Pacific Northwest Prostate Cancer SPORE

Project Leaders

Heather Cheng, MD, PhD
Colin Pritchard, MD, PhD

Prostate cancer (PC) remains a leading cause of cancer-related morbidity and mortality and represents one of the largest health disparities in the US, with men of African ancestry having the highest incidence and mortality rates. Additional risk factors for PC include older age, family history of PC, and germline genetics. We previously reported that rare germline variants in DNA repair genes (gDRG) are enriched in men with lethal/metastatic PC. We have also developed a novel multi-ancestry polygenic risk score (PRSm) that is highly predictive of PC risk across diverse populations and associated with a younger age at PC diagnosis and conversion from active surveillance to treatment. The combined impact of gDRG and PRS on PC progression is not well understood, particularly in multi-ancestry patients. In this Project, we will use a population-based approach to identify and recruit diverse, non-European, multi-ancestry PC patients, examine the interplay between rare variants in gDRG (e.g., BRCA2) with PRSm and the association with PC clinical features. To accomplish this, we will also develop a clinical-grade paired tumor-germline assay, which will additionally enable large-scale examination of gDRG in combination with high PRSm using tumor molecular profiles. We will also parse out specific, individual variants that contribute the greatest effect on a high PRSm, Finally, we will conduct a tailored PC screening clinical trial for individuals at highest risk of PC due to gDRG and determine patterns of interest, enrollment, and adherence to PC screening. Together, we seek to address and mitigate health care disparities related to prostate cancer genetics, and the factors influencing clinical implementation. Ultimately, we seek a better understanding of the interplay between rare gDRG variants and PRSm for a combined analysis of germline genetic information to improve risk prediction and tailored PC screening for men across broader populations.

We will test our hypothesis in the following aims:

Aim 1: Define the independent and combined effect of multi-ancestry PRS (PRSm) and gDRG with clinical characteristics of PC aggressiveness and prognosis across diverse populations.

Aim 2: Develop clinical-grade paired tumor-germline molecular profiling assays to prospectively interrogate multi-ancestry PRS and gDRG.

Aim 3: Conduct a tailored prostate cancer screening clinical trial for at-risk men with gDRG and determine patterns of interest, enrollment and adherence.

Project Leaders

Martin Gleave, MD
Amina Zoubeidi, PhD

The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, which has led to efforts to develop pharmacological agents to ablate AR activity and extend survival in men with metastatic prostate cancer. However, paradoxically, potent AR pathway inhibitors (ARPI) have shaped the emergence of highly aggressive lineage plastic tumours with markedly distinct epigenetic profiles, low canonical AR signaling, and activation of neuronal and developmental/stem cell-associated transcriptional programs. Recent clinical observations support that ~20% of advanced PCa patients with distinct genomic alterations including loss of TP53, RB1 and PTEN and upregulation of EZH2 are primed to develop lineage plasticity and neuroendocrine phenotype. Notably, prognosis remains poor due to a lack of our understanding of the molecular and functional cell states underlying lineage reprogramming. Hence it is crucial to improve our understanding of these emergent resistance mechanisms in genomically segmented populations to better inform future development of novel therapeutic strategies. We developed a clinical and translational neoadjuvant platform as a framework to understand the molecular basis for responses to intensive ARPI therapy. This adaptive multi-stage, multi-arm trial, named the Genomic Umbrella Neoadjuvant Study (GUNS, NCT04812366), will evaluate ARPI-based therapeutic combinations in biomarker pre-selected patients with high-risk localized PC. We hypothesize that genomic alterations determine depth of response to ARPI, and that co-targeting the AR with other contextually relevant targets defined by specific genomic subtype will increase rates of pCR and minimal residual disease in high-risk localized PCa. Certain PC subtypes with loss (isolated or combined) of TP53, RB, PTEN, BRCA or gain in MYC and upregulation of EZH2, are better primed to survive, adapt, develop linage plasticity, and progress after ARPI.

We will test our hypothesis in the following aims:

Aim 1: Define the genomic predisposition of response to potent neoadjuvant ARPI in the GUNS trial.

Aim 2: Assess fidelity of response and pathways activation to ARPI with targeted therapies in PDX models with analogous genomic alterations matched with subprotocols in GUNS.

