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Last Updated: 08/15/19

Michigan Prostate SPORE

University of Michigan, Ann Arbor (Primary)

Wayne State University/Karmanos Cancer Institute, Detroit

Principal Investigators:
Arul M. Chinnaiyan, M.D., Ph.D.
Elisabeth Heath, M.D.
Ganesh Palapattu, M.D.

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Arul M. Chinnaiyan, M.D., Ph.D.
S.P. Hicks Endowed Professor of Pathology; Professor of Urology;
Director, Michigan Center for Translational Pathology;
Investigator, Howard Hughes Medical Institute;
American Cancer Society Research Professor
University of Michigan Medical School
1400 E. Medical Center Drive
5316 Rogel Cancer Center
Ann Arbor, MI 48109-0940
Phone: 734-615-4062
Email: arul@med.umich.edu

Elisabeth Heath, M.D.
Professor of Oncology and Medicine;
Associate Center Director, Translational Sciences
Karmanos Cancer Institute
Wayne State University School of Medicine
Detroit, MI 48201-2013
313-576-8624
heathe@karmanos.org

Ganesh S. Palapattu, M.D.
Chair, Department of Urology
George F. and Sandy G. Valassis Professor of Urology
University of Michigan Medical School
1500 E. Medical Center Dr.
3875 Taubman Center
Ann Arbor, 48109-5330
Phone: 734-936-9269
Email: gpalapat@med.umich.edu

OVERVIEW

Since inception in 1995, the University of Michigan (U-M) Prostate SPORE has endeavored to tap the vast intellectual and physical resources of the U-M community to decrease the morbidity and mortality of prostate cancer (PCa). In the 2018 renewal proposal, U-M joined forces with Karmanos Cancer Institute (KCI) to propose a “Michigan Prostate SPORE” leveraging our institutions’ respective areas of strength. KCI has a non-overlapping patient population as U-M, which includes an underserved population. The Michigan Prostate SPORE supports an interactive group of basic and clinical investigators in a translational research program that has led to major discoveries in the diagnosis, prevention, and treatment of PCa.

The current Michigan SPORE consists of three projects: Project 1: Targeting mCRPC Patients with Biallelic Loss of CDK12; Project 2: Integrating a Novel MiPS-Based Next- Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk PCa; Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for mCRPC; These projects are complemented by strong, ongoing institutional commitments of money and space, successful Career Development and Developmental Research Programs, and three cores: Administration, Biostatistics/Bioinformatics, and Biospecimen/Pathology. The Michigan Prostate SPORE continues to place premiums on rigorous scientific review of its translational research programs, pairing of basic and clinical investigators, drawing on expertise of scientists from within and from outside the PCa field, and utilizing flexibility to fund promising new research approaches. The interaction of our multidisciplinary group of investigators clearly makes the Michigan Prostate SPORE greater than the sum of its individual parts.

Project 1: Targeting Metastatic Prostate Cancer Patients with Biallelic Loss of CDK12

Project Co-Leaders:
Arul M. Chinnaiyan, MD, PhD
Ajjai Alva, MD

With the wide-spread integration of next-generation sequencing technology over the past several years, comprehensive genomic studies have shown that prostate cancers can be classified into different molecular subtypes. Identification of these subtypes and molecular drivers of pathogenesis represents an opportunity to design rational precision oncology approaches for treatment. To this end, we have recently identified and characterized a novel molecular subtype of prostate cancer typified by biallelic inactivation of CDK12 and shown that it is enriched in cases of metastatic castration-resistant prostate cancer (mCRPC). CDK12-mutant prostate cancers exhibit a distinct genomic instability pattern from other prostate cancer subtypes, including homologous recombination and mismatch repair-deficient, that is associated with a focal tandem duplication (FTD) phenotype. Importantly, CDK12-FTDs lead to an elevated neoantigen burden from increased gene fusions, and this is mirrored by an active immune response and increased T cell trafficking in the tumor microenvironment. Accordingly, preliminary results from mCRPC patients in our cohort suggest that they may have a higher likelihood of response to immune checkpoint blockade. We, therefore, hypothesize that inactivation of CDK12 results in an immunogenic class of mCRPC that may benefit from immune-directed therapies. This hypothesis will be explored through the following Specific Aims:

Aim 1: Define the functional relevance of CDK12 loss to prostate cancer biology and identify synthetic lethal targets.

