within this larger milieu. The respective teams of clinicians and researchers at these institutions bring considerable scientific depth and breadth required for confronting the most challenging problems blocking progress in our ultimate goal of reducing the morbidity and mortality associated with prostate cancer. This SPORE proposal provides the blueprint for building a large coordinated translational prostate cancer effort spanning the PNW.

All participating institutions have made substantial commitments toward supporting the SPORE and its innovative, translational projects: 1) A population-based cohort study to identify metastasis-modifier alleles predictive of prostate cancer progression and mortality; 3) A translational study of the role of Hsp27 inhibition to target hormone refractory prostate cancer and mechanisms of cellular response to stress; 4) A neoadjuvant study to confirm preclinical data showing that combined inhibition of androgens and the IGF receptor enhance prostate cancer response; and, 5) A study of tumor response to complete androgen ablation in relation to tissue levels of androgens and AR activity. We also propose four Cores to support these projects: A) leadership and administration; B) tissue/specimens; C) biostatistics; and D) clinical research. In addition, we propose a Career Development Program and a Developmental Research Program that will significantly embellish and strengthen the translational goals of our prostate cancer research program and expand opportunities for engaging young as well as established investigators in our multidisciplinary environment.

 

PROJECT 1: GENETIC SUSCEPTIBILITY TO CLINICALLY AGGRESSIVE PROSTATE CANCER

Project Leader(s): Janet L. Stanford, Ph.D.
Co-Leader(s): Daniel Lin, M.D.
Co-Investigator(s): Elaine Ostrander, Ph.D.

Of the estimated 168,811 men who will be treated for prostate cancer (PC) with curative intent in 2006, >30% will ultimately experience disease recurrence, metastasis, and die of PC. There is substantial uncertainty, however, in predicting which individual patients will have adverse outcomes based on both clinical presentation and pathological features. In the previous proposal, we hypothesized the complexity of the PC progression process could be explained by genetic variants that confer susceptibility to more aggressive or to lethal PC. That is, subtle changes in transcription, translation or the function of gene products due to inherited genetic variants may modify tumor behavior. In the current proposal, we will expand our investigation into whether allelic variation plays a role in metastatic efficiency (i.e.. the ability of a tumor to spread or recur), with the following specific aims:

  1. Evaluate the association of genetic polymorphisms in candidate genes with PC-specific mortality and disease recurrence/progression using two population-based cohorts of PC patients (follow-up mean=10.4 yrs.; range 5-17 yrs.). As part of the initial SPORE proposal a panel of 384 single nucleotide polymorphisms (SNPs) in candidate genes associated with PC pathways (e.g., androgens) has been genotyped in Cohort 1 (n=630). For the current proposal, interesting SNPs (i.e., p<0.15 in relation to PC-specific death from Cox models) from Cohort 1 will be genotyped in patient Cohort 2 (n=840) for confirmation. SNPs that are validated will be examined with outcomes in both cohorts;
  2. Examine tagSNPs in PC metastasis-suppressor genes (e.g., KAI1, MAPKK4) in relation to PC outcomes as defined in Aim 1 in all patients with DNA from both cohorts (n=1,470); and,
  3. Evaluate genotype-phenotype associations within the combined cohort of PC patients to identify SNPs that are correlated with more aggressive or less aggressive disease features. These analyses will consider whether individual SNPs, haplotypes (tagSNPs within candidate genes), or groups of SNPs in candidate genes in defined pathways are independently associated with PC aggressiveness.

We anticipate this study will provide new insights into genetic pathways and mechanisms that determine metastatic potential, pushing PC toward its lethal phenotype. Knowledge of metastasis-modifier alleles may help identify subsets of PC patients at higher risk for adverse outcomes, those who would benefit most from tailored individual therapies (e.g., early adjuvant therapy, or expectant management), from heightened surveillance for recurrence/progression, and early interventions aimed at reducing PC deaths.

 

PROJECT 3: CHARACTERIZATION AND TARGETING OF THE CYTOPROTECTIVE CHAPERONE, HSP27, IN METASTATIC HORMONE REFRACTORY PROSTATE CANCER

Project Leader(s): Martin Gleave, M.D.
Co-Leader(s): Colleen Nelson, Ph.D.
Co-Investigator(s): Kim Chi, M.D.

