University of Wisconsin Prostate Cancer SPORE

University of Wisconsin School of Medicine and Public Health

Principal Investigators

Overview

The University of Wisconsin (UW) Prostate Cancer Specialized Program of Research Excellence (SPORE) is a highly collaborative research proposal that links basic scientists with prostate cancer clinicians to advance treatment strategies for prostate cancer patients. The broad objectives of this SPORE are to: 1) Increase multidisciplinary translational research and develop the next generation of prostate cancer researchers, 2) Develop common resources to promote advances, 3) Translate promising new approaches into patients, and 4) Improve overall survival and quality of life for patients with prostate cancer. A crosscutting theme that encompasses this SPORE is understanding tumor resistance in advanced prostate cancer and exploiting this knowledge to improve patient outcomes.

The UW Prostate Cancer SPORE has three primary research projects:

• Project 1: Tumor Microenvironment Initiators of the Metastatic Cascade in High-Risk Prostate Cancer
• Project 2: Androgen Deprivation as an Immune Modulating Therapy in Combination with Targeted Immunotherapy of Prostate Cancer
• Project 3: Extending Clinical Benefit by Selective Treatment of Resistant Lesions in mCRPC

The SPORE will support this research with three Cores (Administrative, Integrated Pathology Radiology, and Biostatistics and Bioinformatics). The Career Enhancement Program and Developmental Research Program will engage new and established investigators and further translational goals in a rich multidisciplinary environment. When completed, the research of the UW Prostate Cancer SPORE will advance our treatments and understanding of prostate cancer and undoubtedly beneficially impact patients with this disease.

Project 1: Tumor microenvironment initiations of the metastatic cascade in high-risk prostate cancer

Project Co-Leaders

• Joshua Lang, M.D., M.Sc. (Clinical)
• David Beebe, Ph.D. (Basic)
• David Jarrard, M.D.
• Melissa Skala, Ph.D.
• Sheen Kerr, Ph.D.

We have recently found that activated fibroblasts and macrophage sub-populations induce lymphovascular sprouting and permeability. Based on these data sets, we hypothesize that somatic alterations in tumor DNA co-opt stromal and immune cells in the tumor microenvironment (TME) to promote invasion and intravasation of lympho-vascular channels. To test this hypothesis, we have recruited three cohorts of patients with high-risk prostate cancer (surgery alone, neoadjuvant abiraterone, and neoadjuvant chemo-hormonal therapy). They undergo prostate-specific membrane antigen positron emission tomography/magnetic resonance imaging (PSMA PET/MRI) scans prior to surgery. This scan is used to develop a 3D mold of the prostate to perform whole mount sectioning and dissection of multi-focal prostate cancer (PC) for multi-plex molecular analysis. Samples from these specimens are used to create patient-specific “TMEs on a Chip” using a humanized Micro-Physiologic System (MPS) of the prostate with surrounding lympho-vasculature. This novel model system allows culture of patient tumor cells and stromal cells to identify the factors that induce lymphatic permeability and culminate in tumor invasion and intravasation. Success in these studies will identify the biologic interactions in the TME that can initiate the metastatic cascade as potential biomarkers and therapeutic targets for men with high-risk, locally advanced PC.

Specific Aims

• Aim 1: Perform whole exome and transcriptome sequencing, across 3D whole mount sections identified by PSMA PET/MRI, in untreated patients to evaluate heterogeneity and determine the impact of neoadjuvant ARSIs and docetaxel across 3D multifocal PC.
• Aim 2: Extend spatial mapping with PSMA PET/MRI and immunohistochemistry (IHC) data to perform transcriptional Digital Spatial Profiling (DSP) on whole-mount sections collected in Aim 1. This integration will test whether distinct cancer-associated fibroblast phenotype (CAF) and immune cell infiltrates associate with genomic alterations in a spatial configuration of cells invading regional lymphovascular channels.
• Aim 3: Use LumeNEXT MPS technology to create humanized lymphatic vessels cultured in patient-specific humanized prostate TMEs, with genomically engineered PC cells, that reflect the molecular and cellular signatures identified in Aims 1 and 2. When completed, the outcome of this work will advance the field by helping us to understand how prostate cancer metastasizes for both biomarker and drug development.

Project 2: Androgen deprivation as an immune modulating therapy in combination with targeted immunotherapy of prostate cancer

Project Co-Leaders

• Douglas McNeel, M.D., Ph.D. (Basic)
• Christos Kyriakopoulos, M.D. (Clinical)
• David Jarrard, M.D.

Project 2 of the Michigan Prostate SPORE seeks to improve the early detection of unfavorable risk prostate cancer by employing a novel urine-based next generation sequencing (NGS) assay. Recent studies have demonstrated that men with certain germline genetic alterations (e.g., BRCA 1/2 and Lynch syndrome) may be at increased risk of potentially aggressive prostate cancer. Men at increased genetic risk represent a newly recognized group in whom early detection is particularly compelling. Generally speaking, a central problem inherent to prostate cancer screening is the profound overdiagnosis of favorable risk disease. To counterbalance the over treatment of favorable risk (i.e., Gleason 6) prostate cancer, a number of active surveillance strategies have been introduced. Transition to treatment (e.g., surgery or radiation) can be triggered by evidence of risk reclassification often due to grade progression. Improved early detection of grade progression in men with previously-diagnosed favorable-risk prostate cancer on active surveillance represents a major opportunity to improve treatment allocation. How to reliably identify potentially aggressive prostate cancer so treatment can be appropriately recommended continues to represent a critical knowledge gap.

