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Last Updated: 10/10/18

University of Michigan SPORE in Prostate Cancer

Principal Investigator Contact Information

Arul Chinnaiyan, MD, PhD
Professor, Department of Pathology and Urology
Director, Pathology Research Informatics
University of Michigan Medical Center
5316 CCGC, Box 0940
1400 East Medical Center Drive
Ann Arbor, MI 48109
Phone: (734) 615-4062
Fax: (734) 615-4498
Email: arul@umich.edu

Ganesh Palapattu, MD
George F and Sandy G Valassis Professor of Urology
Michigan Medicine Urology Oncology Clinic
Rogel Cancer Center
Floor B1 Reception E
1500 E Medical Center Dr. SPC 5913
Ann Arbor, MI 48109
Phone: (734) 647-8903
Fax: (734) 647-8860
Email: gpalapat@umich.edu

OVERALL SPORE GOALS AND SPECIFIC AIMS

Since its inception in 1995, the University of Michigan (UM) Prostate SPORE has endeavored to tap the vast intellectual and physical resources of the UM community to decrease the morbidity and mortality of prostate cancer (PCa). The UM 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 prostate cancer. This program established key resources and infrastructure such as biospecimen and informatics capabilities which enabled the discovery that a majority of prostate cancers harbor recurrent gene fusions/translocations (Science, 2005). Successful translational discoveries in the most recent grant period include the following.

  1. Establishment of a clinical sequencing framework for precision oncology (Sci Transl Med., 2011a)
  2. Development of a gene fusion-based urine test for prostate cancer (Sci Transl Med. 2011b) which is now available in CLIA reference labs
  3. Discovery that ETS gene fusions induce DNA damage and confer sensitivity to PARP inhibitors (Cancer Cell 2011) which initiated a randomized Phase II trial (NCTO1576172)
  4. Discovery of germline mutations in the HOXB13 gene that conferred increased risk for PCa (N Engl J Med. 2012) which is being developed as a test for assessing prostate cancer risk
  5. Characterization of the mutational landscape of metastatic castration resistant prostate cancer (CRPC) (Nature 2012) which led to a multi-institutional SU2C clinical sequencing cohort study.
  6. Demonstration that cabozantinib has clinical efficacy and decreases bone pain in prostate cancer patients with bone metastasis (J Clin Oncol. 2013)
  7. Discovery of Schlap1 as a novel, long-non-coding RNA (lncRNA) that negatively regulates the SWI/SNF epigenetic complex and is associated with aggressive prostate cancer (Nature Genetics, 2013).

These bench-to-bedside applications were aided by horizontal collaborations with the Dana Farber, Baylor, Mayo Clinic and Johns Hopkins Prostate SPOREs as well as the EDRN and vertical collaborations with SWOG and industry.

This SPORE consists of four multidisciplinary projects:

Project 1: A Precision Medicine Approach to Elucidate Mechanisms of Progression and Resistance to Therapy in Advanced Prostate Cancer

Project 2: Mechanisms of Sensitivity and Resistance to Cabozantinib in CRPC

Project 3: Development of Novel BET Bromodomain Inhibitors for the Treatment of Advanced Prostate Cancer

Project 4: Development of Schalp1 and Other IncRNAs as Prostate Cancer Biomarkers in Urine

These projects are complemented by ongoing, successful Career Development and Developmental Research Programs; a strong ongoing institutional commitment of money and space as well as three cores: Administration, Biostatistics, and Tissue/Informatics. The overarching goal of the UM Prostate SPORE is to reduce the morbidity and mortality of prostate cancer via the rapid translation of high impact discoveries that seek to improve the detection and treatment of prostate cancer. This ambitious goal will be achieved through these Specific Aims:

  1. Support multidisciplinary, collaborative projects that pair basic and clinical investigators and draws on expertise of scientists from within and from outside the prostate cancer field.
  2. Provide support for pilot projects with high potential to advance prostate cancer research to obtain preliminary data that will form the basis for grant submission to extramural sponsors.
  3. Recruit and train early-stage scientists to become the next generation of leaders in translational prostate cancer research through access to mentors that are renowned senior investigators and leaders in basic and clinical arenas as well as networking opportunities among other project co-leaders.
  4. Provide world-class infrastructure to carry out innovative, high-quality, high-impact translational prostate cancer research.
  5. Support efforts to develop bench-side discoveries for clinical diagnostics and therapies.
  6. Foster collaborations among investigators within the institution and other institutional SPORES, SPORES at other institutions and other extramural prostate cancer programs.