This renewal application will build on our previous studies, in which we established a roles heat shock protein (Hsp) 27 as a stress-induced cytoprotective chaperone that increases after hormone- and chemo-therapy to inhibit treatment-induced cell death. We will explore the hypothesis that Hsp27 is a therapeutic “hyper-node”, a target situated as a ‘Hub” at the center of many pathways regulating the response to cell stress and therapeutic stimuli. Hsp27 forms oligomers during cell stress to prevent aggregation, or becomes phosphorylated to chaperone and regulate activity or degradation of many varied client proteins, including the transcriptional activity of stat-3 and AR. Aim 1 will elucidate pathways by which Hsp27 regulates CaP cell survival, using bioprofiling and directed functional approaches. Gene and antibody expression profiles of Hsp27 overexpression vs knockdown, coupled to ingenuity pathway analysis, will identify gene networks affected by Hsp27. In parallel, Aim 2 will focus on roles of Hsp27 in 3 pathways linked to HRPC and therapeutic resistance, and specifically test a) whether ligand-independent (androgen depleted) AR activity associated with AI progression is modulated by interactions between IL-6 signal transduction, ligand-depleted AR transactivation, and increased Hsp27 activity; b) effects of Hsp27-induced PEA-15 phosphorylation on cell proliferation (by promoting ERK/MAPK activation) and inhibition of Fas mediated cell death, and c) whether treatment induced stress up-regulates the unfolded protein response (UPR) in CaP, and the role of Hsp27 is a downstream effector in endoplasmic reticular (ER) stress. Aim 3 will evaluate the safety and activity of an Hsp27 antisense inhibitor (OGX-427) in a Phase I/II study in men with mHRPC. The phase I portion will define the pharmacokinetic and toxicity profile of OGX-427 and determine the recommended phase II dose of OGX-427 given as a 2-hour IV infusion once weekly. The phase II portion of this study will then evaluate the anti-cancer activity of OGX-427, assessed primarily by PSA “response”, in part as a pharmacodynamic surrogate of AR inhibition. Correlative studies are also incorporated to evaluate the biologic effectiveness of OGX-427 by analysis of bone marrow aspirates and tissue for Hsp27 and AR protein levels. Collectively, these studies will improve our understanding of role of Hsp27 in adaptive cell survival, treatment resistance, and most importantly, as a new therapeutic target in mHRPC.

 

PROJECT 4: MECHANISMS BY WHICH THE TYPE 1 INSULIN-LIKE GROWTH FACTOR INHIBITION ENHANCES THE EFFECTS OF CASTRATION ON PROSTATE CANCER

Project Leader(s): Stephen Plymate, M.D.
Co-Leader(s): R. Bruce Montgomery, M.D.

The lethal phenotype of prostate cancer is termed androgen-independent (AI), because it develops following castration in the presence of very low levels of androgen in men or undetectable androgen levels in mouse models. It has been suggested that peptide growth factors, e.g. insulin-like growth factors (IGF) signaling through the IGF tyrosine kinase receptor (IGF-IR), drive the AI phenotype. Recent data clearly demonstrates that androgen receptor (AR) expression is increased in models of AI disease and that in human tissue the AR remains primarily in the nucleus after castration. We have shown inhibition of IGF-IR signaling, with a fully human IGF-IR monoclonal antibody, in androgen-dependent (AD) and AI disease decreases nuclear AR, modifies the AR transcriptional program, and delays emergence of AI disease following castration. In this proposal we will determine the mechanisms of the IGF/AR interaction and efficacy of inhibition of these interactions on human tumors.

Hypothesis: lnsulin-like growth factor signaling contributes to progression of androgen-dependent [1] and androgen-insensitive [2] prostate cancer progression by enhancing AR nuclear localization and AR signaling.

  1. Aim 1: Determine effect of utilizing a human IGF-IR mab combined with castration in a phase 1b/II neoadjuvant trial. This aim will exploit the potential use of IGF-IR blockade using hmabs in association with castration as a potential treatment modality for prostate cancer. In this aim we will utilize both clinical and tissue endpoints.
  2. Aim 2: IGF signaling alters androgen receptor nuclear translocation in prostate cancer through changes in AR phosphorylation. In this aim we will [1] determine if the change in phosphorylation of the AR is associated with an alteration in nuclear import or export of the AR and [2] determine which AR phosphorylation site altered by IGF-IR signaling is responsible for the change in nuclear localization of the AR. [3]. Determine the mechanism by which IGF-IR signaling alters AR phosphorylation.
  3. Aim 3: Determine the effects of changes in AR phosphorylation on association of AR co-regulators and changes in AR transcription patterns. In the Preliminary Data, we note that alteration of AR phosphorylation by inhibition of IGF-IR signaling results in an alteration of AR associated co-factors. Most notably among the cofactors were SMRT and BRCA1. In this aim we will [1], perform a more completed assessment of associated co-regulators, [2] determine effects of co-factors on AR translocation, and [3] determine effects of the associated co-factors on AR transcriptional activity and the AR transcriptional program.

