Translational Research Program in Colorectal Cancer Disparities
Fred Hutchinson Cancer Center
Principal Investigator(s):
Ulrike Peters, PhD, MPH
Christopher Li, MD, PhD
Timothy Thomas, MD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Functional guided risk prediction for colorectal cancer in racially and ethnically diverse populations
- Project 2: Discovery and validation of novel molecular and immune predictors of colorectal cancer mortality and response to treatment in racially and ethnically diverse patient populations
- Project 3: Racial and ethnic differences in the intra-tumoral microbiome: Impact on colorectal cancer mortality and clinicopathologic correlates
- Project 4: Effect of Meal Timing during Cancer Treatment in Alaska Native Patients: A Randomized Clinical Trial
- Administrative Core
- Biospecimen and Pathology Core
- Biostatistics and Bioinformatics Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE website
Principal Investigator(s) Contact Information
Ulrike Peters, PhD, MPH
Professor, Associate Director, Endowed Chair
Public Health Sciences Division
Fred Hutchinson Cancer Center
1100 Fairview Ave N, M4-B402
Seattle, Washington, 98109
(206) 667-2450
Christopher Li, MD, PhD
Professor, Public Health Sciences Division
Vice President, Faculty Affairs and Diversity
Fred Hutchinson Cancer Center
1100 Fairview Ave N, M4-C308
Seattle, Washington, 98109
(206) 667-5948
Timothy Thomas, MD
Physician Researcher, Research Services Department
Division of Community Health Services
Alaska Native Tribal Health Consortium
4000 Ambassador Dr,
Anchorage, Alaska, 99508
(907) 563-2662
Overview
Colorectal cancer (CRC) remains one of the leading causes of cancer death in the United States and considerable racial and ethnic disparities in CRC incidence and mortality persist. These disparities are particularly pronounced among African American and Alaska Native populations. African American individuals have CRC incidence and mortality rates that are 20% and 40% higher, respectively, than the general U.S. population. Alaska Native people have the highest incidence and mortality rates of CRC in the world, with rates that are two to three times higher than those observed in the general U.S. population. These differences cannot be explained by access to screening and health care alone, suggesting underlying yet understudied contributors to disease etiology, progression, and response to treatment. Collectively, this transdisciplinary team will use cutting-edge technologies to investigate CRC disparities and develop prevention, early detection, diagnosis, and treatment approaches that will benefit racially and ethnically diverse CRC patient populations.
Project 1: Functional guided risk prediction for colorectal cancer in racially and ethnically diverse populations
Project Co-Leaders:
Anshul Kundaje, PhD (Basic Co-Leader)
Li Hsu, PhD (Clinical/Applied Co-Leader)
Ulrike Peters (Clinical/Applied Co-Leader)
This project will develop genetic risk prediction models for colorectal cancer in diverse populations.
Aim 1: Genetic Risk Prediction Models. In Aim 1a, we will create scores for genetic variants using data from diverse individuals. This involves using deep learning to understand how variants affect gene activity in colorectal tissue at a detailed level. In Aim 1b, we will combine these scores with data from large genetic studies to build precise risk prediction scores called polygenic risk score (PRS). These models will consider both self-identified race and ethnicity as well as genetic ancestry.
Aim 2: To evaluate the cost-effectiveness of using PRS. Using a microsimulation model, we will evaluate the cost-effectiveness of using these PRS for risk stratification and recommend optimal screening strategies across diverse populations, considering equity and efficiency. This assessment includes comparing costs with current screening guidelines and incorporating environmental risk factors.
As PRS are increasingly entering clinical care, this project has the potential to improve CRC prevention by using PRS to guide personalized interventions aimed at reducing the high CRC burden and persistent disparities experienced by certain racial and ethnic groups.
Project 2: Discovery and validation of novel molecular and immune predictors of colorectal cancer mortality and response to treatment in racially and ethnically diverse patient populations
Project Co-Leaders:
Li Li, PhD (Basic Co-Leader)
Christopher Li, MD, PhD (Clinical/Applied Co-Leader)
Marc Matrana, MD (Clinical/Applied Co-Leader)
This project seeks to uncover new biomarkers in colorectal cancer (CRC) that predict patient outcomes and treatment responses across diverse racial and ethnic groups.
Aim 1 focuses on identifying spatially resolved prognostic biomarkers in CRC tumor tissues from 840 patients of various racial and ethnic backgrounds using advanced technology (PhenoCycler). This aims to predict CRC-specific mortality based on differences in immune and cancer cell locations.
Aim 2 aims to predict treatment responses: We will develop tools to forecast responses to standard CRC therapies across different racial and ethnic groups, leveraging insights from Aim 1. We will also study cell patterns in tumors of 100 CRC patients treated with immune checkpoint therapy to predict treatment effectiveness.
