Prostate Cancer SPORE

Project Co-Leaders

• Rahul Aggarwal, MD (UCSF) - Clinical co-Leader and Project Contact
• Michael Evans, PhD (UCSF) - Basic co-Leader
• Lawrence Fong, MD (Fred Hutchinson) - Applied co-Leader

Project Aims

1. Dissect the intra-tumoral and circulating immune cell states induced with 177Lu-PSMA-617 + anti-PD-1 in prostate cancer patients.
2. Determine whether PSA response-adaptive dosing of 177Lu-PSMA-617 can improve clinical and immunologic efficacy of the combination treatment in prostate cancer patients.
3. Define the immunologic response of external beam vs. beta-particle vs. alpha-particle emitting radioligand therapy in pre-clinical models.

Dissecting immune cell states induced with radioligand therapy will enable the rationale development of future treatment combinations as well as biomarkers for patient selection to realize improved clinical efficacy. Furthermore, determining the optimal form of radiation therapy to modulate immune responses will also help guide the field in improving approaches that combine radiation therapy with immune checkpoint inhibitors.

Project Co-Leaders

• Eric Small, MD (UCSF) - Clinical co-Leader and Project Contact
• Michelle Arkin, PhD (UCSF) - Basic co-Leader
• Felix Feng, MD (UCSF) - Applied co-Leader

Project Aims

1. To investigate how the CpG methylator phenotype promotes disease progression.
2. To identify clinically relevant therapeutic approaches for the CpG methylator phenotype mCRPC patient subset.
3. To develop and evaluate non-invasive clinical methylation biomarkers of CpG methylator phenotype status.

We have identified a novel mCRPC hypermethylated CpG methylator phenotype subtype through deep WGBS. The studies will define the clinical relevance of this relatively common subtype and identify therapeutic approaches by investigating this phenotype from a mechanistic, biomarker, and therapeutic perspective.

Project Co-Leaders

• Eric Small, MD (UCSF) - Clinical co-Leader
• Davide Ruggero, PhD (UCSF) - Basic co-Leader and Project Contact
• Hao Nguyen, MD, PhD (UCSF) Applied co-Leader

Project Aims

1. To target the eIF4E-dependent translational oncogenic program in a pre-clinical mCRPC model.
2. To undertake a clinical trial to examine the effects of tomivosertib in combination with enzalutamide in patients with mCRPC
3. To characterize novel eIF4E interacting partners in PCa that may modulate eIF4E-dependent therapies.

We hypothesize that through the upregulation of eIF4E, prostate cancer cells rely on, and are addicted to, a rapid translation of a network of oncogenic mRNAs (including AR and its splice variant AR-V7), which control the translation of distinct mRNAs essential for regulating key hallmarks of human PCa. This translation rewiring represents a new point of vulnerability for mCRPC. We are in a unique position to understand the mechanisms of “translation addiction” in PCa and target this addiction with novel and highly specific compounds.  

Core Directors:

• Eric Small, MD (UCSF)
• Felix Feng, MD (UCSF)

The overall objective of the Administrative Core is to manage all administrative, financial, and operational needs of the UCSF Prostate Cancer SPORE by providing a strong organizational infrastructure and establishing and managing workflows and standard operating procedures within and between all elements of the SPORE. The Administrative Core will achieve these objectives through coordination of the following components:

1. Leadership
2. Administrative Management
3. Integration of the SPORE within UCSF, HDFCCC, and the broader UCSF research community
4. Cancer Patient Population
5. Data Management
6. Planning and Evaluation Activities

Core Directors:

• Mi-Ok Kim, PhD (UCSF)
• David Quigley, PhD (UCSF)

The Biostatistics and Bioinformatics Core collaborates with SPORE investigators and scientists to ensure that research undertaken is rigorous, reproducible and of the highest quality. The Core personnel have expertise in relevant areas of Biostatistics and Bioinformatics that are required for the success of the SPORE projects. Support will be provided in all stages of research, beginning with the formulation of the research question, through the experimental design and data collection, including genomic sequencing, data analysis, and interpretation, to reporting and dissemination of results.

In addition, faculty statisticians will also focus on tailoring cutting-edge biostatistics, genomic, and bioinformatics approaches to the needs of this SPORE, producing the highest quality of prostate cancer research, through the following aims:

1. Provide biostatistics and bioinformatics expertise in the design and conduct of clinical, laboratory, and high-throughput genomic sequencing experiments;
2. Assist investigators in the processing and examination of high-throughput genomic datasets, and the analysis, interpretation and reporting of clinical, laboratory and genomics data;
3. Provide biostatistics and bioinformatics support for the general governance of this application including assistance to the SPORE Career Enhancement and Developmental Research Programs.

Core Directors:

• Jeffry Simko, MD, PhD (UCSF)
• Donna Peehl, PhD (UCSF)

The Prostate Tissue Core (PTC) provides tissue and pathology resources to support the development and successful completion of research projects involving human tissue. In addition to tissue collection, the PTC monitors and characterizes cell line and pre-clinical model collections; performs pathology and support services, and provides specimen data to the Biostatistics & Bioinformatics Core for analysis and integration with other datasets.

These responsibilities are summarized in the following four specific aims:

1. Collect, process and store high quality biospecimens linked to clinical outcomes
2. Distribute these biospecimens to approved investigators
3. Provide a suite of consultative, histopathology, laboratory services, preclinical model development, and characterization services
4. Seek out collaborations and new sources of valuable biospecimens. 

These aims are accomplished by the efforts of a dedicated team of pathologists, researchers, biostatisticians, lab technologists, and clinical research coordinators, along with the medical oncologists and urologists that recruit patient volunteers to participate in these activities. At project completion, the mCRPC collection of biopsies with matching blood and outcome data from at least 850 patients will represent one of the largest collections of such material in the world.

Program Directors:

• Alan Ashworth, PhD (UCSF)
• Danica Fujimori, PhD (UCSF)

The Developmental Research Program (DRP) in the Prostate Cancer SPORE encourages the development of highly innovative research in prostate cancer. The DRP will identify and fund exceptional projects with translational potential, and act as an incubator for novel projects that might not be funded under other mechanisms because of their high-risk potential.

Program Directors:

• Peter Carroll, MD (UCSF)
• June Chan, ScD (UCSF)

The Career Enhancement Program (CEP) Prostate Cancer SPORE was developed to ensure a pipeline of exceptional prostate cancer translational research investigators. The CEP will 1) identify, recruit, and support new talent in prostate cancer translational research, represented both in early career stage faculty and in more established faculty who are new to prostate cancer research, 2) provide mentorship, particularly to early career stage investigators, and 3) coordinate and leverage programmatic and institutional resources to maximize the impact of CEP funding.