Aim 2: Determine the impact of CDK12 ablation on prostate tumor growth and immune response in vivo.

Aim 3: Identify molecular determinants of response in the first clinical trials of immune checkpoint blockade for CDK12-mutant mCPRC patients.

Project 2: Integrating a Novel MiPS-Based Next-Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk Prostate Cancer

Project Co-Leaders:
Ganesh Palapattu, MD;
Simpa Salami, MD
Todd Morgan, MD
Scott Tomlins, MD, PhD

Project 2 of the Michigan Prostate SPORE seeks to improve the early detection of unfavorable risk prostate cancer (PCa) 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 PCa. Men at increased genetic risk represent a newly recognized group in whom early detection is particularly compelling. Generally speaking, a central problem inherent to PCa screening is the profound overdiagnosis of Gleason 6 (low risk) disease. To counterbalance the overtreatment of Gleason 6 PCa, a number of active surveillance (AS) strategies have been introduced. Transition to definitive 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 Gleason 6 PCa on AS represents a major opportunity to improve and optimize resource utilization (prostate biopsy and MRI) as well as the diagnosis of clinically significant PCa. How to reliably identify potentially aggressive PCa so treatment can be appropriately recommended continues to represent a critical knowledge gap. Building on prior work from a successful SPORE project involving the Mi Prostate Score (MiPS) test (using transcription-mediated amplification quantification of urine KLK3, PCA3, and TMPRSS2:ERG), we have developed a novel urine-based NGS assay (MiPS-NGS) to detect unfavorable risk (≥Gleason 7) PCa. MiPS-NGS is a targeted RNA-seq assay comprised of 83 prostate-, PCa-, and aggressive PCa-specific transcripts (e.g., lncRNAs, ETS genes fusions, HOXB13). We hypothesize that MiPS-NGS can improve the early detection of unfavorable risk PCa and will test this through the following Specific Aims:

Aim 1: To assess the utility of MiPS-NGS as a PCa early detection assay in men at high genetic risk.

Aim 2: To determine whether MiPS-NGS can predict grade progression in men on AS.

Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for Castration-Resistant Prostate Cancer

Project Co-Leaders:
Shaomeng Wang, PhD
Ajjai Alva, MD

The past decade has brought the approval of several new treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) that extend overall survival. However, there is no cure for mCRPC, and development of novel therapeutic strategies is critical. Abiraterone and enzalutamide are two agents targeting the androgen receptor (AR) signaling pathway that extend patient survival, confirming the notion that AR remains a driver of mCRPC despite castrate levels of androgen ligands. Several mechanisms evolve during progression to mCRPC and resistance to abiraterone/enzalutamide that function to maintain AR signaling. These include amplification of AR, mutation of the ligand-binding domain of AR, and emergence of constitutively active alternatively spliced AR variants. This suggests that methods to ablate AR expression in mCRPC and deplete continued AR signaling may be effective in providing further survival benefit to patients. In this project, we will evaluate two approaches to ablate AR in mCRPC: AR antisense oligonucleotides (ASOs) and AR degraders. The AR ASO, IONIS-AR-2.5-Rx, has cleared a Phase I study and showed promising clinical responses in a heavily pretreated mCRPC population. Importantly, IONIS-AR-2.5-Rx targets full-length, mutant, and splice variant forms of AR. We have also undertaken a major effort to develop PROTAC (PROteolysis TArgeting Chimeric) AR degraders that function by targeting AR protein to an E3 ubiquitin ligase. Together, we hypothesize that ablation of AR, through ASOs or PROTAC degraders targeting AR, is a highly attractive therapeutic approach for mCRPC, and we will test this through the following Specific Aims:

Aim 1: Evaluate IONIS-AR-2.5Rx, a next-generation AR ASO, in combination with enzalutamide in a Phase Ib/II clinical trial for the treatment of mCRPC.