The UM Prostate SPORE has a long history of success and has been instrumental in many landmark discoveries that have changed the clinical management of men with prostate cancer. Our strong multidisciplinary program will ensure the successful completion of our proposed aims.

Project 1: A Precision Medicine Approach to Elucidate Mechanisms of Progression and Resistance to Therapy in Advanced Prostate Cancer

Co-Leaders:
Arul Chinnaiyan, M.D., Ph.D.
Ganesh Palapattu, M.D.

The University of Michigan Comprehensive Cancer Center (UMCCC) has taken on a leadership role in developing precision medicine approaches for oncology. In April of 2011, the MI-ONCOSEQ clinical sequencing program was established, which prospectively enrolls patients with advanced cancers for comprehensive mutational analysis using an integrative sequencing approach. Since establishment of this protocol, over 250 adults and 40 children with cancer have been sequenced with return of results through an institutionally sanctioned "precision medicine tumor board" (PMTB). Through support of the UM Prostate SPORE, Dr. Chinnaiyan and colleagues used this approach to establish the first mutational landscape of lethal castration resistant prostate cancer (CRPC) (Nature 2012).

This project will evaluate the mutational landscape of metastatic hormone sensitive prostate cancer (HSPC) along with CRPC, and thus, will employ precision medicine approaches for earlier stages of prostate cancer progression (i.e., prior to castration resistance). Furthermore, we will also explore mechanisms of resistance/progression in UMCCC-based clinical trials in metastatic prostate cancer as well as develop parallel in vitro "tumoroid" model systems.

Specific Aims

Aim 1: Establish a precision medicine approach for patients presenting with metastatic HSPC. Here we will prospectively enroll patients seen in the UM High-Risk Clinic for prostate cancer to our clinical sequencing protocol. We plan to interrogate the germline exome and tumor exome/transcriptome (integrative sequencing) from men with Stage 4 prostate cancer to identify novel molecular alterations that may contribute to this clinical subset of patients. We will include metastatic HSPC patients who will be enrolled on a CDK4/6 inhibitor + androgen deprivation trial that is in the process of being activated at UM.

Aim 2: Determine mechanisms of progression and resistance to therapy of men with metastatic CRPC. Here we will study the mutational landscape of patients with metastatic CRPC that will enroll in a targeted therapy trial to evaluate the tyrosine kinase inhibitor, cabozatanib. We will carry out integrative sequencing of the tumor specimens obtained at time of trial enrollment and at time of progression/recurrence. This will allow for one the first of its kind, temporal assessments of the mutational landscape of prostate cancer progression under targeted therapies.

Aim 3: Establish prostate tumoroid cultures as a parallel model system in the precision medicine approach. These patient derived tumoroid cultures will be used to test predictions made by integrative sequencing.

Project 2: Mechanisms of Sensitivity and Resistance to the Kinase Inhibitor Cabozantinib in Castrate Resistant Prostate Cancer

Co-Leaders:
Evan Keller, Ph.D.
David C. Smith, M.D. and
Scott Tomlins, M.D., Ph.D.

In a recent clinical trial led by co-leader Dr. Smith, Cabozantinib (CABO; XL-184) showed unprecedented bone scan responses in men with castration-resistant prostate cancer (CRPC). Although marked responses are seen, patients eventually progress and about 30% of patients do not respond. CABO is a multi-tyrosine kinase inhibitor with greatest activity against MET, VEGFR2 and RET, which have been implicated in prostate cancer (PCa) progression and the bone microenvironment. Using preclinical models we have found that some PCas show differential sensitivity to CABO when in bone versus soft tissue. Furthermore, through integrative sequencing, we have found that MET activation compensates for loss of androgen receptor (AR) signaling in CRPC. These clinical and pre-clinical results provide a compelling rationale for studying the role of both the tumor itself and the tumor microenvironment in predicting tumor sensitivity and resistance to CABO. Hence, the overarching goal of this proposal is to leverage an ongoing investigator-initiated clinical trial of CABO and use in vitro and in vivo modeling to "reverse-engineer" sensitivity and resistance mechanisms using a bedside to bench approach.