The relevance of this study to the goal of improving treatment for prostate cancer is that it will take the laboratory data we have assembled demonstrating that the inhibition of the IGF-IR with a human monoclonal antibody abrogates prostate cancer progression and apply it in a patient setting to determine its potential efficacy in clinical disease.

 

PROJECT 5: MAXIMAL TARGETED INHIBITION OF ANDROGEN SIGNALING FOR PROSTATE CANCER THERAPY

Project Leader(s): Peter S. Nelson, M.D.
Co-Leader(s): Paul Lange, M.D.
Co-Investigator(s): R. Bruce Montgomery, M.D.; Alvin Matsumoto, M.D.

Clinical and laboratory evidence continues to demonstrate that androgens and the androgen receptor (AR) are the best available targets for treating/preventing both early and advanced prostate cancer. Numerous clinical trials have been designed to interfere with the AR pathway, but few have actually assessed the effectiveness of the therapy by demonstrating maximal target interference. This proposal aims to use a neoadjuvant clinical trial format to rigorously evaluate the effectiveness of maximal androgen suppression through measurements of intraprostatic androgen levels, and to target a maximal suppression of DHT levels to zero. The clinical benefit of this approach will be evaluated through measurements of tumor grade, stage, margin, tumor cell apoptosis and androgen-regulated gene expression.

The aims are:

  1. Aim 1. To determine the anti-tumor efficacy of achieving specific (low) intraprostatic androgen levels and inhibition of AR-signaling through direct assessments of tumor viability, apoptosis, proliferation, and androgen-regulated gene expression.
  2. Aim 2. To evaluate and compare alternative mechanisms capable of maintaining androgen-activity in a ‘castrate’ environment in both primary and metastatic prostate cancer: (i) utilization of adrenal androgens; (ii) active androgen transport; (iii) de novo biosynthesis of androgens by neoplastic prostate epithelium.
  3. Aim 3. To evaluate the pre-clinical efficacy and mechanism(s) of activity of new targeted therapies designed to inhibit testicular, adrenal, and prostatic androgen metabolism and/or AR signaling.

The completion of this research project will: 1) demonstrate the efficacy (or lack thereof) of efforts to ablate tissue androgens; 2) measure tumor responses to specific androgen levels and AR inhibition; and 3) provide a context for additional approaches designed to target the AR.

 

CORE A: LEADERSHIP & ADMINISTRATION

Core Director(s): Peter S. Nelson, M.D.
Co-Director(s): Paul Lange, M.D.; Janet L. Stanford, Ph.D.

The Administrative Core for this specific Northwest Prostate Cancer SPORE will consists of a variety of interacting committees working closely with the PI and Co-PIs.

The administrative staff consists of personnel trained in finance, grants management, clinical research support, and education/editorial services. The committees will involve:

  1. External and Internal advisory boards consisting of outside and inside experts (both MDs and PhD1s, some of which are already prostate cancer SPORE directors) who will advise the PI1s on the scientific progress and direction of the SPORE;
  2. A scientific working committee consisting of four senior members of the SPORE who will oversee the “daily” administrative issues of the SPORE;
  3. A conference and educational committee which will plan and conduct extensive educational and mentoring activities for the SPORE;
  4. A Career Development Committee which will oversee the recruitment, selection, and training of the SPORE Fellows and coordinate the participation of over 20 research mentors. This committee will also assist the scientific working committee and executive committee in soliciting and selecting new innovation pilot research projects;
  5. A Translational Committee consisting of SPORE and outside clinicians and translational researchers whose specific task is to assess the translational progress of the SPORE and suggest new avenues for translational research;
  6. An Advocacy Committee consisting of professional and business prostate cancer survivors whose major function will be to assess the progress and public image of the SPORE and suggest new avenues for inquiry, and to enhance institutional and community support for SPORE activities, concerns, and needs.

 

CORE B: TISSUE & SPECIMEN

Core Director(s): Robert Vessella, Ph.D.
Co-Director(s): Lawrence True, M.D.

