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Last Updated: 10/16/23

The Pacific Northwest Prostate Cancer SPORE

Fred Hutchinson Cancer Center

Principal Investigator(s):

Peter Nelson, MD
Peter Nelson, MD

Principal Investigator(s) Contact Information

Peter Nelson, MD
Vice President, Precision Oncology
Professor, Human Biology Division
Director, Sloan Precision Oncology Institute
Stuart and Molly Sloan Precision Oncology Institute Endowed Chair
Fred Hutchinson Cancer Center
1100 Fairview Ave N
E2-112
Seattle Washington, 98109-1024
(206)-667-3377

Overview

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 including basic, clinical, and population sciences as well as career development: 1) the Fred Hutchinson Cancer Center (FHCC); 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 Science 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, breadth, creativity, and vision 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 enlarges the blueprint for a well-built, distinctive and coordinated translational prostate cancer research effort spanning the entire PNW.

All participating institutions have made substantial commitments toward supporting the SPORE and its innovative, translational projects: 1) Molecular predictors of prostate cancer progression and mortality; 2) Understanding and targeting prostate cancer lineage plasticity; 3) Modulating androgen receptor signaling to enhance the efficacy of CAR T cell therapy for advanced prostate cancer; and 4) Clinical development of therapeutic strategies targeting DNA repair. We also propose three Cores to support these projects: 1) Leadership and administration; 2) Biospecimen and Pathology; and 3) Biostatistics and Bioinformatics. In addition, we propose a Developmental Research Program and a Career Enhancement Program that will substantially 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.

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Project 1: Molecular Predictors of Prostate Cancer Progression and Mortality

Project Co-Leaders:
Dr. Heather Cheng, MD, PhD, Clinical/Applied
Dr. Colin C. Pritchard, MD, Basic

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.

Specific 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.

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Project 2: Understanding and Targeting the Lineage Plasticity in the Genomic Umbrella Neoadjuvant Study (GUNS)

Project Co-Leaders
Dr. Martin Gleave, MD, Clinical/Applied
Dr. Amina Zoubeidi, PhD, Basic

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 tumors 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.

Specific 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.

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Project 3: Modulating Androgen Receptor Signaling to Enhance the Efficacy of CAR T Cell Therapy for Advanced Prostate Cancer

Project Co-Leaders
Dr. John K. Lee, MD, PhD, Clinical/Applied
Dr. Amy Moran, PhD, Basic

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.

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.

Specific 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.

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.

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Project 4: Clinical Development of Therapeutic Strategies Targeting Damage Repair

Project Co-Leaders
Dr. Peter S. Nelson, MD, Basic
Dr. Michael T. Schweizer, MD, Clinical/Applied

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.

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.

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.

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Core A: Leadership and Administrative

Dr. Peter S. Nelson, MD, Core Director

PROJECT SUMMARY

The Leadership and Administrative Core (LAC) will serve to integrate and enhance the research conducted by the Pacific Northwest Prostate Cancer SPORE Projects and Cores — as well as the faculty supported through both the Career Enhancement and Developmental Research Programs — through the application of general administrative support and the facilitation of communication and data dissemination.

The 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., FHCC and other SPORE participatory sites) with laboratories
  4. and clinical facilities wherein occur the research and education components of the SPORE; and
  5. Representatives of the National Cancer Institute (NCI).

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.

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Core B: Biospecimen and Pathology

Core Co-Directors:
Dr. Colm M. Morrissey, PhD
Dr. Lawrence D. True, MD

PROJECT SUMMARY

The Specimen 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.

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.

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.

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Core C: Biostatistics and Bioinformatics

Core Co-Directors
Dr. Ruth Etizioni, PhD
Dr. Gavin Ha, PhD

PROJECT SUMMARY

The Biostatistics and Bioinformatics 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.

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.

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.

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Developmental Research Program

Program Co-Directors
Dr. Daniel W. Lin, MD
Dr. Ruth D. Etzioni, PhD

The Developmental Research Program (DRP) of the Pacific Northwest (PNW) Prostate Cancer SPORE supports early-phase projects that have the potential to open new areas of translational prostate cancer (PC) research and ultimately, contribute to reducing morbidity and mortality and improving quality-of-life for patients with PC. The DRP infrastructure has developed mechanisms to quickly respond to translational research opportunities within the PNW SPORE institutions.

The PNW Prostate SPORE DRP will draw from a large and diverse pool of investigators in the Pacific Northwest that populate four major research institutions: the Fred Hutchinson Cancer Center (FHCC), the University of Washington (UW), the University of British Columbia and the Prostate Cancer Centre of Vancouver General Hospital (UBC/VGH), and the Oregon Health and Science University (OHSU). Each organization is endowed with a vibrant prostate cancer program, and collectively, more than 400 faculty members with relevant research interests and expertise that could plan and execute new translational PC research proposals.

Specific Aims:

Aim 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.

Aim 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.

Aim 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.

Aim 4: Advance early stage-scientific research that addresses prostate cancer health disparities and promote research directed by scientists from under-represented minority group; and monitor (and facilitate) the progress of each DRP project and consider their advancement to a full SPORE project.

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Career Enhancement Program

Program Co-Directors
Dr. Peter S. Nelson, MD
Dr. Ruth Etizioni, PhD

The Career Enhancement Program (CEP) is an essential component of the Pacific Northwest (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.

The CEP has established effective approaches, procedures, and metrics to identify, recruit, mentor, and advance the careers of investigators committed to long-term careers in translational prostate cancer (PC) research.

Specific Aims:

Aim 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.

Aim 2: Provide a coordinated system for mentoring faculty and advanced fellows pursuing PC research across a broad range of disciplines.

Aim 3: Create a framework in which investigators can gain exposure to and training in aspects of translational PC research outside their areas of expertise; and

Aim 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.

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