Building on prior work from a successful SPORE project involving the Michigan Prostate Score (MiPS) test (using transcription-mediated amplification quantification of urine KLK3, PCA3 and T2:ERG) in the previous funding cycle, we have developed an advanced novel urine-based targeted NGS assay (MIPS-NGS) to detect Gleason ≥ 7 (unfavorable risk) prostate cancer. MIPS-NGS is a targeted RNAseq assay comprised of 83 prostate cancer-specific transcripts (e.g., lncRNAs, ETS genes fusions, SPOP), several of which are specific for aggressive prostate cancer. We hypothesize that MIPS-NGS can enable the early detection of unfavorable risk prostate cancer.

Specific Aims

• Aim 1: To develop MIPS-NGS as a prostate cancer early detection assay in men at high genetic risk.
• Aim 2: To develop MIPS-NGS alone, or as part of a multi-dimensional clinical tool, for the early detection of grade progression in a prospective active surveillance cohort.

Project 3: Extending clinical benefit by selective treatment of resistant lesions in mCRPC

Project Co-Leaders

Glenn Liu, M.D. (Clinical)
Robert Jeraj, Ph.D. (Basic)

Development of treatment resistance is the main reason for disease progression in patients with metastatic castration-resistant prostate cancer (mCRPC). What is under-appreciated is that in many patients who are experiencing progression, the majority of individual lesions continue to respond to therapy. Identification of resistant lesions would allow for administration of localized ablative therapies, especially if the systemic therapy is still effective for the majority of metastases. We hypothesize that selective treatment of resistant lesions (e.g., those treated with stereotactic body radiation therapy) will extend duration of clinical benefit in men with mCRPC. We will identify resistant lesions by employing our unique advanced quantitative molecular image analytics — Quantitative Total Extensible Imaging (QTxI) -- which allows lesion-level assessment of treatment dynamics. We will test our hypothesis through the following aims:

Specific Aims

• Aim 1: Characterize resistance at early progression in men with mCRPC treated with second-generation androgen signaling inhibitors by employing QTxI of PET/CT starting at nadir PSA response, PSA progression, and again in 12 weeks,
• Aim 2: Conduct virtual selective radio-ablation study using different PET metrics for target lesion selection of resistant lesions and to model impact of radio-ablation on total tumor burden and anticipated improvement in clinical benefit, and
• Aim 3: Test clinical feasibility of radio-ablation using sterotactic body radiotherapy (SBRT) to selective resistant lesions in a prospective therapeutic clinical trial. This project is highly innovative as it explores lesion-level treatment resistance in mCRPC, uniquely characterized by our technology, as a treatment target. Assessment of resistance at the time of clinical progression is critical, since it triggers high anxiety in the patient and provider. It is thus an urgent area of unmet clinical need. We will conduct the first trial of its kind to identify and treat resistant lesions in the setting of widespread metastatic disease with the goal of improving clinical benefit.

Administrative Core

Core Co-Directors

• David Jarrard, M.D.
• Douglas McNeel, M.D., Ph.D.

The Administrative Core provides scientific leadership and operational structure necessary for the planning, implementation, management, and supervision of all activities of the University of Wisconsin Prostate Cancer SPORE. Embedded within the University of Wisconsin Carbone Cancer Center (UWCCC) Office for Translational Research Services (OTRS), the Administrative Core will centrally provide a wide variety of administrative coordination, oversight, and research support services to all leaders, Co-leaders, investigators, and Core Directors. It will offer these services in a centralized manner, to promote efficiency and ensure that all SPORE research and activities are focused, connected, that complex scientific objectives are met, and existing cancer center resources are utilized and not duplicated. The Administrative Core will provide the oversight, monitoring and auditing required to ensure projects are meeting translational endpoints and reach human application within five years, consistent with the SPORE mission.

Specific Aims

• Aim 1: Leadership (scientific leadership)
• Aim 2: Administrative management
• Aim 3: Planning and evaluation activities
• Aim 4: Institutional support (management of unencumbered institutional resources provided)
• Aim 5: Integration of SPORE within UWCCC, UW-Madison, and regional partnership alliances
• Aim 6: Prostate cancer patient population participation
• Aim 7: Data Management
• Aim 8: Communications

Integrated Pathology and Radiology Core (iPRC)

Core Directors

• Steve Cho, M.D.
• Wei Huang, M.D.

