|
|
||||
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
NORTHWESTERN UNIVERSITY PROSTATE CANCER SPOREChung Lee, Ph.D., Principal Investigator The SPORE (Specialized Programs of Research Excellence) in Prostate Cancer at the Robert H. Lurie Comprehensive Cancer Center brings together a multidisciplinary team of basic scientists, epidemiologists, urologists, oncologists, pathologists, statisticians and bioinformaticists dedicated to advancing research in human prostate cancer. The SPORE represents a consortium of investigators from Northwestern University, the University of Chicago, University of Pittsburgh and North Shore University Health System (formerly Evanston Northwestern Healthcare). The SPORE Principal Investigator is Chung Lee, Ph.D., Professor of Urology. Co-PI’s are: William Catalona, M.D., Professor of Urology and Walter Stadler, M.D., Professor of Medicine (University of Chicago). Four highly translational research projects are led by clinicians and basic scientists working together and include a clinical trial of 5-alpha reductase inhibitor in intermittent androgen ablation therapy (Project 1), radiation induced TNF-alpha therapy for prostate cancer (Project 3), an epidemiologic study of obesity and risk of advanced prostate cancer (Project 2) and chemoprevention of prostate cancer metastasis (Project 4). In addition to research projects, Developmental Research and Career Development Programs infuse the SPORE with new investigators and novel concepts. There are four Core facilities to support and enhance the research activities: Administrative Core, Specimen Procurement Core, Biostatistics/Bioinformatics Core and Clinical Trials and Advocacy Core. The Specimen Procurement Core has a substantial collection of biospecimens and associated clinical and pathologic data that are available for distribution to SPORE and outside investigators who submit requests to our Tissue Review and Disbursement Committee. SPORE investigators meet monthly to present their research and to discuss issues related to operation of the SPORE Program. Internal and External Advisory Committees regularly evaluate program progress and offer guidance to the SPORE leaders. The strong institutional commitment from both Northwestern University and the University of Chicago is critical to the success of this program. We believe that the proposed projects, pilots and career development awards will lead to major improvements in the prevention, early detection, diagnosis, and treatment of human prostate cancer.
PROJECT 1: 5-ALPHA-REDUCTASE INHIBITION IN INTERMITTENT ANDROGEN ABLATION THERAPY IN PROSTATE CANCERPI: Zhou Wang, Ph.D. Prostate cancer patients treated with androgen ablation therapy (AAT) inevitably relapse with androgen refractory tumors and often suffer from side effects caused by AAT. In an attempt to delay cancer progression to androgen independence and to improve the quality of life, Dr. Nicholas Bruchovsky developed intermittent androgen ablation therapy (IAAT). Many prostate cancer patients are being treated with IAAT, sometimes together with a 5α-reductase inhibitor (finasteride or dutasteride). However, the efficacy of IAAT is not defined, and the survival benefits associated with finasteride or dutasteride administration in IAAT have not been addressed. Furthermore, the criteria for switching from off-cycle to on-cycle in IAAT are not clear. With the support of our patient advocacy members, we decided to address the above questions regarding IAAT. We have developed our research hypothesis that blocking the conversion of testosterone (T) to dihydrotestosterone (DHT) by 5α-reductase inhibitor during the off-cycle (when T is recovering) super induces tumor-suppressive androgen-response genes and enhances the efficacy of IAAT. Recent preliminary studies using a subcutaneous LNCaP xenograft tumor model strongly support the above hypothesis. Administration of finasteride during the off-cycle in IAAT significantly enhanced the induction of tumor-suppressive androgen-response gene U19, retarded the tumor growth, and prolonged the survival of the host. To improve IAAT, we propose following four Specific Aims:
The success of this translational project will enhance/optimize IAAT and provide a strong rationale for a phase III clinical trial to determine if dutasteride administration in IAAT can delay the progression to androgen-independence and prolong the survival of patients with metastatic prostate cancer.