Aim 3 integrates findings from Aims 1 and 2 to develop computational models predicting three key outcomes: CRC mortality risk, response to standard treatments, and response to immunotherapy. These models will be validated with patient data to ensure accuracy and reliability.
This project aims to improve identifying high-risk CRC patients and personalize treatments, potentially enhancing monitoring and offering alternative therapies to those at risk of CRC-related mortality. New predictive tools may reduce outcome disparities across racial and ethnic groups by aiding clinicians in selecting optimal treatments. Additionally, insights into immune responses to CRC and treatments could advance future therapies.
Project 3: Racial and ethnic differences in the intra-tumoral microbiome: Impact on colorectal cancer mortality and clinicopathologic correlates
Project Co-Leaders:
Meredith Hullar, PhD (Basic Co-Leader)
Amanda Phipps, PhD (Clinical/Applied Co-Leader)
This project investigates the role of bacteria in colorectal cancer across diverse population groups to detect differences in bacterial presence and distribution.
Aim 1: Will use digital droplet PCR assays to measure new types of bacteria in colorectal tumors (a) to look for differences in how these bacteria are distributed among CRC patients from different racial and ethnic backgrounds and (b) to see if these bacteria are linked to a higher risk of deadly CRC overall and within specific racial and ethnic groups.
Aim 2: Will study how the composition of the tumor-associated microbiome differs based on clinicopathologic factors that vary across racial and ethnic groups and affect prognosis (like where the tumor is located, age at CRC diagnosis, and tumor marker status).
Aim 3: Will use artificial intelligence and machine learning models with 16S rRNA sequencing data to find specific microbial patterns in CRC tumors linked to CRC-related deaths. We will also examine how these patterns differ among racial and ethnic groups.
Discoveries may reveal new bacteria useful for early detection tests, particularly benefiting high-risk groups. For patients already diagnosed, understanding specific bacteria present could lead to more targeted treatments, such as specialized medications, delivery methods, bacteriophage therapies, and dietary adjustments.
Project 4: Effect of Meal Timing during Cancer Treatment in Alaska Native Patients: A Randomized Clinical Trial
Project Co-Leaders:
Jane Figueiredo, PhD (Basic Co-Leader)
Timothy Thomas, MD (Clinical/Applied Co-Leader)
Alaska Native people suffer disproportionately from metabolic disease and have the highest colorectal cancer incidence and mortality rates of any racial and ethnic group in the world. This proposed clinical trial builds on the research infrastructure of our P20 SPORE planning grant (P20CA252733) and our ongoing randomized clinical trial of TRE in patients with rectal cancer (CHRONO Trial, R01CA258222, NCT04722341). We aim to conduct a randomized Phase II clinical trial involving 100 Alaska Native rectal cancer patients receiving treatment at the Alaska Native Medical Center (ANMC). Our goals are:
Aim 1: Determine the impact of TRE during neoadjuvant treatment on treatment response, treatment-related toxicities, quality of life, and adherence among Alaska Native patients with rectal cancer. We will look at how well the treatment gets rid of cancer completely (pathological complete response of pCR rate), the side effects of treatment using specific criteria, how people feel about their health-related quality of life and how well patients stick to the eating plan (adherence).
Aim 2: To study how TRE affects changes in biomarkers related to metabolic function, cancer, and DNA damage we will measure blood-based biomarkers of interest including IGF-1, IGF-BP3, insulin, glucose, CRP, and DNA damage markers in leukocytes. We will also look at rectal tumor tissue to see how cells are affected.
Aim 3: Examine disparities in clinical outcomes, adherence rates, and biomarker responses across five racial and ethnic groups. We will compare findings from Alaska Native participants in our study with those from African American, Asian, Hispanic, and non-Hispanic White individuals with rectal cancer from the CHRONO Trial.
The proposed trial is innovative in testing a promising approach in a population with a high burden of CRC and metabolic disease.
Administrative Core
Core Directors:
Ulrike Peters, PhD, MPH
Christopher Li, MD, PhD
Timothy Thomas, MD
The Administrative Core (AC) will provide overall leadership and administrative support, program management, integration with existing programs and shared resources, infrastructural support, communication within and across TRPCD investigators and partnering institutions, and evaluation of all TRPCD activities and components. This Core has the following specific aims:
Aim 1. Leadership: To provide the organizational structure and scientific and administrative leadership needed for the successful execution and evaluation of key TRPCD objectives.
Aim 2. Administrative Management: To provide administrative management of all SPORE components including fiscal oversight, regulatory compliance, SPORE leadership succession plans, communication, data management, and engagement with NCI.
Aim 3. Integration of the P50 Program with the host institutions: To coordinate TRPCD activities with various projects, programs, and shared resources at partnering institutions such that integration of these existing institutional resources will successfully support the TRCPD.
