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Mayo Clinic/University of Minnesota Prostate Cancer SPORE

Mayo Clinic 

University of Minnesota

Principal Investigators

 

Elisabeth I. Heath M.D., FACP
Chair, Department of Oncology
Professor of Oncology
Senior Associate Consultant, Department of Oncology
Deputy Director, Mayo Clinic Comprehensive Cancer Center
200 First Street SW
Rochester, MN 55905
(507) 538-5337

 

Emmanuel S Antonarakis, M.D.
Clark Endowed Professor of Medicine
Department of Medicine; Division of Hematology, Oncology and Transplantation
Associate Director Translation Masonic Cancer Center
University of Minnesota
410 Delaware Street SE, MMC 480
Minneapolis, MN 55455
(612) 301-2180

Overview

The Mayo Clinic–University of Minnesota SPORE in Prostate Cancer (Mayo/UMN Prostate Cancer SPORE) combines prostate cancer translational research expertise across two NCI-designated Comprehensive Cancer Centers: Mayo Clinic Comprehensive Cancer Center in Rochester, MN, Phoenix, AZ, and Jacksonville, FL; and the University of Minnesota Masonic Cancer Center in Minneapolis. Led by Drs. Elisabeth Heath and Emmanuel Antonarakis, with laboratory-based Co-Investigators Drs. Josep Domingo-Domenech and Scott Dehm, the Mayo/UMN Prostate Cancer SPORE bridges clinical and laboratory science to reduce morbidity and mortality from metastatic castration-resistant prostate cancer (mCRPC). Its overarching goal is to develop molecularly targeted therapies for patients (together with advocates) afflicted by mCRPC. The SPORE includes four Translational Research Projects, supported by Career Enhancement and Developmental Research Programs, institutional matching funds, research space, and three integrated cores: Administrative, Biospecimen/Pathology, and Biostatistics/Bioinformatics. Altogether, we anticipate that the results obtained from our research endeavors will have a significant impact on the health and longevity of patients with metastatic prostate cancer.

  • Aim 1: Support multidisciplinary projects that pair basic, translational, and clinical investigators with expertise from within and outside the prostate cancer field.
  • Aim 2: Provide world-class infrastructure to conduct innovative, high-quality, high-impact translational prostate cancer research with direct near-term relevance to patients.
  • Aim 3: Support efforts to develop bench-to-bedside discoveries in clinical diagnostics and therapeutics. 
  • Aim 4: Provide support for pilot projects with high potential to advance prostate cancer research by generating preliminary data that will form the basis of future progress against prostate cancer.  
  • Aim 5: Recruit and train early-stage scientists to become the next generation of leaders in translational prostate cancer research through access to mentors who are experts in the basic and clinical sciences, as well as networking opportunities among other Project and Core leaders.
  • Aim 6: Foster collaborations among investigators within and between the two institutions, and to the broader community of prostate cancer investigators at large.

Project 1: Targeting TP53-altered castration-resistant prostate cancer with bipolar androgen therapy (BAT) plus carboplatin

Project 1 Co-Leaders:

Specific Aims

Prostate cancer is the most frequently diagnosed cancer in men. Localized prostate cancer is often treated with surgery or radiation, while advanced or metastatic disease is treated with endocrine therapies targeting the androgen receptor (AR). Although these therapies are initially effective, most patients eventually develop metastatic castration-resistant prostate cancer (mCRPC). Bipolar androgen therapy (BAT), which alternates between supraphysiologic and castrate testosterone levels, offers a paradoxical treatment strategy for mCRPC patients. Preliminary data suggest that patients with TP53-altered mCRPC may respond better to BAT than to enzalutamide, while patients without TP53 alterations respond better to enzalutamide. TP53-altered tumors also show higher rates of AR amplification, potentially through AR extrachromosomal DNA (ecDNA). Our patient-derived xenograft data show strong BAT responses in AR ecDNA-amplified tumors, followed by resistance marked by AR ecDNA downregulation. Based on these findings, we will conduct a BAT-based randomized clinical trial targeting mCRPC patients with TP53 alterations, a population representing 30–50% of cases and with limited response to current hormonal and chemotherapeutic options.