PROJECT 2: PEDF REGULATION OF ADIPOGENESIS AND LEPTIN IN PROSTATE CANCERPI: Susan Crawford, M.D. Obesity has become a major health epidemic in the United States, affecting nearly 30% of the population, and it significantly increases the risk of developing a wide spectrum of diseases including cancer. Although large studies have demonstrated a consistent link between men with a body mass index (BMI) >30 kg/m2 and an increased risk of death from prostate cancer (PCa), studies evaluating the risk of PCa in obese men are not conclusive. Adipose tissue functions as an endocrine organ and is a rich source of soluble proteins including leptin and pigment epithelium-derived factor (PEDF). Leptin levels are elevated in obese individuals, and it functions to maintain normal body weight since mice null for leptin or the leptin receptor become obese. Leptin can also induce angiogenesis and stimulate the proliferation of androgen-insensitive PCa cells, and its levels are elevated in the serum of PCa patients with more aggressive disease. In contrast to leptin’s tumor promoting activities, our data revealed that PEDF is a potent inhibitor of angiogenesis that can suppress PCa cancer cell growth in vivo by inducing apoptosis of the supporting vasculature. Moreover, PEDF-null mice develop progressive prostatic PIN with high stromal vascularity and have increased deposition of adipose tissue in the abdominal and pelvic regions with increased leptin and leptin receptor expression in target tissues, including the prostate stroma. In PCa patients, PEDF levels in serum were significantly lower in patients with higher Gleason scores. From these data, we hypothesized that PEDF is an important negative regulator of prostate growth and of adipogenesis, in part, through negative regulation of leptin. Therefore, obesity can promote an imbalance in local and circulating leptin and PEDF levels leading to a pro-tumorigenic environment. This study intends to (a) elucidate the roles of PEDF and leptin in tumor progression and identify the signaling pathways between these molecules, (b) determine if Gleason score correlates with circulating levels of free leptin and PEDF in PCa patients, and (c) assess if prostate tissue expression levels of leptin, PEDF and their receptors, or adipocyte density, have prognostic value. Obesity is an increasing public health problem in the United States and the risk of certain cancers are higher in obese individuals. The biology underlying the link between these two diseases remains unclear. Our preliminary studies suggest that a signaling network exists between fat cells, leptin and pigment epithelium derived factor and dysregulation of any one of these factors can promote a pro-tumorigenic environment. The studies proposed here have the potential to provide mechanistic insight into the enhanced cancer risk in obese patients and could identify new prognostic markers for prostate cancer.
PROJECT 3: RADIATION INDUCIBLE TNF-A THERAPY FOR PROSTATE CANCERPI: Ralph Weichselbaum, M.D. Outcomes for patients with high-risk localized prostate cancer treated with standard radiotherapy and androgen ablation are unacceptable. The addition of radiation sensitizing agents to radiotherapy is useful in other locally advanced cancers such lung and rectal cancer. TNF-alpha is a potent radiosensitizing antitumor agent, but toxicity limits its use as a systemic drug. Ad.Egr-TNF.11D (TNFeradeTM, GenVec, Gaithersburg, MD) is a replication deficient E1, E3, E4 deleted adenoviral vector that encodes radio-inducible DNA sequences upstream from a cDNA for human TNF-alpha. Ad.Egr-TNF.11D is activated following radiation to produce intratumoral therapeutic levels of TNF-alpha and enhanced tumor regression via vascular destruction and thrombosis. To develop this concept clinically we will conduct an early phase clinical trial of Ad.Egr-TNF.11D, radiotherapy, and androgen ablation to determine if the combination is safe in these patients. It is recognized that addition of inducible local TNF is unlikely to be sufficient for this population and that additional measures need to be explored. Furthermore, there is a need to develop markers for predicting which patients are most likely to benefit. As regards the former, activation of NFkB by both TNF and radiation may be critical to promoting survival and inhibiting both the cancer and endothelial cell death required for successful treatment. Therefore, we will determin whether inhibition of NFkB activation through use of the triterpenoid CDDO or an adenoviral vector that inhibits NFkB by encoding a non-degradable (“super-repressor”) form of IKBα (Ad.CMV.IkBα) further enhances the activity of Ad.Egr-TNF.11D and radiotherapy in preclinical prostate cancer models. Finally, it has been demonstrated that STAT1 is induced by radiation and preliminary evidence suggests that up-regulation of STAT1 predicts for resistance to irradiation, raising the hypothesis that patients with baseline elevated tumor STAT1 levels will respond less well to standard radiation. It will thus be determined if STAT1 and NFkB overexpression are associated with tumor recurrence in a historical group of locally- advanced prostate cancer patients with the prediction that the association will be stronger in patients treated with radiotherapy than in patients treated with surgery.