Aim 3: Conduct sub-protocol 5 in GUNS to evaluate combined ARPI with EZH2 inhibitor, tazemetostat, in PCs with defined genetic subtypes.

Project Leaders

John K. Lee, MD, PhD
Amy Moran, PhD

Adoptive cell transfer in the form of chimeric antigen receptor T cell (CART) therapy has revolutionized the treatment of hematologic malignancies and is making inroads into solid tumors. Challenges to the efficacy and safety of CARTs in prostate cancer (PC) include antigen heterogeneity, an immunologically “cold” tumor microenvironment, poor persistence, and exhaustion. We have developed a novel CART therapy targeting STEAP1 which we found to be expressed more broadly than prostate-specific membrane antigen (PSMA) in over 87% of lethal metastatic PCs. In preclinical human-in-mouse and mouse-in-mouse studies, STEAP1 CART demonstrated 1) specificity and antitumor activity in multiple PC models with varying levels of STEAP1 antigen density and 2) preliminary evidence of safety. The STEAP1 CART program has been accepted into the NCI Experimental Therapeutics (NExT) Program to support clinical translation to a first-in-human study in men with metastatic castration resistant PC (mCRPC). Furthermore, androgens are well known to be immunosuppressive, yet CART therapy is used without consideration of local androgen concentrations or the sex of the patient. We demonstrate that androgen receptor signaling inhibitors (ARSI) improve antigen presentation and promote T cell function within the prostate tumor microenvironment. Together, our observations suggest that combining CART therapy with ARSI could improve therapeutic outcomes in advanced prostate cancer patients.

The goal of this proposal is to test the hypothesis that we can improve STEAP1 CART cell persistence and function by combining it with ARSI treatment.

We will test this hypothesis in the following aims:

Aim 1: Evaluate the effect of AR modulation on STEAP1 CART phenotype and function;

Aim 2: Investigate whether inflammation and ARSI impacts safety and toxicity of STEAP1 CART therapy; and

Aim 3: Conduct a phase I clinical trial to assess the feasibility, safety, and efficacy of STEAP1 CART therapy alone and in combination with enzalutamide in men   with STEAP1+ mCRPC.

These studies provide the preclinical framework for understanding how ARSI and/or AR deletion impacts the function of a novel prostate CART product. Importantly, these studies will provide critical insight into the safety and toxicity of STEAP1 CART therapy alone or with ARSI and reveal potential therapeutic toxicity.

Project Leaders

Peter S. Nelson, MD
Michael T. Schweizer, MD

Co-Investigator

R. Bruce Montgomery MD

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.

Prostate cancer (PC) is notable for the expression and activity of a unique therapeutic target – the androgen receptor (AR). PC growth and survival is driven by AR, a nuclear transcription factor activated by androgens such as testosterone (T) and dihydrotestosterone (DHT). AR activity can be suppressed through ligand reduction in the form of androgen deprivation therapy (ADT). While ADT is initially effective in treating metastatic PC, disease progression, termed metastatic castration-resistant prostate cancer (mCRPC), inevitably occurs after several years. Additionally, long-term ADT is associated with significant mental and physical quality of life complications. Consequently, there has been a longstanding interest in the development of therapeutic modalities that can further exploit AR signaling to enhance treatment responses and also improve quality of life. In this proposal, our objective is to integrate and leverage two key aspects of PC biology: AR activity and DNA damage/repair. Integrating AR signaling and HDR has important treatment ramifications as a substantial body of preclinical and clinical work indicates that HDR deficiency (HDR-D) result in vulnerabilities to at least two drug classes: platinum (PLAT) chemotherapy and PARP inhibitors (PARPi) as well as radiation therapy.

We propose three Specific Aims:

Aim 1: Conduct a Phase 2 clinical trial genotoxic therapeutics and supraphysiological androgen (SPA) in patients with mCRPC to determine response rates, identify resistance mechanisms, and establish biomarkers that associate with clinical responses.

Aim 2: Identify the mechanism(s) by which therapeutics overdriving AR activity induce DNA damage, regulate DNA repair processes, and enhance genotoxic chemotherapy.

Aim 3:  Identify therapeutic drug combinations and dosing/administration strategies that optimize the therapeutic window resulting from AR expression and activity in mCRPC.

