ColoCare has already supported over 100 projects including over 59 by early-stage investigators. Major grants supported by ColoCare are as follows:
NIH R01 CA189184 (Li CI, Ulrich CM): Discovery and verification of novel biomarkers of colorectal cancer recurrence (4/2015-3/2021)
Abstract: In order to realize the promise of precision medicine, more and better biomarkers are needed to guide clinical decision making. This is of particular importance for patients with colorectal cancer (CRC) as: 1. CRC is the third most common cancer in both men and women accounting for 9% of all incident Cancers in the United States; 2. The 5-year survival rates for the most common Cancers in men and women, prostate and breast cancer, are 99% and 89%, respectively, but is only 64% for CRC making it the second most common cause of cancer related Death in the U.S.; 3. At present there is a lack of clinically useful biomarkers predictive of recurrence or survival for CRC patients that can be used to guide surveillance and treatment. Consequently, there are issues of both overtreatment and undertreatment because treatment is based largely on clinical and pathologic parameters, but little else to risk stratify patients. This study will utilize 1,574 participants in a multi-center prospective cohort (the ColoCare Study) of newly diagnosed CRC patients. Detailed demographic, clinical, epidemiologic, and follow-up data are ascertained on all participants along with blood samples collected at multiple time points. Thus, this study is specifically designed to meet the overarching goal of this proposal, the Discovery and verification of novel blood-based biomarkers predictive of recurrence among CRC patients, through achieving the following specific aims: 1. Discovery and verification of novel biomarkers predictive of recurrence among CRC patients: Utilizing samples collected at the time of diagnosis we will evaluate the plasma proteome, glycome, and autoantibody repertoire, including assessment of promising markers reported in the literature, using well-validated laboratory approaches to identify markers predictive of risk of recurrence for well-defined clinical applications (predicting recurrence in stage I/II patients and in stage III patients). Top candidates from our Discovery experiments meeting particular statistical criteria will be evaluated in a group of patients completely separate from those used in the Discovery set. 2. Discovery and verification of novel biomarkers useful for the early detection of CRC recurrence: Utilizing serial samples collected at regular intervals post-diagnosis we will discover novel biomarkers potentially useful for disease monitoring using proteomic, glycomic, and autoantibody platforms. Markers will be evaluated in the context of CEA, a clinically used biomarker of recurrence that has a 60% sensitivity and 90% specificity for detecting Recurrent colorectal cancer in stage II and III patients. If successful, this project could lead to the development of clinical grade biomarker assays that could have significant impact on reducing the morbidity and mortality associated with colorectal cancer. This study is innovative in that the cohort that will be used is unique, highly characterized, and possesses serial samples collected at regular intervals; the unique platforms that will be used have been shown to yield potentially useful biomarkers and can also evaluate existing markers of interest; and this study is powered to identify biomarkers with clinically meaningful performance characteristics.
NIH R01 CA207371 (Ulrich CM, Li CI): Metabolomic strategies for discovery and validation of biomarkers of colorectal cancer recurrence (4/2017-3/2023)
Abstract: Clinical decision making will increasingly depend on validated, high-quality biomarkers that can be used to guide cancer surveillance and tailor appropriate treatment. Identifying colorectal cancer (CRC) markers is particularly critical, as CRC is common in both men and women (8% of all incident USA Cancers) and is frequently lethal (USA 5-year survival rate: 65%). To date, clinically useful biomarkers predictive of recurrence or survival for CRC patients are limited. Treatment decisions are based largely on clinical and pathologic parameters, with little else to guide risk and treatment stratification of patients. This study will focus on metabolite biomarker discovery and validation utilizing 1,840 patients (stage I-III) with 6,004 repeat blood samples from the existing ColoCare Study, a multi-center prospective cohort of newly diagnosed CRC patients, including detailed demographic, clinical, epidemiologic, and follow-up data, for which blood samples are collected at multiple standardized time points, using identical protocols across study sites. This diverse population ensures broad generalizability and clinical applicability of identified biomarkers. CRC is known to affect metabolism, and thus it is anticipated that markers of altered metabolism should yield useful diagnostic information. Our discovery of metabolic biomarkers will yield novel, distinct findings, and will also be synergistic with ongoing, separate analyses of proteomic, glycomic, and autoantibody biomarkers in the ColoCare Study patient population. This project’s specific aims are: To use state-of-the art, well-validated Metabolomic platforms to discover and verify novel biomarkers: 1. Predictive of recurrence among CRC patients: Using samples collected at diagnosis and follow-up, we will identify metabolites predictive of risk of recurrence in stage I/II and stage III patients. 2. Capable of early detection of CRC recurrence: Using serial samples collected at regular post-surgical intervals (6, 12, and 24 months), we will identify biomarkers useful for disease monitoring for recurrence. Metabolite biomarkers will include >2,500 lipids and aqueous metabolites (MW<1,000; distinct from proteins). We will evaluate the Performance of identified markers separately for men and women and perform analyses to understand factors that affect their Performance. Our long-term goal is to develop clinical-grade biomarker assays that have a significant impact on reducing morbidity and mortality associated with CRC through guidance of treatment/follow-up decision making and characterization of risk of recurrence. The proposed metabolomics platforms are state-of-the art, have yielded potentially useful biomarkers in the past, and have not yet been used in the context of CRC prognosis. The study uses a rigorous multi-step design and is expected to yield clinically robust markers ready for rapid translation.