Aim 4. Planning and evaluation of SPORE activities: To plan SPORE activities, assist with and prepare progress reports, organize regular Advisory Board meetings, and support evaluations conducted by our Advisory Boards.
Aim 5. Sustain collaborations: To develop and support multi-institutional intra- and inter-SPORE interactions and initiate and sustain collaborations with key external partners.
Biospecimen and Pathology Core
Core Directors:
Amanda Koehne, DVM, PhD
Cecilia Yeung, MD
The Biospecimen and Pathology Core (BPC) has set up a robust system for collecting, processing, and providing access to biospecimens across institutions. This resource meets the critical need for biospecimens from diverse colorectal cancer (CRC) patients. The BPC offers advanced laboratory technologies and specializes in tissue-based assays and biomarker analyses. This Core has the following specific aims:
Aim 1 is to establish a high-quality CRC biospecimen repository from diverse populations, including blood, frozen and preserved tumor and normal tissues, saliva, urine, and stool, all meticulously annotated.
Aim 2 involves processing, evaluating, and storing biospecimens, with services such as pathology review, H&E staining, tumor microarray development, digital imaging, DNA extraction, and single cell preparation. These biospecimens will support SPORE, CEP, DRP projects, and external collaborations.
Aim 3 focuses on comprehensive data collection, harmonizing demographic, lifestyle, clinical, social determinants of health, and outcomes data. Medical chart abstractions for CRC patients and data harmonization from epidemiological studies maximize research value.
Aim 4 through the TRPCD Biospecimen Utilization Committee prioritizes access based on translational cancer disparities research merit, optimizing research across SPORE, CEP, DRP projects, and external collaborations.
Aim 5 expands technological capabilities, leveraging Institutional Shared Resources to offer advanced technologies supporting innovative research across SPORE, CEP, DRP, and external partnerships.
Biostatistics and Bioinformatics Core
Core Directors:
Li Hsu, PhD
Jeroen Huyghe, PhD
The Biostatistics and Bioinformatics Core (BBC) is pivotal in uncovering disparities by employing systematic, unbiased approaches. By rigorously conducting research across all phases — from standardized study designs and data collection methods to sophisticated analyses — the BBC aims to identify molecular and genomic features linked to colorectal cancer (CRC) risk and mortality. This knowledge will inform improved prevention, diagnosis, and treatment strategies.
Aim 1 focuses on providing statistical and bioinformatic support in risk prediction, observational studies, survivorship, treatment response, and clinical trials. Utilizing advanced omics data like single cell ATACseq and RNAseq, genome-wide genetic sequencing, digital spatial single cell profiling, microbiome profiling, and blood-based biomarkers, the BBC collaborates on study design, ensures data quality, conducts analyses, and interprets results biologically using bioinformatics tools. The BBC also supports manuscript preparation and result dissemination across racial and ethnic groups to ensure unbiased and valid data presentation.
Aim 2 involves monitoring methodological advancements and evaluating state-of-the-art statistical methods and computational tools to handle complex data from SPORE projects. The BBC adapts existing methods or develops new ones as needed to propel SPORE research forward.
Developmental Research Program (DRP)
Program Directors:
William Grady, MD
Li Li, PhD
The Developmental Research Program (DRP) provides key support to develop novel translational early-phase projects in the area of cancer disparities that, ultimately, will evolve into full projects. Our DRP is designed to achieve several specific aims: First, it promotes innovative early-stage cancer disparities research across translational areas such as molecular biology, epidemiology (including primary and secondary prevention), risk prediction, early detection, treatment, and survivorship. Second, it encourages high-risk, high-reward pilot projects to maintain the leading edge of our SPORE research efforts. Third, the program actively involves underrepresented minority investigators in leading these early-stage research initiatives. Fourth, it provides essential funding, infrastructure, and mentorship to support the feasibility and success of DRP projects. Fifth, the DRP assists in advancing the projects to becoming full research endeavors.
Career Enhancement Program (CEP)
Program Directors:
Christopher Li, MD, PhD
Diana Redwood, PhD
The Career Enhancement Program (CEP) identifies and supports promising junior investigators, and those new to the field of cancer disparities. Recruitment of candidates will be conducted across all partner sites, and tailored career enhancement programs will be developed to meet the needs of each awardee. The CEP will bring together junior, mid-level, and senior investigators by providing funding and scientific support for innovative projects that study cancer disparities. By providing mentorship and finding sponsors within their institutions, the CEP will help participants develop their careers in this specialized field. The CEP will provide leadership training and actively support the hiring of new researchers focused on cancer disparities. Our goal is to strengthen our research community and make significant progress in reducing differences in cancer rates and outcomes.