University of California, San Francisco
Principal Investigators
Susan Chang, MD
Susan Chang MD
Professor in Residence
Department of Neurological Surgery
UCSF, 1450 Third St., Box 0112
San Francisco, California 94143
(415) 353-3785
Franklin Huang, MD, Ph.D.
Franklin Huang MD, PhD
Associate Professor
Department of Medicine Institution
University of California, San Francisco
UCSF, 513 Parnassus Ave., Box 1346
San Francisco, California 94143
(415) 502-0696
Overview
The overall goal of this SPORE is to improve cancer outcomes by investigating the interplay between genomic and immune characteristics with individual risk factors and external drivers of health. We have developed three translational cancer research projects to study cancers with well-known differences in clinical outcomes: meningioma, prostate cancer, and breast cancer. Project 1 aims to understand meningioma incidence and disease burden in the context of upstream individual-level risk factors and external drivers of health using human samples, bioinformatics, preclinical models, and epidemiological data. Project 2 will characterize the variables that explain prostate cancer outcomes, focusing on the complex interactions among stress and inflammation across different populations. The response of the immune system to breast cancer therapy is a major determinant of breast cancer outcomes, and the tumor immune microenvironment varies substantially by genetic ancestry. The goal of Project 3 is to identify the genetic and environmental factors that underlie these differences and to understand the underlying pathway mechanisms. Supported by three important resource cores (Administrative, Biospecimen/Pathology, and Community Outreach and Engagement) as well as the Developmental and Career Enhancement Programs, the work proposed will yield valuable insights and make meaningful progress in understanding meningioma, prostate cancer, and breast cancer. The SPORE leverages the expertise of members of multidisciplinary internal and external advisory boards and the community advisory board to provide direction and guidance.
Project 1: Genomic and biochemical mechanisms underlying differences in meningioma patient outcomes
Project Co-Leaders:
David Raleigh, MD, PhD (Basic Science Lead)
Nancy Ann Oberheim Bush, MD, PhD (Clinical Lead)
The World Health Organization (WHO) has historically graded meningiomas according to histological features, and many WHO grade 1 meningiomas can be effectively treated with surgery or radiotherapy. Many WHO grade 2 or grade 3 meningiomas, which are malignant, are resistant to treatment and cause significant neurological morbidity and mortality. Meningiomas are more common and have higher rates of recurrence in some patient populations. These data indicate urgent, unmet needs for new treatments and predictive biomarkers to improve and personalize meningioma treatments. Using data from the Central Brain Tumor Registry of the United States (CBTRUS), we showed differences in the risk of developing these brain tumors across patient populations. Using multiplatform molecular profiling on 2092 meningiomas from 13 institutions, we developed DNA methylation and gene expression biomarkers that suggest meningiomas in some patients are enriched in high-risk molecular features that underlie therapeutic vulnerabilities. These preliminary data provide an epidemiological and molecular framework for defining and addressing differences in meningioma incidence and outcomes. Our central hypothesis is that tumor biology, external drivers, and individual-level risk factors underlie these differences. Our objective is to establish the generalizability of predictive DNA methylation and gene expression biomarkers and provide data to support new treatments for meningiomas. To do so, we will integrate retrospective and prospective human samples, bioinformatics, preclinical models, and epidemiological data from 5 institutions. We will define the molecular architecture of meningiomas across external drivers and individual-level risk factors (Aim 1), define how an enigmatic progesterone receptor (PGRMC1) drives meningioma growth (Aim 2), and develop therapeutics to block PGRMC1 (Aim 3). Successful completion of this project will define tumor biology, external drivers, and individual-level risk factors that underlie differences in meningioma clinical outcomes across population groups and provide data to support predictive biomarkers and new treatments.