Specific Aims

Aim 1. Determine if clinical response to CABO in men with CRPC is associated with inhibition of MET/VEGFR/RET signaling. Clinical response to CABO with AR, MET, VEGF and RET signaling activity in bone and soft tissue will be evaluated. A novel method of diffusion-weighted MRI to evaluate bone response will be used and flash frozen pre-treatment and on-study biopsies for interrogation in Aim 3 will be obtained.

Aim 2. Assess the role of the microenvironment in conferring sensitivity and resistance to CABO. The response to CABO in multiple prostate cancer cell lines with varied AR and MET pathway activity in the context of tissue culture, soft tissue sites and bone sites will be evaluated. Activation and targeting of CABO-sensitive pathways (MET, VEGFR, RET and downstream effectors and AR signaling) will be evaluated. Tumors will be subjected to RNA-seq analysis to identify novel predictors of sensitivity and resistance.

Aim 3: Interrogate the role of tumor genotype and phenotype in conferring sensitivity and resistance to CABO. An integrative sequencing strategy on the pre- and on- treatment biopsies to characterize genomic and transcriptomic predictors of sensitivity and resistance to CABO will be performed. CABO-resistant cell models will be developed and subjected to integrative sequencing to identify mechanisms of acquired resistance. Candidate mediators of resistance will then be tested in appropriate in vitro and in vivo models.

Project 3: Development of Novel BET Bromodomain Inhibitors for the Treatment of Advanced Prostate Cancer

Co-Leaders:
Shaomeng Wang, Ph.D.
Felix Feng, M.D. and
Maha Hussain, M.D.

Currently, metastatic castration-resistant prostate cancer (CRPC) is invariably and unfortunately a lethal disease. The vast majority of CRPC is dependent upon and driven by androgen receptor (AR) signaling. While recent advances have resulted in the development of second generation therapeutics targeting the androgen signaling axis (e.g. enzalutamide and abiraterone), the responses to these new agents are often not durable. Thus, there is a clear and urgent need to develop completely new therapeutic approaches directed against the AR axis. Recently, our team identified a novel strategy for targeting the AR signaling axis via inhibition of bromodomain containing 4 (BRD4), a conserved member of the bromodomain and extraterminal (BET) family of transcriptional co-activators (In Revision at Nature). We discovered that AR physically interacts with BRD4, and that treatment with the BET-bromodomain inhibitor JQ1 disrupts the AR-BRD4 interaction as well as AR recruitment to target gene loci. Compared to the direct AR antagonist enzalutamide, BET bromodomain inhibitors are much more effective in inhibition of AR-mediated gene transcription, including induction of AR targets such as TMPRSS2:ERG and PSA. Significantly, JQ1 was also more effective than enzalutamide in inhibiting the growth of CRPC xenografts. Based upon our findings, we hypothesize that BET bromodomain inhibition is a promising approach for targeting the AR axis and for treating advanced prostate cancer. Our goal in this SPORE project is to develop a potent BET-bromodomain small-molecule inhibitor (BET inhibitor) with optimized in vivo properties for the treatment of advanced prostate cancer.

Specific Aims

Aim 1: Develop a highly potent and selective BET inhibitor with optimized in vivo properties

Aim 2: Interrogate the AR-BRD4 signaling axis with novel BET inhibitors.

Aim 3: Establish the efficacy of BET bromodomain inhibitors using in vivo and ex vivo tumor models, and develop biomarkers of response.

Upon successful completion of the Aims, we expect to nominate promising candidate(s) that could be developed further for clinical use to treat metastatic CRPC. The ultimate goal of this project is introduce BET bromodomain inhibitors as a novel therapy for CRPC based on a unique understanding of its mechanism of action.

Project 4: Developing Schlap1 and Other IncRNAs as Prostate Cancer Biomarkers in Urine

Co-Leaders:
John Wei, M.D. and
Arul M. Chinnaiyan, M.D., Ph.D.

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer death in American men. Recent recommendations by the US Preventative Services Task Force on PSA screening highlighted the public health concerns relating to the imprecision of PSA testing and the overtreatment of prostate cancer. PSA’s limited ability to discriminate cancer from benign disease leads to well over a million prostate biopsies each year in the United States. Moreover, low grade prostate cancer is often non-fatal and the excessive use of definitive therapies such as surgery has led to significant morbidity and costs. The long-term objective of this project is to develop novel panels combining the TMPRSS2:ERG fusion with long non-coding RNAs (lncRNAs) that will allow improved clinical risk assessments for prostate biopsies and active surveillance of low grade cancer.