  • Aim 1: Conduct a biomarker-rich randomized trial of BAT plus carboplatin versus cabazitaxel plus carboplatin in TP53-altered mCRPC.
  • Aim 2: Determine molecular profiles of clinical response to BAT plus carboplatin in mCRPC patients.
  • Aim 3: Define the mechanistic basis for clinical response to BAT plus carboplatin.

Project 2: Harnessing synthetic lethality in DNA replication stress for SPOP-mutated castration-resistant prostate cancer

Project Co-Leaders:

Specific Aims

Treatment options remain limited for patients with castration-resistant prostate cancer (CRPC) harboring Speckle Type BTB/POZ protein (SPOP) mutations. These mutations disrupt DNA replication licensing and create dependence on the Ataxia telangiectasia and Rad3-related kinase (ATR) pathway, a key regulator of replication surveillance and repair. We hypothesize that ATR inhibition will exploit this vulnerability and produce synthetic lethality in SPOP-mutant prostate cancer. This project will define mechanisms of ATR sensitivity, identify resistance pathways and biomarkers, and evaluate tuvusertib (formerly M1774, an ATR inhibitor) in a phase II trial with serial biopsies and blood-based correlative studies. Findings may establish ATR inhibition as a precision therapy for refractory SPOP-mutant CRPC.

  • Aim 1: Determine the molecular basis of synthetic lethality of ATR inhibition in SPOP-mutated prostate cancer. 
  • Aim 2: Determine the role of compensatory SPOPL in SPOP-mutated mCRPC.
  • Aim 3: Analyze and evaluate patient outcomes in a phase II clinical trial of ATR inhibitor, tuvusertib (formerly M1774), in castration-resistant SPOP-mutant prostate cancer.

Project 3: Targeting B7-H3 using tri-specific killer engagers (TriKE) to treat metastatic castration-resistant prostate cancer 

Project Co-Leaders:

Specific Aims

Prostate cancer is a leading cause of cancer death in men, and current immunotherapies have shown limited benefit in metastatic castration-resistant prostate cancer (mCRPC). Our team has extensive experience developing natural killer (NK) cell therapies, including more than 500 treated patients across 18 INDs and first-in-human IL-15 agent trials. To overcome limited tumor specificity, we have developed trispecific killer engagers (TriKEs) that activate NK cells through CD16, support NK cell survival with IL-15, and direct targeting to tumor antigens. For treatment of mCRPC, we engineered a camelid nanobody anti-B7-H3 TriKE (camB7-H3 TriKE), because B7-H3 is widely expressed in mCRPC, including in PSMA-negative tumors, increases with advanced disease, and persists after androgen receptor pathway inhibitor (ARPI) therapy. We will conduct a multicenter, first-in-human phase Ia trial to assess camB7-H3 TriKE safety and determine the maximum tolerated dose, followed by a phase Ib trial in mCRPC patients progressing on novel ARPIs using a composite PSA/radiographic response endpoint. Correlative studies will evaluate peripheral blood, tumor immune signatures, and tumor characteristics before and during treatment. We will also test dual B7-H3/PSMA-targeted TriKE Poly-Antigen Cytokine Complex (PACC) formulations to reduce antigen escape. This project integrates expertise in NK-cell therapy, engager design, prostate cancer trials, and spatial omics and may establish the first NK-cell engager approach for mCRPC.

  • Aim 1: Conduct a first-in-human phase Ia clinical trial to investigate the safety of camB7-H3 TriKE and then a phase Ib study for the treatment of mCRPC patients with progression on novel ARPI. 
  • Aim 2: Evaluate peripheral blood and the tumor microenvironment immune signatures and tumor characteristics before and during camB7-H3 TriKE therapy.
  • Aim 3: Pre-clinical evaluation of dual-antigen targeting strategies, using novel camB7-H3/camPSMA TriKE-PACCs, for improved NK cell immunotherapy in prostate cancer.