Aim 2: Develop potent, orally bioavailable AR degraders and study their mechanism of action.

Aim 3: Evaluate AR degraders in preclinical models of prostate cancer to select a candidate for a Phase I clinical trial in mCRPC.

Administration Core

Directors:
Arul M. Chinnaiyan, MD, PhD
Elisabeth Heath, MD
Ganesh Palapattu, MD

The Michigan Prostate SPORE Administration Core is responsible for the leadership, guidance and management of this proposal. The Administration Core oversees all aspects and performs numerous duties across the wide scope of the SPORE to support the translational goals of the investigators. The SPORE Administration Core is guided by the following Specific Aims:

Aim 1: Provide scientific, programmatic and administrative leadership to all aspects of the SPORE.

Aim 2: Develop, facilitate and monitor progress of translational aims with project Co-Leaders.

Aim 3: Identify, support, and facilitate scientific collaborations. The Administration Core is charged with creating a culture of collaboration through fostering and helping to establish and maintain successful collaborations.

Aim 4: Facilitate communication between investigators and groups within the Michigan Prostate SPORE as well as with other institutional SPOREs, the SPORE network outside the University of Michigan (U-M), Karmanos Cancer Institute (KCI), NCI and investigators across the spectrum of translational cancer research.

Aim 5: Perform fiscal and data management functions.

Aim 6: Coordinate patient advocacy and provide functional and ethical oversight to projects and cores.

The Core provides support and oversight to ensure that all investigators have IRB and animal approvals in place to conduct research. The Core will develop and maintain an advocacy portal for our prostate cancer patient community. Arul M. Chinnaiyan, MD, PhD (U-M) serves as Core Director. Ganesh Palapattu, MD (U-M) and Elisabeth Heath, MD (KCI) will serve as Core Co-Directors of the Administrative Core and provide overall scientific oversight. Dr. Chinnaiyan will be responsible for overall program organization and fiscal oversight as well as the Biostatistics/Bioinformatics and Biospecimen/Pathology Cores. Dr. Palapattu will be responsible for mentorship and development of collaborators and trainees, oversight of the Career Enhancement Program and synergies between U-M and KCI programs. Dr. Heath will oversee clinical trials and therapeutics, patient advocacy, minority community engagement, and the Developmental Research Program. This Core provides the framework to support the success and mission of the Michigan Prostate SPORE as a cohesive group of investigators committed to supporting translational research in prostate cancer.

Biostatistics/Bioinformatics Core

Director:
Alexander Tsodikov, PhD

The goal of the Biostatistics/Bioinformatics Core is to collaborate with SPORE Investigators and other Core resource scientists to enhance the quality of the research undertaken in the Michigan Prostate SPORE. The Core personnel have been chosen because of their expertise in relevant areas of Biostatistics and Bioinformatics that is specifically required for the SPORE projects to succeed. Support will be provided in all stages of the research, beginning with the formulation of the research question, through the experimental design stage and data collection stage, including genomic sequencing, data analysis, and interpretation, to the writing of reports and dissemination of results. It will be apparent from this proposal that Core personnel have played a significant role in designing the proposed experiments and planning the data analyses. The exact nature of the collaboration will depend on the specifics of the science and the needs of the project. In addition to direct support of the projects and other Cores, senior statisticians will also focus on statistical methodology development and the advancement of genomic/bioinformatic capabilities related to the needs of prostate cancer research in this SPORE. Thus, the Specific Aims of the Core are:

1) Assist Investigators in the design of clinical, laboratory, and high-throughput genomic sequencing experiments;

2) Assist Investigators in the analysis and interpretation of data from clinical and laboratory experiments, the processing and examination of high-throughput genomic datasets, and in writing of manuscripts relaying Michigan Prostate SPORE results to the scientific community;

3) Undertake translational biostatistics/bioinformatics research to develop methodology and software implementation relevant to prostate cancer including the development of algorithmic toolkits for emerging types of genomic assays and the adaptation/refinement of existing computational approaches to the needs of the Michigan Prostate SPORE;

4) To establish a center of excellence for immunogenomics in prostate cancer. The center will provide state-of-art support for interdisciplinary research at the interface of cancer immunology and genomics and facilitate the rapid clinical translation of immunogenomic findings.