Specific Aims

We will employ transcriptome sequencing (RNA-Seq) in Aim 1 on a large panel of prostate cancer tissues and cell lines to provide an unbiased assessment of RNA species whose aberrant expression associates with prostate cancer or prostate cancer disease progression. This innovative approach is able to capture all disease-associated RNAs, including mRNAs encoding for proteins and long non-coding RNAs (lncRNAs). Sequencing data is processed to distinguish high-confidence, recurrent transcripts from background or spurious sequencing signal. High-confidence transcripts are then further categorized relative to annotated genes. From the final compendium of prostate cancer transcripts, we will then nominate and validate transcripts dysregulated in prostate cancer. We will select the most promising transcripts for assessment and validation in urine as putative prostate cancer biomarkers. Taking advantage of the large clinical data and tissue repositories in Aim 2, novel lncRNAs will be multiplexed with other existing RNA-based urine tests, including assays for the TMRPSS2:ERG RNA and the known prostate cancer lncRNA PCA3, to develop a panel assay with a sufficiently high negative predictive value to prevent unnecessary prostate biopsies. Aim 3 will similarly deploy lncRNAs to develop a panel capable of identifying high grade cancer based on a urinary assay. Our latest preliminary data suggests that PCAT-114 (SChLAP-1) is our most promising lncRNA for clinical development as it is associated with aggressive prostate cancer in tissues and in urine.

Core 1: Administration

Core Director:
Arul M. Chinnaiyan, M.D., Ph.D.

Co-Core Director:
Ganesh Palapattu, M.D.

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

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

Specific Aim 2: Develop, facilitate and monitor progress of translational aims with project co-leaders. The Clinical Applications Committee, the annual review with the External Advisory Board and Steer Committee and the monthly meetings between project leaders and the SPORE PI all function to maintain a robust SPORE infrastructure and facilitate the progress of translational objectives.

Specific 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.

Specific Aim 4: Facilitate communication between investigators and groups within the Prostate SPORE as well as with other UM SPOREs, the SPORE network outside UM, NCI and investigators across the spectrum of translational cancer research.

Specific Aim 5: Perform fiscal and data management functions.

Specific 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 to prostate cancer patient community.

Arul M. Chinnaiyan, M.D., Ph.D., serves as principal investigator of the Administrative Core and provides overall scientific oversight. Kathleen Cooney, M.D., continues to serve as a co-director to oversee all of the developmental programs, patient advocacy efforts, as well as the Biostatistics and Tissue Cores. Ganesh Palapattu, M.D., serves as a co-director responsible for the translational science of the UM Prostate SPORE as Director of the Clinical Applications Committee. Ms. Jill Miller has served as UM Prostate SPORE administrator since 1998 and will continue in this role. This core provides the framework to support the success and mission of the UM Prostate SPORE as a cohesive group of investigators committed to supporting translational research in prostate cancer.

Core 2: Biostatistics Core

Core Director:
Alexander Tsodikov, Ph.D.

The goal of the Biostatistics Core is to collaborate with SPORE investigators and other core resource scientists to enhance the quality of the research undertaken in the University of 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, to 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 in planning the data analysis. 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 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 and laboratory experiments;
  2. Assist investigators in the analysis and interpretation of data from clinical and laboratory experiments and in writing of manuscripts relaying prostate cancer SPORE results to the scientific community;

Undertake translational biostatistics research to develop methodology and software implementation relevant to prostate cancer.

Core 3: Tissue / Informatics Core

Core Director:
Priya Kunju, M.D.

Co-Core Director:
Arul Chinnaiyan, M.D., Ph.D.

Core Technical Director:
Javed Siddiqui, M.S.

The goal of UM Prostate SPORE Tissue/Informatics Core is to collect biological material 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, and UM Prostate SPORE researchers, the Core has a developed a unified bioinformatics infrastructure that provides researchers a wide range of annotated samples. To date, detailed information exists on over 4200 radical prostatectomy patients operated on at the Univ. of Michigan between 1994-present. The specific goals of the Tissue 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 (i.e., protein, DNA and RNA) are available from several established and new sources. These include benign prostate tissue from patients without any known prostatic disease (cystoprostatectomy specimens and transplant donor prostates), clinically localized prostate cancer, and metastatic hormone refractory prostate cancer (Rapid Autopsy Program). (3) Maintenance of clinical and pathology data with links to molecular studies. The Tissue 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. (4) High quality pathologic review of prostate tissues. Expert GU pathologists assure uniform review of prostate tissue samples. (5) 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. (6) Quality assessment of prostate tissues and clinical data. The Tissue Core staff regularly evaluates frozen and formalin fixed tissues for adequacy. (7) Development of technology appropriate for pathology-based translational research. New technologies such as integrative high-throughput sequencing to identify causative, driving mutations in patient tumors have been introduced. The Core will continue to be integral to the sample preparation, analysis of biopsy tissue tumor content and long-term storage of all these patient samples. 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

Co-Directors:
Ganesh Palapattu, M.D. and
Mark L. Day, Ph.D.

