Pacific Northwest Prostate Cancer SPORE

Project Leaders

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

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 a broader populations.

Project Leaders

Martin Gleave, M.D.
Amina Zoubeidi, Ph.D.

Project Leaders

John K. Lee, M.D., Ph.D.
Amy Moran, Ph.D.

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, M.D.
Michael T. Schweizer, M.D.

Co-Investigator

R. Bruce Montgomery M.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. (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, Ph.D. (Co-Director)
Lawrence True, M.D. (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, Ph.D. (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.