The Pacific Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE), one of eight Prostate Cancer SPOREs in the nation, represents a coordinated effort between Fred Hutch, University of Washington and its affiliated institutions, the University of British Columbia and the Prostate Centre of Vancouver General Hospital, and Oregon Health and Sciences University, working together toward a common goal of reducing morbidity and mortality associated with prostate cancer.
This work begins with gaining a better understanding of this disease via established programs with strengths in translational prostate cancer research including basic, clinical, and population sciences, as well as career development.
Heather Cheng, M.D., Ph.D.
Colin Pritchard, M.D., Ph.D.
Daniel Lin, M.D.
Prostate cancer (PC) is a major cause of cancer-related morbidity and mortality. Prostate-specific antigen (PSA) screening is controversial, and current consideration of high-risk men is inadequate. Additionally, clinicopathological criteria are insufficient to differentiate indolent versus aggressive disease. The recent discovery of a high prevalence of high-to-moderate penetrance germline cancer risk mutations in metastatic PC (mPC) will lead to increased genetic testing and cascade testing of unaffected male relatives, thus identifying men at high risk for developing aggressive PC. Preliminary evidence suggests the need for refined cancer screening in this high-risk group. The overall intent of this project is to find men with germline mutations of interest, both those with mPC as well as their male first-degree relatives who are at high risk for aggressive PC. We seek to further characterize PC in the context of germline DNA repair gene (gDRG) defects using evaluation of clinical, pathologic and molecular features, including targeted next generation sequencing methods; to recruit at-risk male first-degree relatives through cascade genetic testing; and to offer a novel PC early detection clinical trial incorporating novel biomarkers, including age-adjusted PSA thresholds, imaging, novel urine biomarkers and the tumor prognostic biomarkers we discovered and validated in the past grant period, and to further understand the crucial process of cascade genetic testing that will be required for optimal outcomes. The proposed aims are:
This effort builds upon our current population-based SPORE work focused on finding and validating novel prognostic biomarkers for aggressive PC and transitions towards a more direct clinical applicability. We believe our approach will be of high interest and relevance to men with mPC and gDRG, and their sons and brothers who may be at increased risk for mPC due to carrying the same gDRG mutation. At present, no unified PC early detection recommendations exist for men at increased PC risk defined by inherited gDRG mutations. Our PC early detection clinical study will use established and novel minimally invasive biomarkers with a goal of changing the standard of care for this high-risk group.
Colm Morrissey, Ph.D.
Joshi Alumkal, M.D.
Eva Corey, Ph.D.
Hung-Ming Lam, Ph.D.
Laure Heiser, Ph.D.
Tomasz Beer, M.D.
Victor Thomas, M.D., MMED SCI
The completion of the proposed work will lead to the development of rational clinical trials of BETi drug combinations to block critical networks that sustain the survival of AR-independent, lethal prostate cancers.
Mads Daugaard, Ph.D.
Martin Gleave, M.D.
Nader, Al Nakouzi, Ph.D.
David Perrin, Ph.D.
Anomalous expression of glycosaminoglycans (GAG) such as chondroitin sulfate (CS) has been recognized in prostate cancer (PC) for decades. While CS is a potentially attractive tumor antigen in PC, utility of CS variants as therapeutic targets represent a technical challenge due to inherent low avidity of antibodies towards complex GAG structures. Embracing that challenge, we have developed a cross-disciplinary CS targeting strategy for PC based on engineered recombinant proteins from the malaria parasite Plasmodium falciparum. As a survival strategy to avoid host clearance, the malaria parasite has evolved a protein VAR2CSA that mediates high affinity binding to distinct CS in the placenta. PC express the same type of CS as placental trophoblasts thus recombinant malarial VAR2CSA (rVAR2) proteins can be re-purposed to target oncofetal CS (ofCS) modification in PC. Expression of ofCS in primary PC is not restricted to the tumor epithelium but is also present in the stromal cell compartment. Moreover, the rVAR2 protein can detect and isolate circulating tumor cells (CTCs) from complex blood samples. Finally, we have an rVAR2-Drug Conjugate (VDC886) able to engage ofCS-expressing PC cells in vitro and in vivo. Combined, our technology can access and target a tumor-selective GAG structure in PC for diagnostic and therapeutic applications.