The Specimen Core provides part of the infrastructure support for Projects 1 - 5 as well as for future pilot and developmental projects. It has been designed to meet the needs of these projects plus serve as a stand-alone resource for collaborative efforts with other SPOREs. This Core will provide a well-organized and standardized system of specimen collection, storage, distribution and related clinical/research information dissemination that is based on over two decades of experience. There will be consistency and quality assurance in the pathological analysis of tissue specimens. Furthermore, the centralized management of the specimens will facilitate their distribution based upon the priorities defined by a panel of investigators familiar with all of our SPORE research endeavors. The operations of this Core group into 5 components:

  1. Specimen acquisition, processing, quality control, storage and accessioning into databases.
  2. A development program to continually improve the quality and efficiency with which we obtain tissue samples and derivative products.
  3. A prostate cancer xenograft maintenance, development and study program.
  4. Laboratory services, including interpretation of tissues and tissue localization studies by a urologic pathologist, immunohistochemistry (IHC), quantitative RT-PCR, and immunoassays, i.e. PSA, and tissue culture. The Core will also perform pre-clinical studies using our xenograft resources, and
  5. An administrative program to obtain samples from minority patients, prioritize the distribution of specimens, conduct a quality control program, ensure patient confidentiality and compliance with IRB requirements, and to interact with other prostate SPOREs.

The performance of translational research mandates that investigators have ready access to well documented clinical specimens and relevant biological models. The investigators directing the Biospecimen Core have decades of experience in recognizing these needs and providing such services not only to local investigators but to those who request specimens on a world-wide basis. For example, samples of specimens from our rapid autopsy program (e.g. prostate cancer bone metastases) and our LuCaP series of prostate cancer xenografts have been distributed internationally. In this renewal, such interactions with our own SPORE investigators, those collaborations with other SPORE investigators and collaborations with non-SPORE investigators will be a high priority. This will truly enhance the translational aspects of the NW Prostate Cancer SPORE.

 

CORE C: BIOSTATISTICS

Core Director(s): Ruth Etzioni, Ph.D.
Co-Director(s): Ziding Feng, Ph.D.

The Biostatistics Core will provide essential biostatistical support to investigators on the Northwest Prostate Cancer SPORE. This Core will link study design, data collection, measurement, and analysis to the critical hypotheses and questions of the Northwest Prostate Cancer SPORE through the following Specific Aims:

  1. Study Design: Define study hypotheses, study populations and experimental parameters to answer the research questions of interest, reduce systematic bias and ensure a high likelihood of detection of biologically meaningful effects.
  2. Analysis and Interpretation: Identify and implement state-of-the-art quantitative methods to address the scientific questions of interest and provide valid statistical inferences about the evidence supporting the various study hypotheses. Provide necessary bioinformatics expertise for study interpretation.
  3. Methods Development: Where appropriate statistical methods are inadequate or lacking, devise and implement novel quantitative approaches to address study questions of interest.

During the prior funding period, the Biostatistics Core played an integral role in the collection, validation and analysis of data for SPORE projects. Our experience has shown that involvement of statisticians from the concept phase yields studies that are better designed, more likely to answer the scientific questions of interest, and, ultimately, more compelling in their conclusions. Therefore the Core will continue to function though close collaboration with investigators from the beginning through the life of each SPORE study.

The Biostatistics Core operates from within the Biostatistics Program at the Fred Hutchinson Cancer Research Center. Investigators on the Biostatistics Core play leadership roles on funded studies and programs whose missions overlap considerably with that of the Core. These include the Data management and Coordinating Center for the Early Detection Research Network, and the Program in Computational Biology and Bioinformatics at the Fred Hutchinson Cancer Research Center. Access to and collaboration with these programs will enhance the Core’s ability to address analytic questions raised by SPORE studies using cutting-edge, and, if necessary, novel techniques.

 

CORE D: CLINICAL

Core Director(s): Celestia Higano, M.D.
Co-Director(s): Evan Yu, M.D.

The Clinical Core will support projects and cores in areas relevant to clinical research. The three major components to the core include clinical trials, the prostate cancer clinical research information system, and advocacy activities.

  1. Specific Aim 1: To design, execute, accrue to, or otherwise facilitate the conduct and timely completion of clinical trials relevant to SPORE projects or Cores. UW, UBC, and OHSU clinical investigators will participate in this aspect of the core. Clinical trials specific to projects include pre- and post-radiation biopsy (Project 2), neoadjuvant IMC-A12 (Project 4), and MAXTAP (Project 5) studies. Numerous SPORE related trials, including InterSPORE trials, are in progress or in planning.
  2. Specific Aim 2: To continue to develop and enhance Caisis, the prostate cancer clinical research information system. Development of clinic abstraction templates, biospecimen clinical annotation protocol, quality control and assurance procedures, patient consent and specimen acquisition processes, and specimen tracking are priorities.
  3. Specific Aim 3: To support and engage the SPORE Advocacy Committee in the activities of the SPORE as well as in their own mission as a group. Goals of the committee include: continued interaction with local support groups, involvement of minority members on the committee and in clinical trials, invitation of UBC and OHSU patients to join Advocacy Committee. In order to better understand and interact with the SPORE projects, each Advocate will focus on a single project.

