Pacific Northwest Prostate Cancer SPORE

Project Leaders

Heather Cheng, M.D., Ph.D.
Colin Pritchard, M.D., Ph.D.

Co-Investigators

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:

Project Leaders

Colm Morrissey, Ph.D.
Joshi Alumkal, M.D.

Co-Investigators

Eva Corey, Ph.D.
Hung-Ming Lam, Ph.D.
Laure Heiser, Ph.D.

Other Significant Contributors

Tomasz Beer, M.D.
Victor Thomas, M.D., MMED SCI

Project Leaders

Mads Daugaard, Ph.D.
Martin Gleave, M.D.

Other Significant Contributors

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:

• Specific Aim 1: Preclinical evaluation of VDC886 as a novel treatment for metastatic CRPC (mCRPC).
• Specific Aim 2: Visualization of metastatic PC lesions by ofCS PET imaging.
• Specific Aim 3: Design and execute a phase I trial of VDC886 in mCRPC.
  

Project Leaders

Peter S. Nelson, M.D.
R. Bruce Montgomery, M.D.

Co-Investigator

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 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.

Core Leaders

Peter Nelson, M.D. (Co-Director)
Daniel Lin, M.D. (Co-Director)
Colm Morrissey, Ph.D. (Co-Director)

This Core will also provide formal links between the following entities:

1. All investigators comprising the Pacific Northwest (PNW) SPORE in prostate cancer.
2. Advisory Panels (e.g., External Advisory Board [EAB], Internal Advisory Board [IAB], etc.).
3. The institutions (e.g., Fred Hutch and other SPORE participatory sites) with laboratories and clinical facilities wherein occur the research and education components of the SPORE
4. Representatives of the National Cancer Institute (NCI)

This Core has the following specific aims:

1. To provide the organizational structure, based on a group of interacting committees, for supporting and evaluating the key objectives of the PNW SPORE.
2. To provide oversight of all SPORE activities involving the independent research projects, the Career Enhancement Program (CEP), the Developmental Research Program (DRP), the shared resource Cores, and the parent institutions.
3. To organize and coordinate forums for interactions of the Executive Committee, Internal Advisory Board, and External Advisory Board.
4. To provide efficient and effective fiscal management of SPORE grant funds.
5. To communicate and consult with the NCI Project Officer(s) and staff in the preparation of required progress reports, publications lists, and regulatory documents.
6. To develop and maintain virtual mechanisms that efficiently facilitate multi-institutional, intra- and inter-SPORE interactions.

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.

Core Leaders

Colm Morrissey, Ph.D. (Co-Director)
Eva Corey, Ph.D. (Co-Director)
Lawrence True, M.D. (Co-Director)

This Core has five specific aims:

1. Clinical specimen acquisition (i.e. tissues, including those from surgery and the rapid autopsy program, serum, plasma and urine), processing, quality control, storage, distribution and database entry
2. A program to continually improve the quality and efficiency of biospecimen acquisition, processing and storage to increase the fidelity of specimens provided to the SPORE investigators
3. Maintain prostate cancer xenograft lines established by the Core and make specimens available for biological study and/or perform pre-clinical studies for SPORE investigators and collaborators
4. Laboratory services, including production of tissue microarrays, interpretation of immunohistology by urologic pathologists, production of specimen derivatives and perform PSA immunoassays for research
5. An administrative program to obtain samples from minorities, prioritize the distribution of specimens, ensure patient confidentiality and compliance with IRB requirements, maintain and improve quality control measures and interact with other SPOREs.

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. 

Core Leader

Ruth Etzioni, Ph.D. (Core Director)

This Core will link study design, data collection, measurement, and analysis to validly address the critical hypotheses and questions of the Pacific 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. As part of this aim Core C will provide power calculations when needed for each project.
2. Analysis and interpretation. Identify and implement quantitative methods to address the scientific questions of interest and provide valid statistical inferences about the evidence addressing the various study hypotheses. Work with study investigators to clearly communicate methods and results in study publications and insure that reported conclusions are justified.

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.

This Core will provide:

1. Prompt responsiveness with respect to biostatistical and bioinformatics analyses
2. Appropriate expertise to select and implement an optimal approach to study design and analysis
3. Customized dataset creation and analysis
4. Clear communication of study findings, conclusions, and limitations to investigators and the broader community.