PROJECT 4: MODULATION OF PROSTATE CANCER CELL MOTILITY BY THE CHEMOPREVENTIVE AGENT GENISTEINPI: Raymond Bergan, M.D. Genistein is a NCI high-priority putative prostate cancer (PCa) chemopreventive agent. Our preliminary studies demonstrate that genistein inhibits PCa cell detachment and invasion that are initial steps in the metastatic cascade. We hypothesize that genistein will also inhibit PCa metastasis by inhibiting the movement of prostate cancer cells from the prostate gland into the circulation in man. In in vitro studies, we demonstrated that genistein inhibits activation of the pro-cell-motility signaling p38-HSP27 (heat shock protein 27) pathway, while enhancing activation of the anti-motility ALK-2 signaling pathway. In mice, we showed that genistein inhibited human PCa cell detachment and metastasis. Our first SPORE trial was a phase I clinical trial, and it defined genistein’s pharmacology in PCa patients. Our second SPORE trial was a phase 2 pre-prostatectomy design. It demonstrated that (1) genistein was well tolerated, (2) that it inhibited prostate cell detachment, and (3) that it selectively modulated genes that regulate prostate cell motility. In this proposal, we propose three Aims:
CORE A: ADMINISTRATIVE COREDirector: Chung Lee, Ph.D. The Administrative Core maintains a central role in guiding SPORE investigators through strong leadership and effective program management. Drs. Lee, Catalona and Stadler have significant expertise in this regard. In response to reviewers’ comments in the last submission, we have described in detail the criteria for evaluation of all projects. The Administrative Core is an active command structure that makes the necessary decisions to focus and optimize SPORE research activities in order that they align with high priority areas/goals identified independently, as well as in cooperation with the NCI leadership, the Internal, and the External Advisory Committees. The Core facilitates interactions among the different projects and cores, provides appropriate administrative assistance to investigators in the SPORE and manages all SPORE finances. The Core is responsible for the administration of the Developmental Research and the Career Development Programs. The Core’s leadership emphasizes the highest quality in scientific productivity in translational/interventional prostate cancer research and keeps abreast of progress of SPORE projects through coordinating SPORE monthly meetings and meetings of the Internal Advisory Committee and the External Advisory Committee. The specific aims are:
CORE B: BIOSTATISTICS/BIOINFORMATICS CORECore Director: Borko Jovanovic, Ph.D. The goals of the Biostatistics and Bioinformatics Core of the Prostate Cancer SPORE are (a) to maintain and continue to develop the clinical and tissue databases of the SPORE, (b) to provide experimental design, epidemiological and biostatistical expertise to all of the SPORE projects (c) to conduct data analysis and (d) to provide infrastructure and expertise for inter-SPORE and other scientific collaborations. The expertise of key members of this core facilitates planning, development and analysis of SPORE clinical trials, biomarker studies, molecular diagnostics and high throughput technologies such as DNA/RNA microarray, tissue microarray, proteomics experiments and retrospective studies. The SPORE Biostatistics and Bioinformatics Core leverages existing resources and expertise of the Biostatistics Shared Resource and the Bioinformatics Shared Resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. This enables the core to offer comprehensive bioinformatics and biostatistics services at minimal cost. During the past funding period, the Core has developed a fully operational, web-based, CDE-driven (common data element) central database for the SPORE that houses the clinical, tissue and laboratory data of prostate cancer patients seen at Northwestern Memorial Hospital (NMH), Jesse Brown Veterans Affairs Medical Center (VA), and North Shore University Health Systems (formerly Evanston Northwestern Healthcare-principally Evanston Hospital {ENH}) sites. The created database is essential to the SPORE as it provides a means of obtaining timely and high quality specific information regarding patients in the SPORE. Procedures are in place whereby a standardized set of data are collected, checked, edited and entered from the various components of the SPORE. During the next funding period, the Core will expand to incorporate the University of Chicago, will increase the use of CDEs, and incorporate technology and software coming from the NCI’s caBIG initiative. The Biostatistics and Bioinformatics Core interacts extensively with the Clinical Trials and Advocacy Core and the Specimen Procurement Core of the SPORE. Direct interaction among the cores expedites data organization, data management and data analysis, enables the fluid creation of project-based teams for SPORE projects incorporating individuals with a broad range of expertise, and maximizes the efficiency of the SPORE-supported activities.
CORE C: CLINICAL TRIALS AND ADVOCACY CORECore Director: Timothy Kuzel, M.D. The Clinical Trials and Advocacy Core provides a much needed resource for the successful advancement of our SPORE translational research projects. In addition to supporting the existing SPORE clinical trials, the Core brings the expertise of designing and completing clinical trials to other laboratory investigators who wish to contribute translational concepts to the SPORE. The active participation of the patient advocates in trial design and accrual strategies represents a unique aspect of the Clinical Trials and Advocacy Core. The Clinical Trials and Advocacy Core has 3 specific aims: 1. To develop a Clinical Trials Resource Core to rapidly design, activate and monitor the four trials/projects proposed in the revised renewal application. The Director and Co-Directors will supervise all aspects of personnel and study management and will assist in the ongoing regulatory processes required for novel translational/interventional studies across multiple institutions within and outside of the SPORE. 2. To provide clinical insight and mentorship to junior faculty and laboratory scientists receiving SPORE pilot and career development funding to aid in the writing of trials and to provide appropriate assistance with regulatory and sponsorship hurdles to more rapidly develop the next generation of translational prostate cancer clinical trials. 3. To support our Advocacy/Outreach Program that assists with clinical trial development and accrual of patients, functions as ambassador between the SPORE and various patient advocacy constituencies, and oversees community outreach activities. These goals will be accomplished through meetings of the Core, SPORE investigator meetings, meetings with the Biostatistics/Bioinformatics Core, meetings with individual investigators, community outreach activities and attendance at the National SPORE meetings.