Project 4: The synergy of PARP inhibition plus Aurora Kinase inhibition in advanced prostate cancer therapy

Project Co-Leaders:

Specific Aims

Prostate cancer is the most commonly diagnosed cancer in men. Historically, single agent androgen deprivation therapy (ADT) has been the cornerstone of treatment for metastatic prostate cancer. In recent years, second-generation androgen receptor pathway inhibitors (ARPIs) have been combined with ADT to treat metastatic hormone sensitive patients. In most cases, even though ADT-based therapy is initially effective, >95% of patients will progress, indicative of metastatic castrate-resistant prostate cancer (mCRPC) and require new treatment options. Recent FDA approvals of PARP inhibitors (PARPi) have broadened treatment options for mCRPC patients with homologous recombination repair (HRR) deficiencies, but resistance is common and PARPi activity in HRR-proficient disease remains limited. Using data-driven drug screening followed by experimental validation, we identified synergy between PARPi and Aurora kinase inhibition (AurKi). In BRCA wild-type and mutant prostate cancer models, this combination induced ferroptosis-mediated cell death. We hypothesize that PARPi and AurKi will have a synergistic therapeutic effect through induction of ferroptosis, leading to enhanced cell death. Clinically, adding AurKi could enhance PARPi efficacy and expand its potential usage to patients with normal HRR function.

  • Aim 1: Evaluate how PARPi plus AurKi synergistically kill prostate cancer cells through inducing ferroptosis.
  • Aim 2: Evaluate and validate the effect of single and combined PARPi and AurKi therapy using prostate cancer xenografts, mCRPC PDX models (with or without BRCA mutations), and immune-competent prostate cancer models.
  • Aim 3: Conduct a phase I/II clinical trial to determine the dose, safety, and preliminary efficacy of the PARPi/AurKi combination treatment. Additional correlative studies will be performed to study pathways related to ferroptosis.

Administrative Core

Core Co-Directors:

Specific Aims

The Administrative Core (Core A) provides scientific leadership, operational oversight, and coordination for the Mayo/UMN Prostate Cancer SPORE. Led by Drs. Elisabeth Heath and Emmanuel Antonarakis, with support from Drs. Josep Domingo-Domenech and Scott Dehm, Core A integrates basic, clinical, and translational research across Mayo and UMN; supports DRP/CEP activities; facilitates collaboration with other SPOREs and external partners; coordinates responses to NCI; promotes effective governance, mentorship, communication, and cross-institutional collaboration.

  • Aim 1: Provide scientific leadership and managerial oversight, integrating clinical, translational, and basic research across both NCI-designated Comprehensive Cancer Centers.
  • Aim 2: Maintain clear governance structure for decisions, conflict resolution and escalation process involving Internal and External Advisory Boards (IAB and EAB) for conflicts unresolved by SPORE Executive Committee.
  • Aim 3: Create and sustain collaborations and new research opportunities through DRP funding and new translational investigator CEP recipients.
  • Aim 4: Facilitate interactions within SPORE, external Prostate Cancer SPOREs, and other Mayo and UMN SPOREs.
  • Aim 5: Ensure regular communication among SPORE leadership team, DRP/CEP recipients, Mayo, UMN, their Schools and Departments, NCI and sponsors.
  • Aim 6: Disseminate information and communication across SPORE team, research programs, Executive Committee, IAB, EAB, NIH/NCI, patient advocates, and community.

Biospecimen/Pathology Core

Core Co-Directors:

Specific Aims

The Biospecimen/Pathology Core (Core B) provides Mayo/UMN Prostate Cancer SPORE investigators with high-quality, consented prostate cancer biospecimens and linked clinical data. Core B supports standardized collection, processing, annotation, quality control, pathologic review, tissue microarrays, IHC, FISH, blood processing, immune monitoring, and patient-derived models. A Biospecimen Access Committee prioritizes specimen use; coordination with Core C (Biostatistics/Bioinformatics Core) ensures clinical annotation and data integration. Core B supports DRP and CEP awardees, shares resources with SPORE investigators, and broader prostate cancer research community to advance translational research and improve patient outcomes.