The Biostatistics/Bioinformatics Core will be led by Dr. Alexander Tsodikov, Ph.D., a Professor of Biostatistics at U-M. He has served as the Director of the Prostate SPORE Biostatistics Core since 2009 and has substantial experience in the development of mechanistic statistical models of prostate cancer and biostatistical methodology and software, and statistical models in cancer. Drs. Jeremy Taylor, Ph.D. (U-M), Hui Jiang, Ph.D. (U-M), Lance Heilbrun, Ph.D. (KCI), and Marcin Cieslik, Ph.D. (U-M), will serve as Co-Investigators.

Biospecimen/Pathology Core

Directors:
Lakshmi Priya Kunju, MD
Arul M. Chinnaiyan, MD, PhD

The goal of Michigan Prostate SPORE Biospecimen/Pathology Core is to collect biological materials with associated clinical information to facilitate translational prostate cancer research. The Core places patient confidentiality and clinical care as a top priority. As a coordinated effort between pathology, urology, medical oncology, radiation oncology, and Michigan Prostate SPORE researchers, the Core has developed a unified informatics infrastructure that provides researchers a wide range of annotated samples. The specific goals of the Core include:

(1) Protection of patient welfare. The highest priority is given to assure that no research protocol compromises pathology diagnosis or tumor staging.

(2) Acquisition and processing of prostate tissues for research. The Core assures that the widest range of prostate tissues and derived biomolecules are available from various sources, including benign prostate tissue from patients without any known prostatic disease, clinically localized prostate cancer, and metastatic hormone refractory prostate cancer (Michigan Legacy Tissue Program).

(3) High quality pathologic review of prostate tissues. Expert GU pathologists assure uniform review of prostate tissue samples.

(4) Pathology consultation for the purpose of designing translational research projects. This service focuses on determining the types of tissues and amount required for the successful completion of the research projects.

(5) Quality assessment of prostate tissues and clinical data. The Biospecimen/Pathology Core staff regularly evaluates frozen and formalin fixed tissues for adequacy.

(6) Development of technology appropriate for pathology-based translational research. New technologies such as integrative high-throughput sequencing, RNA in situ hybridization, and single-cell analysis have been introduced.

(7) Provide support to ongoing clinical studies. The Core will continue to provide tissue procurement services and/or high-quality pathology reviews of specimens from patients enrolled in various clinical trials and studies.

(8) Maintenance of clinical and pathology data with links to molecular studies. The Core will continue to expand the detailed clinical and pathology database conforming to the NCI’s Common Data Elements (CDE) guidelines, permitting queries between molecular findings and clinically relevant outcomes.

In summary, the Core will provide SPORE investigators with a wealth of carefully annotated samples for translational research, while maintaining the highest level of clinical care and patient confidentiality.

DEVELOPMENTAL RESEARCH PROGRAM

Directors:
Elisabeth Heath, MD
Evan Keller, DVM, PhD

Recognizing that developmental research funds are an integral part of the SPORE, we commit approximately $150,000 per year to these endeavors. This represents a significant portion of the Prostate SPORE budget and reflects the continued commitment to the development of innovative translational research in prostate cancer. The focus of the Developmental Research Program (DRP) is to provide investigators the resources to generate preliminary data for the submission of an R01 grant application or an equivalent proposal.

CAREER ENHANCEMENT PROGRAM

Directors:
Diane Robins, PhD
Goutham Narla, MD, PhD
Jennifer Beebe-Dimmer, PhD, MPH

Prostate cancer research has been greatly hindered by the paucity of new investigators entering the field. In recognition of the need to help establish independently funded investigators in the field of translational prostate cancer research, the Michigan Prostate SPORE has supported two to three junior faculty per year. The focus of the Career Enhancement Program (CEP) is to provide investigators the resources to generate preliminary data for subsequent NIH R01 grant applications or future SPORE projects.