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Michigan Prostate Cancer SPORE

University of Michigan 

Principal Investigators

Photo of Dr. Arul Chinnaiyan

Arul Chinnaiyan, M.D., Ph.D.

Arul Chinnaiyan, M.D., Ph.D.
S.P. Hicks Endowed Professor of Pathology
Director, Michigan Center for Translational Pathology
Professor, Department of Pathology and Urology
Investigator, Howard Hughes Medical Institute
University of Michigan Medical School
1500 E. Medical Center Drive
5316 Rogel Cancer Center
Ann Arbor, MI 48109
734-615-4062

Ganesh Palapattu, M.D.

Ganesh Palapattu, M.D.
George F. and Sandy G. Valassis Professor of Urology
1500 E. Medical Center Drive
SPC 5913
Ann Arbor, MI 48109
734-355-7844

Overview

Since its inception in 1995, the Michigan Prostate SPORE has harnessed the extensive intellectual and physical resources of the University of Michigan (U-M) community to reduce the morbidity and mortality associated with prostate cancer. The program supports an interactive group of basic and clinical investigators engaged in translational research, leading to significant advancements in the diagnosis, prevention, and treatment of prostate cancer. These translational research efforts are bolstered by horizontal and vertical collaborations with numerous institutions, resources, and biotech companies. The current Michigan Prostate SPORE consists of three Projects:

  • Project 1: Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in neuroendocrine prostate cancer.  
  • Project 2: Validation and clinical utility of a multiplex urine biomarker for identification of clinically significant prostate cancer.
  • Project 3: Development of serine/threonine phosphatase PP2A molecular glues for the treatment of advanced prostate cancer.

These Projects are supported by ongoing institutional commitment of funding and space, successful Career Enhancement and Developmental Research Programs, and three Cores: Administrative, Biostatistics/Bioinformatics, and Biospecimen/Pathology. The Michigan Prostate SPORE continues to prioritize rigorous scientific review of its translational research programs, the collaboration of basic and clinical investigators, leveraging expertise from within and outside the prostate cancer field, and maintaining flexibility to fund promising new research approaches. The Michigan Prostate SPORE has a long history of success and has been instrumental in many landmark discoveries that have changed the clinical management of prostate cancer patients. Our strong multidisciplinary program will ensure the successful completion of our proposed aims for each Project and Core.

Project 1: Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in neuroendocrine prostate cancer

Project Co-Leaders

Neuroendocrine prostate cancer (NEPC) is an aggressive form of advanced prostate cancer with few treatment options other than systemic chemotherapies, for which patients invariably develop resistance. Targeted therapies are, thus, urgently needed for this lethal disease. Although NEPC can arise de novo, most cases result from an adenocarcinoma to neuroendocrine transdifferentiation process that occurs in tumors of castration-resistant prostate cancer (CRPC) patients receiving standard of care therapies targeting the androgen receptor (AR). The tumor microenvironment of NEPC is often hypoxic and nutrient-depleted, leading to enhanced dependence on autophagy and lysosome-dependent nutrient survival pathways within cancer cells. Blocking autophagy with genetic methods suppresses tumor growth and increases survival in preclinical models. Here, we have identified the lipid kinase PIKfyve as a key player mediating autophagy and lysosomal adaptation processes in NEPC. Interestingly, although AR-positive CRPC is sensitive to PIKfyve inhibitors in vitro, PIKfyve inhibitor treatment results in cytotoxicity in NEPC cells and enhanced tumor growth inhibition and regression. Our preliminary data also suggest that PIKfyve inhibition results in increased de novo lipid synthesis and that combined targeting of the MAPK pathway and PIKfyve may be a synthetic lethal strategy for NEPC. Here, we will develop potent, selective PIKfyve degraders and employ them to validate PIKfyve as a viable therapeutic target for NEPC. Pathways leading to enhanced activity of PIKfyve inhibition (e.g., MEK inhibition) in NEPC will also be delineated. The following specific aims will be pursued:

Aim 1: Employ novel proteolysis-targeting chimera (PROTAC) degraders to define the mechanism by which PIKfyve loss preferentially impacts NEPC. 

Aim 2: Define synthetic lethality relationships with PIKfyve antagonism in NEPC. 