 

DEVELOPMENTAL RESEARCH PROGRAM

Director(s): Peter S. Nelson, M.D.
Co-Director(s): Janet L. Stanford, Ph.D.

The main purpose of the Developmental Research Program (DRP) of the Pacific Northwest (PNW) Prostate Cancer SPORE is to support innovative translational prostate cancer (PC) research pilot projects aimed at reducing the morbidity and mortality due to PC and at improving the survival and quality of life of PC patients. During the initial funding of the DRP, substantial progress has been made in the development and implementation of this unique and successful research program. During the first four years of the DRP, 46 pilot project proposals were submitted and 19 projects were funded (total of $798,100.00 direct funding). Ten publications and 7 grants have resulted to date from the DRP. For this continuation grant, the DRP program will continue to provide a mechanism to quickly respond to new translational research opportunities that may develop within the SPORE environments of participating institutions: Vancouver General Hospital (VGH) Prostate Centre in Vancouver, British Columbia, Canada; the University of Washington (UW), the Fred Hutchinson Cancer Research Center (FHCRC), and the Institute for Systems Biology (ISB) in Seattle, WA; and, Oregon Health Sciences University (OHSU) in Portland, OR. Support provided by the DRP will continue to allow innovative pilot projects to be initiated, with the expectation that the projects will mature sufficiently so that they can successfully compete for additional funding from sources either within or outside the SPORE grant. This program also attracts more senior investigators with diverse scientific expertise and new investigators into translational PC research.

The specific aims for the DRP are:

  1. Solicit innovative, translational prostate cancer research study proposals for pilot funding on an annual basis;
  2. Convene a panel of experts to provide rigorous scientific review of pilot study proposals following NIH guidelines for selection of the most promising research projects;
  3. Provide pilot study funding for 1-2 years for the most innovative investigator-initiated ideas for research in all areas of prostate cancer research (including etiology, prevention, diagnosis, biological mechanisms, genetics, and treatment) with a special emphasis on projects that address issues relevant to advancing knowledge of disease aggressiveness or metastasis; and,
  4. Allow the SPORE leadership to target funds to specific areas that are especially likely to advance the translational research goals of the PNW prostate cancer SPORE.

 

CAREER DEVELOPMENT PROGRAM

Director(s): Peter S. Nelson, M.D.
Co-Director(s): Janet L. Stanford, Ph.D.; Paul Lange, M.D.

A Career Development Program will be a major and essential part of this proposed SPORE. Its goal will be to develop physicians, basic and population scientists for lifelong productive careers in translational prostate cancer research. The program will strive to make these individuals scientifically productive, academically successful and influential nationally, and good role models for recruitment of individuals to similar careers.

The program will involve all of the institutions within the SPORE: in Seattle, the Fred Hutchinson Cancer Research Center (FHCRC), and the University of Washington (UW); in Vancouver, the University of British Columbia (UBC) and Prostate Center at the Vancouver General Hospital (VGH); and, in Portland the Oregon Health Sciences University (OHSU). The coordination between the three areas will involve recruitment, development and educational opportunities, and the interchange of mentors and research opportunities.

The specific goals of this program are to:

  1. Recruit and train four to seven post-doctoral fellows in prostate cancer translational research per year;
  2. Recruit and nurture one to two faculty members at each institution whose main interest is prostate cancer translational research every 2-3 years;
  3. Enhance and develop a broad program of education and mentoring within the SPORE environment. This educational program will involve not only a large spectrum of individual research opportunities, but also a more formal educational experience of didactic courses and a large number of scheduled conferences and seminars.

Recruitment of fellows and junior faculty will occur through the planned educational program and by systematic recruitment efforts. These individuals will be monitored and mentored by a specific Career Development committee, and by 47 multidisciplinary investigators at these institutions both within and outside the SPORE whose research interests and accomplishments reflect prostate cancer research concerns. In addition to SPORE grant support, this program will be supported by extensive institutional resources.

http://www.fhcrc.org/science/phs/prostate_spore/

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