University of Wisconsin Prostate SPORE
University of Wisconsin School of Medicine and Public Health
Principal Investigator(s):
David Jarrard, MD
Douglas McNeel, MD, PhD
- Principal Investigator(s) Contact Information
- Overview
- 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
- Administrative Core
- Integrated Pathology and Radiology Core (iPRC)
- Biostatistics and Bioinformatics Core (BBC)
- Developmental Research Program (DRP)
- Career Enhancement Program
Principal Investigator(s) Contact Information
David Jarrard, MD
Professor
Vice Chair in Urology
John P. Livesey Chair in Urologic Oncology
Deputy Director, UW Carbone Cancer Center
University of Wisconsin SMPH
1685 Highland Ave
Madison, Wisconsin, 53705-2281
(608) 262-0759
Douglas McNeel, MD, PhD
Faculty, Hematology/Oncology
University of Wisconsin SMPH
1111 Highland Ave
Madison, Wisconsin, 53705-2275
(608)- 263- 4198
Overview
The University of Wisconsin (UW) Prostate Cancer 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 Initiators of the Metastatic Cascade in High-Risk Prostate Cancer
Project Co-Leaders:
Joshua Lang, MD, MSc (Clinical)
David Beebe, PhD (Basic)
David Jarrard, MD
Melissa Skala, PhD
Sheen Kerr, PhD
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 TME to promote invasion and intravasation of lympho-vascular channels. To test this hypothesis, we have three cohorts of patients with high-risk prostate cancer (surgery alone, neoadjuvant Abiraterone, and neoadjuvant chemohormonal therapy) that undergo PSMA PET/MRI scans prior to surgery. This scan is used to develop 3D mold of the prostate to perform whole mount sectioning and dissection of multi-focal 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 IHC data to perform transcriptional Digital Spatial Profiling (DSP) on whole-mount sections collected in Aim 1. This integration will test whether distinct 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, MD, PhD (Basic)
Christos Kyriakopoulos, MD (Clinical)
David Jarrard, MD
The hypothesis to be tested in this proposal is that combined androgen deprivation, with AR-targeted vaccination and T-cell checkpoint blockade, will lead to increased tumor-specific CD8+ T cell infiltration, tumor eradication, and persistent immune memory. This proposal will use relevant murine models of prostate cancer (PC) to conduct a mechanistic evaluation of the effects of AD with vaccination and ICR blockade on the development of T-cell memory and antigen spread. This approach will also be evaluated in the clinic using tissue samples collected from patients treated in a pilot investigator-initiated clinical trial that will be conducted in patients with high-risk PC prior to prostatectomy, a stage of disease not requiring long-term AD, yet permitting detailed biomarker assessments using tissue samples.
Specific Aims
Aim 1: Determine whether different methods of androgen deprivation affect the immune recognition of prostate tumors and lead to increased anti-tumor immune response in combination with AR-targeted vaccination.
Aim 2: Determine whether AR-targeted vaccination, in combination with androgen deprivation and T cell checkpoint blockade, leads to increased AR-specific CD8+ T cell infiltration and persistent anti-tumor immune memory.
Aim 3: Discover whether AR-targeted vaccination, in combination with androgen deprivation and PD-1 blockade, leads to increased tumor-infiltrating CD8+ T cells with memory and effector function, and persistent CD8+ T cell memory, in patients with newly diagnosed high-risk prostate cancer.
PROJECT 3: Extending Clinical Benefit by Selective Treatment of Resistant Lesions in mCRPC
Project Co-Leaders:
Glenn Liu, MD (Clinical)
Robert Jeraj, PhD (Basic)
Development of treatment resistance is the main reason for disease progression in patients with mCRPC. What is under-appreciated is that many patients who are experiencing progression have the majority of individual lesions that 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., 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 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, as it triggers high anxiety in the patient and provider, and thus it is 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 Directors:
David Jarrard, MD
Douglas McNeel, MD, PhD
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 also 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 (efforts to increase diversity in clinical and translational research populations)
Aim 7: Data Management
Aim 8: Communications
Integrated Pathology and Radiology Core (iPRC)
Core Directors:
Steve Cho, MD
Wei Huang, MD
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, MD, MSE
Jens Eickhoff, PhD
Menggang Yu, PhD
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 (DRP)
Program Directors:
Will Ricke, PhD
Glenn Liu, MD
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
Core Directors:
Josh Lang, MD, MsC
Melissa Skala, PhD
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 towards 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 specifically recruit women and URM 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