The research plan is structured to drive bidirectional assessments of clinically-relevant mechanisms involving AR signaling and DNA repair in the context of treating advanced prostate cancer.

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, MD (Director)

This Core will 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., FHCC 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 six specific aims:

Aim 1: To provide the organizational structure, based on a group of interacting committees, for supporting and evaluating the key objectives of the PNW Prostate Cancer SPORE.

Aim 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.

Aim 3: To organize and coordinate forums for interactions of the Executive Committee, Internal Advisory Board, and External Advisory Board.

Aim 4: To provide efficient and effective fiscal management of SPORE grant funds.

Aim 5: To communicate and consult with the NCI Project Officer(s) and staff in the preparation of required progress reports, publications list, and regulatory documents.

Aim 6: To develop and maintain virtual mechanisms that efficiently facilitate multi-institutional, intra- and inter-SPORE interactions.

Core Leaders

Colm Morrissey, PhD (Co-Director)
Lawrence True, MD (Co-Director)

The Biospecimen  & Pathology Core provides part of the infrastructure support for the major projects comprising the PNW Prostate Cancer SPORE as well as for future pilot and developmental projects. It has been designed to meet the needs of these projects and 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. This Core has 5 components:

This Core has five specific aims:

Aim 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.

Aim 2: A development 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.

Aim 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.

Aim 4: Laboratory services, including production of tissue microarrays, interpretation of immunohistology by urologic pathologists, and production of specimen derivatives for research.

Aim 5: An administrative program to obtain samples from minorities, prioritize the distribution of specimens, ensure patient confidentiality and compliance with IRB requirements, continually improve quality control measures, and interact with other SPOREs.

Core Leaders

Ruth Etzioni, PhD (Core Director)
Dr. Gavin Ha, PhD (Core Co-Director)

The Biostatistics and Analytics Core will provide essential data and analytics support to investigators on the Pacific Northwest Prostate Cancer SPORE. This Core will link study design, data collection, measurement, and analysis to validly address critical hypotheses and questions of SPORE investigators through the following specific aims:

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:

Aim 1: Study design. Define study hypotheses, target populations, and outcomes to efficiently interrogate the research questions of interest, reduce the chance of systematic bias, and ensure a high likelihood of detection of biologically meaningful effects.

Aim 2: Statistical analysis. Implement quantitative methods tailored to study design and data features to estimate effects of interest, quantify uncertainty, and provide valid inferences about the evidence supporting the study hypotheses.

Aim 3: Bioinformatics support. Source appropriate bioinformatics tools and routines to explore biological or mechanistic explanations for study findings and generate hypotheses for further investigation based on molecular information from study samples.

The Biostatistics and Bioinformatics 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 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; and (4) clear communication of study findings, conclusions, and limitations to investigators and the broader community.

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.

Program Directors

Daniel Lin, MD (Director)
Peter S. Nelson, MD (Co-Director)

The specific aims of the CEP are to:

1. Provide research support and collaborative expertise for junior faculty, advanced fellows, and established investigators who wish to either develop or refocus their careers on translational PC research
2. Provide a coordinated system for mentoring faculty and advanced fellows pursuing PC research across a broad range of disciplines
3. Create a framework in which investigators can gain exposure to and training in aspects of translational PC research outside their areas of expertise
4. Attract and retain women, minorities, and early career junior faculty who can make key contributions to translational PC research at the institutions comprising the PNW Prostate SPORE

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.

Program Directors

Peter S. Nelson, MD
Daniel Lin, MD (Co-Director)

The specific aims for the Developmental Research Program are to:

1. Stimulate the development of innovative, impactful early-phase research studies that include multi-disciplinary interactions with basic, clinical, and population scientists across the PNW Prostate SPORE institutions and including inter-SPORE collaborative studies
2. Provide funding (1-2 years) and infrastructure (e.g., biospecimens, biostatistical support) to rapidly test the feasibility of original investigator-initiated projects in all areas of PC research
3. Prioritize funding to rapidly exploit new opportunities or support specific areas of strategic importance for advancing the translational research goals of the PNW Prostate SPORE
4. Monitor (and facilitate) the progress of each DRP project and consider their advancement to a full SPORE project

2018

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.

2013

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.

2006

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.

2002

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.