CORE D: SPECIMEN PROCUREMENT CORECore Director: Karen Kaul, M.D., Ph.D. The overall goal of this specimen procurement core is the collection, maintenance, and distribution of high quality biologic samples from a spectrum of prostate cancer and control patients, along with collection of accurate linked clinical and pathologic data on these samples. The Robert H. Lurie Comprehensive Cancer Center's Specialized Program of Research Excellence (SPORE) in prostate cancer consists of three prostate cancer treatment centers; Northwestern Memorial Hospital (NMH), North Shore University Health System (principally Evanston Hospital), and the Jesse Brown Veterans Administration Medical Center (VA). The University of Chicago is now integrated into our SPORE, and in the future will contribute biologic samples as well. Because these institutions see large numbers of new prostate cancer patients from a spectrum of socioeconomic and ethnic groups, with over 500 annual radical prostatectomies performed, our access to patient derived tissues for research is high and diverse. NMH, the VA, and Evanston Hospital have successfully implemented sample procurement to support the prostate SPORE efforts and collectively, these facilities have procured samples on approximately 1900 patients since 2001. Samples (tissue, serum, DNA, RNA, and TMAs) and data have been provided for 48 studies to date. The Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility (RHLCCC-PCF), a shared resource of the RHLCCC, is independent of the Specimen Procurement Core, but complements the tissue procurement by providing research histology expertise. This core will continue the collection of fixed embedded and fresh frozen tissues, urine, blood and blood components, prostatic fluid, seminal vesicle fluid, as well as the acquisition and database storage of essential pathologic and clinical information needed for conducting translational research. Additionally, the facility has constructed numerous tissue microarrays to suit the needs of SPORE investigators. This resource will benefit not only our SPORE investigators, but will facilitate research activities of scientists within and outside the parent institution. This process is supervised by a Sample Review and Disbursement Committee, (including physicians, pathologists and a patient advocate), the SPORE Executive Committee, and reviewed by the individual Institutional Review Boards (IRBs) on an annual basis.
DEVELOPMENTAL RESEARCH PROGRAMThe Developmental Research Program (DRP) serves as an essential component of the SPORE in Prostate Cancer. The DRP provides a mechanism to bring the latest technologies and opportunities into prostate cancer translational research. It has enabled the SPORE to support innovative cancer studies by junior or established investigators who have, in several instances, developed their projects into full SPORE projects or have obtained national funding for their projects. In the last funding period, the Prostate SPORE funded 25 pilot projects (20 distinct projects, 5 funded for a second year), selected from a pool of over 60 proposals. The studies funded during the current funding term have generated a total of 58 peer-reviewed publications. Eleven of the investigators were successful in obtaining national funding (19 grants total) related to their SPORE pilot projects. Conversely, bringing new investigators into the DRP has infused the SPORE program with new ideas for interactions and collaborations. In the last SPORE submission, the DRP was favorably reviewed, having received an assessment of “Outstanding”. We thank the reviewers for their positive comments. In this revised application, we again describe the highly structured process for solicitation, evaluation and selection of pilot projects. We have updated all of the project descriptions, publications and grants. We also note that institutional support from both Northwestern University and the University of Chicago will supplement SPORE funding and will enable us to support 4-5 projects each year. The specific aims of the Developmental Research Program are:
CAREER DEVELOPMENT PROGRAMThe goal of the Career Development Program of the Northwestern University-University of Chicago SPORE in Prostate Cancer is to recruit talented investigators to a career in translational prostate cancer research. In the current project period the SPORE Career Development Program (CDA) funded 7 CDA investigators from a pool of 20 applicants. These investigators were successful in obtaining 14 grant awards and they published 66 papers related to their CDA projects. The fact that the faculty come from a variety of departments has provided a source of diversity and scientific expertise to the investigators in the Program. Special efforts have been placed to emphasize the recruitment of women and minorities to the SPORE CDA. The Career Development Program has demonstrated flexibility in terms of offering awards and the length of the award. In the current funding period, the Prostate SPORE has maintained a consistent and highly structured process for advertisement of CDA positions, selection of CDA investigators and a good tracking system for monitoring and evaluating their progress. In the last SPORE submission, the CDA received an assessment of “Excellent”. In this revised application, we have updated information of all CDA investigators and we again propose CDA funding for two investigators, one is to a woman (Hou) and the other is to a minority applicant (Posadas). http://www.cancer.northwestern.edu/research/prostate_spore.cfm |
|
|||
|
|