Aim 3: Determine whether PIKfyve degradation combined with standard of care therapies for NEPC enhances outcomes in preclinical models. 

Aim 4: Establish an investigator-initiated phase II trial evaluating a clinical PIKfyve inhibitor (ESK981) in NEPC.  

Project 2: Validation and clinical utility of a multiplex urine biomarker for identification of clinically significant prostate cancer

Project Co-Leaders

While serum prostate-specific antigen (PSA)-based screening for prostate cancer early detection reduces cancer-specific mortality, the limited specificity of PSA for clinically significant cancer (csPCa; Grade Group [GG]≥2) results in the over-detection of indolent disease, subjecting patients to the harms of overtreatment. Similarly, while unequivocal evidence has demonstrated the safety of active surveillance (AS) for favorable-risk disease, adoption has been modest. While multiparametric magnetic resonance imaging and current biomarker tests have both been utilized in the AS and initial diagnostic settings, their prognostic performance in these scenarios is mixed. Thus, there remains a critical need for a reliable, accurate biomarker for csPCa detection. Our long-term goal is to enable accurate, large-scale, non-invasive biomarker testing to reliably identify individuals with csPCa and demonstrate clinical utility of a biomarker-based approach for early detection. The objective of the current project is to evaluate, optimize, and validate a novel urine-based biomarker (MPS2) to detect csPCa. MPS2 is an 18-gene multiplex, qPCR-based assay that was externally validated in the prospective National Cancer Institute–Early Detection Research Network PCA3 Evaluation Trial. With AS now the recognized standard of care for patients with low-risk prostate cancer, the goals of both early detection and AS have merged: namely, to detect csPCa and spare others from unnecessary procedures or treatments. The absence of reliable biomarkers to identify men with csPCa among those with an elevated PSA or on AS represents a significant clinical gap. We hypothesize MPS2 will improve strategies for csPCa detection in both settings. To test this hypothesis, we propose the following aims:
     
Aim 1: Evaluate the clinical utility of MPS2 testing for detection of csPCa in patients with elevated PSA.

Aim 2: Validate a urine-based molecular assay in the AS setting to identify patients likely to harbor or subsequently develop csPCa.

Project 3: Development of serine/threonine phosphatase PP2A molecular glues for the treatment of advanced prostate cancer 

Project Co-Leaders

Protein Phosphatase 2A (PP2A) functions as a tumor suppressor and is frequently inactivated in cancer by genetic and non-genetic mechanisms. PP2A biogenesis is highly regulated through predominantly non-genetic mechanisms, specifically carboxymethylation of the terminal L309 residue catalyzed by the enzyme leucine carboxy methyltransferase (LCMT1). In general, carboxymethylation of L309 is required for the formation of tumor suppressive PP2A holoenzymes, and loss of this post-translational modification is commonly seen in cancer. We recently showed that loss of PP2A carboxymethylation is a common event in prostate cancer and is associated with progression, increased metastatic potential, and treatment resistance to androgen deprivation therapies. Genetic depletion of LCMT1 results in AR and MYC activation and drives prostate cancer growth. We and others have demonstrated that, specifically, the PP2A AB56αC heterotrimer is a major negative regulator of AR and MYC signaling. We have developed a series of first-in-class PP2A molecular glues (PMGs) that stabilize the tumor suppressive PP2A AB56αC heterotrimer, resulting in inhibition of prostate cancer growth both in vitro and in vivo. The lead compound, RPT04402, has undergone extensive preclinical toxicology studies in two animal species and has entered IND-enabling studies. The goals of this project are to define the depth and breadth of activity of RPT04402 in translationally aligned xenograft and patient-derived xenograft models of metastatic castration-resistant prostate cancer (mCRPC), identify substrate/effector pathways that drive preclinical efficacy, and evaluate RPT04402 as a monotherapy and, if preclinical data warrant, in combinations (e.g., enzalutamide) through a clinical trial. 

Aim 1: Elucidate the mechanism of action of PP2A molecular glues (PMGs) in affecting AR signaling and prostate cancer growth in cell line and organoid models. 

Aim 2: Conduct comprehensive efficacy studies of RPT04402, a clinical candidate PMG, alone and in combination with AR-targeting agents employing multiple preclinical models of CRPC. 