Project 2: Elucidating interactions between genetic and environmental drivers of prostate cancer outcomes
Project Co-Leaders:
Franklin Huang, MD, PhD (Basic Science Lead)
Matthew Cooperberg, MD (Clinical Lead)
This project aims to explain the persistent differences in outcomes for patients with prostate cancer, particularly the burden of aggressive and lethal disease. The overarching goal is to explore the complex interplay between contributing biological and environmental factors. By focusing on the interactions among stress, inflammation, and immune pathways within the tumor microenvironment, the research seeks to uncover mechanisms that drive the development of aggressive prostate cancer in at-risk populations. Aim 1 will focus on identifying how adverse external factors predict aggressive prostate cancer. Using tissue samples from a large cohort of prostatectomy patients, this aim will also assess both genomic risk and immune activation patterns across population groups to understand ethnic differences in tumor biology. The goal is to determine how adverse external factors drive differences in immune activation and the development of unfavorable prostate cancer histology. Aim 2 will dig deeper into prostate cancer biology using advanced genomics and spatial multi-omics technology. The research will map out the local immune environment in both cancerous and benign prostate tissues across different population groups, providing a high-resolution analysis of the immune cell composition and their spatial relationships within the tumor microenvironment. This Aim will yield a comprehensive molecular atlas, allowing the investigators to correlate specific immune and inflammatory profiles with external factors and aggressive disease biology. Aim 3 will leverage the molecular data generated in the first two aims to develop machine learning models that integrate genomic, immune, and external data. These models will be designed to predict which men are at the highest risk for aggressive prostate cancer, enabling more accurate screening and early intervention. By combining molecular insights with clinical and environmental data, the study aims to improve the precision of prostate cancer prognosis, guide more personalized treatment strategies for high-risk populations, and address a critical public health issue.
Project 3: Understanding genomic and social and structural drivers of response-predictive inflammatory states underlying differences in health outcomes in patients with breast cancer
Project Co-Leaders:
Jennifer Rosenbluth MD, PhD (Basic Science Lead)
Elad Ziv MD (Clinical Lead)
The tumor immune microenvironment is a strong predictor of patient outcomes for many tumors, including breast cancer. Various features of the tumor immune microenvironment vary across populations of different genetic ancestry. Our hypotheses are that the tumor immune microenvironment varies across different ancestry populations and that these differences in the tumor immune microenvironment lead to differences in treatment response. We have already performed genetic studies on the effects of the tumor immune microenvironment and identified variants that have large allele frequency differences and are candidates for effects on outcomes. We will expand our existing matched germline genotype and tumor gene expression dataset to unravel genetic variants that affect the tumor immune microenvironment. We will examine how individual variants and combinations of variants - called polygenic scores - vary according to ancestry and whether the resultant tumor immune microenvironment differences affect treatment outcomes. We will prioritize the study of two genetic variants with large allele frequency differences across populations for detailed tumor immune microenvironment analyses using spatial transcriptomics. We will leverage tumor organoid models from diverse populations to analyze the effects of the genotypes on therapeutic responses. In addition, we will analyze the effects of external drivers on the tumor immune microenvironment of breast cancer. At the conclusion of these studies, we will have identified genetic variants affecting the tumor immune microenvironment that result in differences in cancer treatment outcomes and developed specific predictors of breast cancer outcomes that can be evaluated in clinical trials.
Administrative Core:
Core Co-Directors:
Susan Chang, MD
Franklin Huang MD, PhD
The emphasis of this SPORE will be to provide a better understanding of the specific biological mechanisms in relation to individual risk factors and external drivers of cancer health and to ultimately translate this knowledge into improved patient outcomes. The goal of the Administrative Core is to supervise the activities of the SPORE to ensure the success of the research conducted across the components within the SPORE. The core will provide fiscal management, administrative support, and the framework by which researchers can communicate and interact to achieve their research goals. The specific aims of the Administrative Core are: 1) To provide administrative support through the coordination of monthly team meetings and the annual scientific advisory board retreat. The Core will also work with the investigators to prepare the yearly progress reports and SPORE-related manuscripts. 2) To evaluate research progress and oversee the effective utilization of core resources across the projects to successfully conduct the aims 3) To provide fiscal management through timely distribution and budgetary reporting to all leaders of the components of the SPORE as well as the DRP/CEP awardees, and subcontracts at other institutions. 4) To assist in compliance by ensuring the regulatory compliance and scientific integrity, including biostatistical considerations, of the relevant components of the SPORE. 5) To facilitate communication among SPORE investigators and between the SPORE and outside entities, including the NIH. The Administrative Core will serve all Projects, Programs, and Cores in the SPORE.