We hypothesize that our rVAR2-based ofCS-targeting system constitutes a novel therapeutic and diagnostic opportunity in human PC. Our hypothesis will be tested in the following Specific Aims:
Peter S. Nelson, M.D.
R. Bruce Montgomery, M.D.
Colin Pritchard, M.D., Ph.D.
Metastatic prostate cancer (mPC) is a lethal disease with essentially no curative therapy. However, in unselected patients, widely divergent responses to conventional and experimental therapeutics are routinely observed, with occasional ‘outlier’ or ‘exceptional’ responders exhibiting durable complete responses and others exhibiting immediate disease progression. This diversity suggests that underlying biological mechanisms accounting for treatment responses can be identified and exploited to prioritize specific therapeutics predicted to have benefit and avoid treatments predicted to lack activity.
The genomic landscapes of mPC demonstrate that a substantial fraction of mPC tumors harbor somatic defects in DNA repair genes (DRGs) including BRCA1, BRCA2, ATM, MSH2/6 and others. This finding has important treatment ramifications as a substantial body of preclinical and clinical work indicates that particular types of DNA repair deficiency, particularly Homology Directed Repair (HDR) Deficiency (HDR-D) result in heightened vulnerabilities to at least two drug classes: platinum (PLAT) chemotherapy and PARP inhibitors (PARPi). Also, of importance, tumors without a HDR-D genotype/phenotype are less responsive to these drugs.
In this proposal we will test the hypothesis that specific aberrations (germ-line or somatic) in genes involved in repairing DNA strand breaks by HDR are predictive of meaningful clinical responses to FDA-approved genotoxic therapeutics and drugs that impair mechanisms of repairing DNA. We will also determine if rational combinations of novel therapeutics targeting DNA repair processes or inducing DNA damage in cancers with HRD will bypass or overwhelm resistance pathways. We have three aims:
The consortium aims to focus on finding molecular and other factors associated with the risk of prostate cancer recurrence and progression as well as its response – and resistance – to treatment. To this end, it is structured around five research projects, some ongoing and some new.
Supporting these research projects are four shared resource cores:
The Leadership and Administrative Core (LAC) will serve to integrate and enhance the research conducted by the Pacific Northwest Prostate SPORE Projects and Cores – as well as faculty supported by the Career Enhancement and Developmental Research Programs – through the application of general administrative support and the facilitation of communication and data dissemination.
Peter Nelson, M.D. (Co-Director)
Daniel Lin, M.D. (Co-Director)
Colm Morrissey, Ph.D. (Co-Director)
The Biospecimen and Pathology Core provides part of the infrastructure support for the major projects comprising the Pacific Northwest Prostate Cancer SPORE as well as for research conducted through the developmental research and career enhancement programs. It has been designed to meet the needs of these projects and serve as a resource for collaborative efforts with other SPOREs. This Core will provide a systematic 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.
Colm Morrissey, Ph.D. (Co-Director)
Eva Corey, Ph.D. (Co-Director)
Lawrence True, M.D. (Co-Director)
Specimens from our repository, especially those from our rapid autopsy program (e.g. PC bone metastases) and our LuCaP series of prostate cancer xenografts have been, and will continue to be distributed to other PC investigators on an international basis.
The Biostatistics and Analytics Core will provide essential data and analytics support to investigators on the Pacific Northwest Prostate Cancer SPORE.
Ruth Etzioni, Ph.D. (Core Director)
The Biostatistics Core is integral to the collection, validation and analysis of data for SPORE projects. Further, where appropriate statistical methods are inadequate or lacking, Core personnel devise and implement novel analytic approaches.
The Clinical Core is specifically designed and supported with the objective of facilitating the translational mission of the Pacific Northwest (PNW) Prostate Cancer SPORE. Each of the five major projects directly utilizes patient-derived materials and attendant clinical data, and most are designed with a patient-directed interventional trial. However, there are major barriers between clinical, basic and population-based research that constrain progress; thus, the aims of this Core were formulated to assist the major projects, developmental projects, and career development awardees in the rapid advancement of their research objectives.