Aim 3: Determine predictive biomarkers of response to PMGs and initiate a phase I/II trial with RPT04402 in metastatic CRPC patients. 

Administrative Core

Core Co-Directors

The Administrative Core is responsible for the leadership, guidance, and management of the program. The Administrative Core oversees all aspects and performs numerous duties across the scope of the SPORE to support the translational goals of the investigators. The Core provides support and oversight to ensure that all investigators have IRB and animal approvals in place to conduct research. The Administrative 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 Administrative 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, NCI, and investigators across the spectrum of translational cancer research. 

Aim 5: Perform fiscal and data management functions. 

Aim 6: Provide functional and ethical oversight to projects and cores and coordinate patient advocacy.  

Biospecimen/Pathology Core

Core Director

The overall goal of the 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 with a wide range of annotated samples. The specific aims of the Core include:

Aim 1: Protection of patient welfare and assurance that no research protocol compromises pathology diagnosis or tumor staging.

Aim 2: Acquisition and processing of prostate tissues for research. 

Aim 3: High quality pathologic review of prostate tissues by expert GU pathologists.

Aim 4: Pathology consultation for the purpose of designing translational research projects.

Aim 5: Quality assessment of prostate tissues and clinical data. 

Aim 6: Development of technology appropriate for pathology-based translational research. 

Aim 7: Provide support to ongoing clinical studies. 

Aim 8: Maintenance of clinical and pathology data with links to molecular studies.  

Biostatistics/Bioinformatics Core

Core Directors

The goal of the Biostatistics/Bioinformatics Core is to collaborate with investigators and other Core resource scientists to enhance the quality of research in the Michigan Prostate SPORE. Support will be provided at all stages of research, beginning with the formulation of the research question, through the experimental design and data collection stages, including genomic sequencing, data analysis, and interpretation, to manuscript preparation. Core personnel have played a significant role in designing the proposed experiments and planning the data analysis throughout the SPORE. 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. The specific aims of the Core are:

Aim 1: Assist investigators in the design of clinical, laboratory, and high-throughput genomic sequencing experiments.

Aim 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.

Aim 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. 

Developmental Research Program

Program Directors

The Michigan Prostate SPORE Developmental Research Program (DRP) plays a pivotal role in advancing our understanding of prostate cancer and is crucial for improving patient outcomes and treatment strategies. Moreover, our DRP fosters innovation, collaboration, and diverse perspectives within the prostate research community at the University of Michigan. Through interdisciplinary approaches and the integration of cutting-edge technologies, researchers can explore novel avenues of investigation and uncover previously unknown aspects of prostate cancer biology. Furthermore, our DRP provides a foundation for translational research, facilitating the translation of fundamental discoveries into clinical applications. By bridging the gap between basic research and clinical practice, this program can expedite the development of new diagnostic tools, prognostic indicators, and targeted therapies. Ultimately, the hope is that integration of developmental research findings into clinical practice has the potential to revolutionize the management and care of prostate cancer patients, contributing significantly to the overall reduction in prostate cancer-related mortality rates. 

Career Enhancement Program

Program Co-Directors

The Michigan Prostate SPORE Career Enhancement Program (CEP) aims to cultivate the next generation of scientists and clinicians dedicated to advancing the understanding and treatment of prostate cancer. The CEP provides structured support tailored to meet the specific needs of translational prostate cancer researchers at the University of Michigan. This can encompass cutting-edge research techniques, bioinformatics, epidemiology, data analysis, and clinical trial design. Moreover, the program emphasizes soft skills, such as communication, collaboration, and leadership, to equip CEP awardees with the ability to effectively communicate their findings, collaborate with peers and clinicians, and lead successful prostate cancer research projects. CEP participants will benefit from exposure to leading prostate oncology experts at U-M, as well as engage in the inter-SPORE meeting. Collaborations with industry partners and other research institutions offer participants access to state-of-the-art technologies, resources, and funding opportunities to further their research. Research efforts supported by the SPORE have led to landmark studies published in high impact journals, and CEP investigators have gone on to obtain numerous independent grants, furthering their career and the overall field of prostate cancer research. 
 

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