Biospecimen/Pathology Core
Core Co-Directors:
Joanna Phillips MD, PhD
Cornelia Ding MD, PhD
Alexander Borowsky MD, PhD
The Biospecimen/Pathology Core will provide outstanding leadership, expertise in biospecimen sciences, pathology, and technology to maximize biospecimen analyses and data sharing. Experts in brain, breast, and prostate pathology will ensure well-annotated biospecimens are optimally acquired, preserved, distributed, and analyzed. This includes the acquisition of prospective and retrospective biospecimens from properly-consented patients being treated at the UCSF Hospitals and Clinics and at partnering institutions and seeing that these patients confidentiality is protected and that patient identifiers (protected health information or PHI) are never released to researchers. Leveraging the expertise and resources at UCSF and the University of California Davis, including the UCSF Brain Tumor SPORE, UCSF Prostate SPORE (Prostate Cancer Tissue Bank/PCTB), and the Breast Oncology Program and ISPY2, the Biospecimen/Pathology Core will pursue the following Aims:
Aim 1: To provide pathology and biospecimen expertise to ensure optimal sample quality and extraction of maximal, high-quality data from each biospecimen. This includes performing quality control assays on archived biospecimens and extraction of appropriate quantitative and semi-quantitative parameters from whole slide images.
Aim 2: To provide state-of-the-art tissue-based analytical techniques as needed by the Projects, including spatial transcriptomics and proteomics, mass cytometry, imaging mass cytometry, multiplexed ion beam imaging, multiplexed in situ hybridization and immunoassays, and quantitative whole slide image analysis. In addition, the Core will provide routine procedures, including tissue microarray construction and DNA/RNA extraction.
Aim 3: To acquire, preserve, and store high-quality patient biospecimens that are fully annotated with respect to preanalytical parameters, demographics, and clinical pathology and molecular data. This includes tumor tissue and blood components.
Aim 4: To provide consistent oversight and tracking of biospecimens, their acquisition parameters, and their molecular characterization to ensure stringent compliance with Project needs and with regulations governing informed consent and patient confidentiality.
Impact. These aims are accomplished by the efforts of a dedicated team of pathologists and lab technologists from the Biospecimen Core. High-quality, well-annotated biospecimens are essential to the success of all SPORE projects.
Community Outreach and Engagement Core
Core Co-Directors:
Samuel Washington, MD
Scarlett Lin Gomez, PhD
The goal of the Community Outreach and Engagement (COE) Core is to ensure that all activities within the SPORE are responsive and relevant to communities lived experiences and will ultimately advance cancer health. Working with an experienced Community Advisory Board (CAB), this will be accomplished through three broad aims: (1) catalyze collaborations between SPORE researchers and communities through activities to promote synergistic interactions, build community capacity for engaging in translational research, and identify opportunities for impactful dissemination; (2) identify factors that facilitate participation in clinical trials through the application of machine learning to clinical trials enrollment and population-based cancer registry data; and (3) support research on external drivers by developing a collaborative community-research framework and approach that reflects communities lived experiences and that is integrated into planned research and training activities. These Core activities will leverage the extensive infrastructure, capacity, and programmatic activities available at UCSF, including the HDFCCC Office of Community Engagement and the innovative and impactful SF CAN initiative. We will additionally leverage Core expertise in community-engaged research, machine learning, and accrual of underserved populations into clinical research and conduct of cells-to-society research, incorporating measures of external drivers to develop and disseminate community-informed methodologies. The COE Core will ensure these methodologies are applied in support of the projects and shared across the U54 network.
Developmental Research Program
Program Director:
The Developmental Research Program is an integral part of this SPORE and represents the best opportunity to explore new ideas as pilot projects, to develop new resources, to apply new technologies to translational CHD research, and to promote collaborations among scientists at UCSF and outside institutions. The fundamental objective of the DRP is to identify and recruit exceptional investigators. The DRP will advance the SPORE s scientific mission by supporting feasibility studies with high potential for impacting patient outcomes.
Career Enhancement Program
Program Director:
The Career Enhancement Program (CEP) exists to identify, support, and mentor candidates with promising independent careers in translational cancer health research. The CEP also represents an opportunity to encourage new and established non-translational investigators to consider careers in translational research.