Evan Yu, M.D. (Co-Director)
John Gore, M.D. (Co-Director)
Exercise can help those living with prostate cancer to overcome the side effects of androgen-deprivation therapy, and it may have helpful effects on cancer biology. Yet many people with prostate cancer aren’t sure how to start an exercise routine. Fred Hutch experts and local patients created a series of videos to show people with prostate cancer how to safely exercise at home to improve their health.
The Career Enhancement Program (CEP) is an essential component of the PNW Prostate Cancer SPORE that serves to sustain and enhance our mission by attracting and nurturing new and talented research faculty. The CEP will continue to implement a strategy that has successfully developed clinical, basic, and population scientists for productive careers in translational prostate cancer research.
Daniel Lin, M.D. (Director)
Peter S. Nelson, M.D. (Co-Director)
The CEP will be coordinated between Fred Hutch and the University of Washington (UW); the Prostate Centre at the Vancouver General Hospital (VGH); and the Oregon Health Science University (OHSU). Our organizational structure works across sites and includes recruitment and monitoring of candidates by a career enhancement committee, educational coordination through a conference and education committee, and access to more than 50 multidisciplinary investigators both within and outside the SPORE whose research interests provide relevant experience in translational prostate cancer research. The CEP educational program combines a wide spectrum of individual research opportunities, formal educational courses, and a large number of conferences and seminars in translational prostate cancer research. We plan to continue to recruit both qualified faculty members and senior research fellows who wish to expand their work in translational prostate cancer research, focusing on the inclusion of women and underrepresented minority applicants. In addition to SPORE grant support, this program will be augmented by substantial institutional resources.
The Developmental Research Program (DRP) of the Pacific Northwest (PNW) Prostate Cancer SPORE is designed to solicit, evaluate, and support innovative pilot projects in translational prostate cancer research. Projects funded under the DRP are intended to rapidly advance a new idea or concept that has the potential to substantially impact our understanding of prostate cancer, and ultimately influence the clinical management of this disease through improved prevention and treatment strategies. Since the inception of the PNW Prostate Cancer SPORE, the infrastructure of the DRP has established mechanisms to quickly respond to translational research opportunities within the PNW SPORE institutions that require support to advance hypotheses or confirm feasibility in order to justify larger resource investments. Developmental projects include research in basic science, clinical science, and population-based studies, and will continue to build collaborations between PNW SPORE sites and other institutions with SPOREs in prostate cancer.
Peter S. Nelson, M.D
Daniel Lin, M.D. (Co-Director)
Martin (Mac) Cheever, M.D.
The NCI renews the PNW Prostate Cancer SPORE through 2023. This iteration of the project is led by Drs. Peter S. Nelson, Janet L. Stanford, and Dan W. Lin. This continuing 5-year, $11.14M award will support the exceptional resources and infrastructure created by the SPORE and the continued efforts to translate groundbreaking basic science research to clinical therapies.
The PNW Prostate Cancer SPORE is awarded an $11.3 million, five-year competitive grant renewal for its continued leadership of a multi-center prostate cancer research consortium whose collective goal is to reduce the morbidity and mortality associated with prostate cancer. This continuation represents a coordinated effort between four institutions, each with established programs and strengths in translational prostate cancer research.
NCI renews the PNW Prostate Cancer SPORE grant under the direction of Dr. Peter Nelson, PI, and co-PIs, Drs. Janet Stanford and Paul Lange. A new five-year, $11.8 million grant was awarded to further the PNW SPORE’s aim to address fundamental questions underlying prostate cancer risk, prognosis, and therapeutic response, reinforcing the reputation of the Pacific Northwest consortium as a major force in prostate cancer research.
NCI awards Fred Hutchinson Cancer Research Center $12.7 million to lead a multi-center, multi-project, five-year investigation into the genetic mechanisms of prostate cancer progression. Understanding how and why prostate cancer can turn deadly is key to developing therapies that may effectively treat men with recurrent or advanced prostate cancer, for which there is no cure. Under the direction of Principal Investigator (PI) Paul Lange, MD, and co-PIs Janet Stanford, PhD, and Peter Nelson, MD, the initiative involved more than 50 investigators from four institutions in Seattle and Vancouver, BC.
Fred Hutchinson Cancer Research Center
1100 Eastlake Avenue, E2-112
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SPORE Fiscal Manager
SPORE, Prostate Cancer Program