Recognizing that developmental research funds are an integral part of the SPORE, we commit $205,000 per year to these endeavors. This represents a significant percent in the budget of the UM Prostate SPORE and reflects the continued commitment of this program 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. Investigators from outside the field of prostate cancer are encouraged to apply through campus-wide announcements as well as through personal interactions with the SPORE investigators. We developed a stepwise proposal solicitation and review process for pilot projects utilizing an NIH-type PHS 398 format that has been streamlined for rapid turnaround of research proposals and which recognizes that these projects may have little preliminary data. Investigators may apply for pilot project grants ($40,000 - $50,000 each) or seed grants ($5,000 - $10,000 each). In addition, we set aside funds for summer student projects ($5,000 each). Since 1995, we have invested $3.5 million in our DRP, funding a total of 83 investigators though 68 pilot projects, 63 seed grants and 35 summer student projects. These awards have led to over $32 million in subsequent SPORE and non-SPORE peer-reviewed funding and 127 published manuscripts. During this current grant cycle, we funded 51 projects: 16 pilot projects ($50K each), 4 seed grants ($10K each) and 35 summer student projects ($5K each). Drs. Maha Hussain and Mark Day serve as co-Directors for the DRP. Dr. Hussain is a Professor of Internal Medicine and Urology and is internationally recognized for her clinical research expertise in prostate cancer. Dr. Hussain participates with the Oncology Training Grant. She serves as the "clinical" expert for the DRP. Dr. Mark Day is a Professor of Urology and has published extensively in the area of prostate cell biology. He serves as the "basic science" mentor of the DRP. Dr. Day participates as a mentor in the Cancer Biology Training Grant. Drs. Hussain and Day meet twice with each project investigator to review progress.

CAREER DEVELOPMENT PROGRAM

Co-Directors:
Ganesh Palapattu, M.D. and
Diane M. Robins, Ph.D.

Prostate cancer research has been greatly hindered by the paucity of new investigators entering into the field. In recognition of the need to help establish independently funded investigators in the field of translational prostate cancer research, the UM Prostate SPORE has supported two to three junior faculty per year. The focus of the Career Development Program (CDP) is to provide investigators the resources to generate preliminary data for subsequent NIH R01 grant applications. The UM Prostate SPORE commits $70,000 annually per investigator. Career Development awardees are funded for a maximum of two years, subject to annual review. The awardees’ departments supply another $10,000 per year in matching funds. Investigators, many of whom are outside the field of prostate cancer, meet quarterly with Drs. Cooney and Robins who act as clinical resource and basic science mentors, respectively. A former CDP investigator, Dr. Cooney is a medical oncologist with appointments in internal medicine and urology. Dr. Cooney is the "clinical" resource mentor for the career development program. Dr. Robins is a Professor of Human Genetics and has a leadership role in the new Cancer Biology Program with past service as Director of graduate studies in the Department of Genetics. Dr. Robins is the "basic science" resource mentor for the career development program. Both Drs. Cooney and Robins have a long history of training clinical and basic science fellows and faculty. The progress of the Career Development investigators is monitored yearly by presentation to the Operating Committee and funding can be terminated if the investigators are not fulfilling their commitment to translational prostate cancer research. Since 1995, our CDP has invested $2.7 million in the program and supported 21 investigators. In return, the CDP investigators have generated an impressive $43.6 million in subsequent grants and produced 119 manuscripts during that time period. The effectiveness of this program is reflected by the fact that five career development investigators (Drs. Cooney, Chinnaiyan, Wei, Tomlins and Feng) have become project co-Directors on the UM Prostate SPORE during this time. Six investigators have been supported during the current grant cycle and they are each making significant contributions to the field of translational prostate cancer research. During the most recent grant period, CDP investigators have generated $4.2M in new grant funding.