The Integrated Pathology Radiology Core (iPRC) of the UW Prostate Cancer SPORE is dedicated to providing expert and reliable pathology and imaging services to enhance translational prostate cancer (PC) research. The iPRC will provide services and infrastructure to allow for reliable, reproducible, and high-quality pathology data to be linked with radiologic imaging tumor identification and lesion-to-lesion correlation. This will integrate pathology-radiology data and be linked to comprehensive clinical information as well as tumor-specific bioinformatics. The unique infrastructure and resources created to support the UW Prostate Cancer SPORE projects will provide an integrated pathology and radiology database repository to benefit collaborative translational PC research projects at UW and the wider PC research community.

Specific Aims

• Aim 1: To collect, process, preserve, annotate, and distribute quality biospecimens and provide a full range of expert pathology consultation and services to the SPORE investigators.
• Aim 2: To build a digital whole slide image (WSI) database with detailed histological and clinical annotations for pathology-radiology correlation studies for SPORE investigators and future collaboration projects.
• Aim 3: To provide advanced radiology imaging services, integrated with pathology, to enable translational correlation and analyses.
• Aim 4: To build a co-registered pathology-radiology image repository to serve and support UW Prostate Cancer SPORE investigators, and the wider prostate cancer (PC) research community.

Biostatistics and Bioinformatics Core (BBC)

Core Directors

• George Zhao, M.D., M.S.E.
• Jens Eickhoff, Ph.D.
• Menggang Yu, Ph.D.

The objective of the Biostatistics and Bioinformatics Core (BBC) of the University of Wisconsin (UW) Prostate Cancer SPORE, is to promote excellence in prostate cancer translational and clinical research by providing dedicated and outstanding biostatistical and bioinformatic consultation and collaborative support to the Prostate Cancer SPORE projects, cores and DRP and CEP. This support and collaboration will include laboratory and clinical-based research, focusing on translation from laboratory studies to clinical studies. The BBC will achieve its objective by supporting investigators and providing statistical, bioinformatics, and data management expertise, thus enhancing the quality and ensuring the validity of the research undertaken in the Prostate Cancer SPORE.

Specific Aims

• Aim 1: Collaborate with the UW Prostate Cancer SPORE investigators in study design, analysis, and interpretation of data, and writing of scientific manuscripts.
• Aim 2: Ensure the transparency and validity of statistical and bioinformatic analysis via rigorous data collection, standardization of the variety of data that arise from the UW Prostate Cancer SPORE projects, confidential and secure data archiving and data sharing, and centralized data management activities including validation and consistency checking of all collected data.
• Aim 3: Develop new statistical and bioinformatics methods relevant to the individual projects.

Developmental Research Program

Program Directors

• Will Ricke, Ph.D.
• Glenn Liu, M.D.

The University of Wisconsin Prostate Cancer SPORE Developmental Research Program (DRP) supports early phase projects that have the potential to open new areas of translational research opportunity, and lead to reduced morbidity and mortality in patients with prostate cancer. Developmental projects include research focused on basic science discoveries, prevention, early detection, treatment, development of prognostic and predictive biomarkers, as well as survivorship. The DRP provides pilot funding to support innovative and high impact research in prostate cancer and will solicit, advise, review, select, and monitor DRP projects to ensure that DRP resources are effectively used.

Specific Aims

• Aim 1: Stimulate creation of multi-disciplinary teams to conduct impactful research studies in prostate cancer that include basic, clinical, and population researchers, as well as collaboration with outside SPORE institutions and investigators.
• Aim 2: Provide 1-2 years of funding to support investigator-initiated research that may lead to subsequent grants, clinical trials, or insight on project feasibility, as well as become a future SPORE project.
• Aim 3: Support high-risk, high-reward ideas that may be too early for traditional grant mechanisms but deemed innovative and important to explore.
• Aim 4: Monitor progress of funded DRP projects and recommend which projects should be advanced to a full SPORE project.

Career Enhancement Program

Program Co-Directors

• Josh Lang, M.D., Ms.C.
• Melissa Skala, Ph.D.

This Career Enhancement Program (CEP) provides a unique collaborative structure and mechanism to cultivate the development of outstanding research careers for junior faculty and mid-level investigators desiring to focus their careers on translational research in prostate cancer. Importantly, each awardee will have the opportunity to utilize cross-campus opportunities for research and didactic training (e.g., NIH Clinical and Translational Science Award). The specific aim of the CEP is to provide scientists and physician-scientists with integrated training and career enhancement support such that they develop into successful, independently funded translational researchers and leaders in the field of prostate cancer. Our goal is to produce future scientists, including physician-scientists, who will meet the great need for innovation in methods to prevent and treat prostate cancer. The CEP will thereby foster the development of knowledge, skills, professional attitudes, and experience required for successful academic careers in prostate cancer translational research.

The Career Enhancement Program includes:

• A strong pool of exceptional mentors across UW
• Identification and targeted marketing/promotion of the program to potential awardees
• A formal recruitment process to Schools and Departments across UW
• A formal process to recruit scientists and physicians into cancer research
• A formal application review, interview, and selection process
• A mechanism for consistent progress reporting and assessment of awardees
• Evaluation of mentor and awardee/mentor relationships
• Oversight of program funds, including matching institutional funds