  • Aim 1: Coordinate acquisition of biospecimens for prostate cancer research.
  • Aim 2: Provide quality-control metrics and pathologic characterization of procured biospecimens.
  • Aim 3: Orchestrate timely distribution of biospecimens internally and externally, prioritizing Prostate Cancer SPORE projects and investigators.
  • Aim 4: Provide research services for tumor sectioning, antibody optimization, IHC, FISH, immune-profiling and generation of organoid and xenograft models.
  • Aim 5: Facilitate characterization of archived prostate cancer specimens at the two centers.
  • Aim 6: Interface with Core C to coordinate selection of study sets, provision of data sets, and maintenance of databases.
  • Aim 7: Facilitate collaborations between the Mayo/UMN Prostate Cancer SPORE and other Prostate Cancer SPORE groups outside the two institutions.

Biostatistics and Bioinformatics Core

Core Director:

Specific Aims

The Biostatistics/Bioinformatics Core (Core C) provides centralized study design, data management, analysis, and bioinformatics support for all Mayo/UMN Prostate Cancer SPORE projects. By standardizing these functions across projects, Core C promotes efficiency, reproducibility, open science, and high-quality statistical and bioinformatics practices. Core investigators bring expertise in clinical trial design, biomarker development and validation, high-dimensional data analysis, and collaborative team science. Core C also supports CEP/DRP projects, facilitates cross-project analyses, and helps investigators maximize the value and impact of SPORE-generated data.

  • Aim 1: Provide statistical and bioinformatics expertise in support of design, implementation, analysis, integration, and dissemination of results for all Mayo/UMN Prostate Cancer SPORE projects.
  • Aim 2: Design and execute a comprehensive plan to manage, integrate, and store data collected by each of the SPORE projects.
  • Aim 3: Facilitate interaction among the SPORE projects, including pan-SPORE secondary statistical and informatics analyses. 

Developmental Research Program

Program Co-Directors:

Specific Aims

The Developmental Research Program (DRP) supports innovative prostate cancer projects with strong translational potential through seed funding, rigorous review, and ongoing monitoring. By fostering multidisciplinary collaboration and new research directions, the DRP builds a pipeline of projects that may become future full SPORE projects or secure external funding. Its goal is to accelerate discoveries that improve treatment strategies, survival, and quality of life for patients with prostate cancer.

  • Aim 1: Identify and cultivate innovative research proposals spanning laboratory, clinical, early detection, prevention, and population health, all of which exhibit strong translational potential.
  • Aim 2: Integrate DRP awardees into the larger Mayo/UMN Prostate Cancer SPORE community by fostering participation in monthly meetings, group communications, and opportunities to expand funding and collaborations.
  • Aim 3: Implement rigorous mentoring, continuous monitoring, evaluation, and outcomes tracking of developmental research projects, identify opportunities for sustained funding of successful initiatives.

Career Enhancement Program

Program Co-Directors:

Specific Aims

The Career Enhancement Program (CEP) strengthens the prostate cancer translational research workforce by identifying, funding, and mentoring promising junior investigators and established scientists refocusing on prostate cancer. The CEP provides pilot funding for one year, with a possible second year based on progress, and uses rigorous review, mentoring, SPORE integration, and oversight to support career development. By leveraging Mayo Clinic and UMN strengths, the CEP prepares awardees to become independent prostate cancer researchers, secure extramural funding, and advance discoveries that improve patient outcomes.

  • Aim 1: Identify and fund the most promising junior faculty for careers in prostate cancer.
  • Aim 2: Identify and fund senior investigators not previously focusing on prostate cancer translational research.
  • Aim 3: Provide individualized mentoring to CEP investigators to facilitate their development into independent prostate cancer translational investigators.
  • Aim 4: Conduct rigorous monitoring and evaluation of all awardees.
  • Aim 5: Facilitate CEP awardee achievement of extramural grant funding.
  • Aim 6: Integrate awardees into future SPORE projects and develop them as future leaders in prostate cancer translational research.
     
  • Posted:

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