NINR R01 NR018762 (Figueiredo JC, Jim H): Novel biomarkers for cancer-related fatigue: Integrating metabolomics, genomics and behavior (5/2020-3/2025)
Abstract: From initial diagnosis through treatment and into survivorship, patients frequently report fatigue as a significant problem. Studies suggest that up to 90% of cancer patients experience moderate to severe fatigue during treatment and nearly 30% after treatment completion. Fatigue pathophysiology is thought to be multifactorial and complex, including host susceptibility, pro-inflammatory cytokine production, disruption in circadian rhythms of sleep/activity patterns, and neuroendocrine and metabolic dysregulation. However, to date most studies examining the biology of cancer-related fatigue have limited their focus to inflammation. We propose a new approach, the Predisposing, Precipitating, and Perpetuating (3P) model, to comprehensively examine cancer-related fatigue pathophysiology. The 3P model hypothesizes that: (1) genetic variants predispose patients to fatigue, (2) inflammation and metabolic dysregulation caused by cancer and its treatment are precipitating factors, and (3) behaviors such as poor diet, physical inactivity, and sleep disruption perpetuate the problem. In the current study, we will use a metabolomics approach, the study of small molecules, to examine the relative contributions of precipitating endogenous metabolism and cytokines as well as perpetuating Behavioral factors to fatigue pathophysiology, and how these are modified by predisposing genetic variants and other factors. This approach offers an exciting opportunity to interrogate cancer-related fatigue at a multi-omics systems level. To our knowledge, cancer-related fatigue has never been studied in the context of the metabolome. We will leverage detailed clinical, epidemiological, and objective and subjective Behavioral data as well as blood samples obtained at diagnosis/surgery and sequentially up to 2 years post-diagnosis from the ColoCare Study, a large, international, multi-site, prospective colorectal cancer (CRC) survivor cohort (n=2,379) to determine and validate predictors of fatigue. The ColoCare study is the only large cohort study that collects such comprehensive biological and Behavioral data in the context of CRC. The study has three aims. In Aim 1, we will examine genomic variation and other baseline characteristics as predisposing factors for cancer-related fatigue. In Aim 2, we will examine the metabolome and inflammasome as precipitating factors for cancer-related fatigue. In Aim 3, we will conduct an integrative analysis to evaluate sleep, physical activity, diet, and their relationships with the genome, metabolome and inflammasome as perpetuating factors for cancer-related fatigue. This study is unique in using the 3P framework, detailed longitudinal evaluation of fatigue, and use of cutting-edge technologies to measure multi-omic and Behavioral changes over time. Results will provide new avenues for risk prediction, prevention, and treatment of cancer-related fatigue.
NIH R01 CA254108 (Ulrich CM, Hursting SD): Adipose tissue-colorectal tumor cross-talk: new targets for breaking the obesity-cancer link (9/2022-8/2027)
Abstract: The pandemic rise of obesity worldwide is alarming, with the highest increases occurring in the United States. Obesity is a major risk factor for many cancer types, including colon cancer (CC). To date, the biologic mechanisms underlying this relationship, specifically the potential signaling between dysregulated adipose tissue and adjacent tumor, are incompletely understood. Given the rising rates of obesity and the challenges for many people to lose excess adipose tissue, an integrated, multilevel approach to efficiently identify crosstalk and validate key molecular targets is needed to develop effective mechanism-based strategies for prevention and control of obesity-driven CC. We hypothesize that the metabolic and inflammatory perturbations induced by obesity increase CC risk through altered signaling between adipocytes and colon epithelial/tumor cells, and that inhibition of this crosstalk will disrupt the obesity-CC link. We will test this hypothesis through the integration of: 1) a unique, prospective, multicenter epidemiologic cohort of normoweight to obese CC patients, from whom paired serum, tumor, and tumor-adjacent adipose tissue samples will be used to discover and validate lead targets; and 2) complementary in vivo models of lean and diet-induced obese mice with CC, together with in vitro/in vivo organoid models in which potential targets underlying the effects of obesity on CC will be tested mechanistically. This unique transdisciplinary approach utilizes innovative clinical/epidemiological and preclinical studies of biochemical, transcriptomic, and metabolomics analyses in rigorous study designs to identify and validate new targets for disrupting the reciprocal crosstalk between adipocytes and colonic epithelial cells. We propose three synergistic aims: 1a) to discover and validate targets underlying the adipose tissue-CC link, using 400 CC patients; b) to identify and validate metabolic and transcriptomic signatures of adipocyte-colonocyte crosstalk; 2) to characterize the adipocyte-colonocyte crosstalk underlying the obesity-CC link, using two rigorous mouse models of CC; 3) to determine the causal role of candidate epithelial target genes in obesity-associated CC progression using murine in vitro and in vivo organoid CC models. This paradigm-shifting transdisciplinary collaboration builds on extensive preliminary data and generates maximum synergy through complementary human and murine studies, using identical state-of-the-art biomarker panels and platforms across clinical and preclinical studies. We anticipate that findings from these proposed studies will address the clinical challenges associated with obesity and CC by establishing causal links of the most promising targets for intercepting and disrupting adipocyte-epithelial cell crosstalk.
NIH R21 CA173570 (Robins HS): High-throughput sequencing of the T cell receptor in colorectal tumor infilt (7/2013-6/2016)
Abstract: Colorectal cancers (CRC) are the second leading cause of cancer mortality in the United States. Management of CRC patients includes the need to accurately ascertain patient prognosis and to detect progression following therapy. We hypothesize that Tumor Infiltrating Lymphocyte (TIL) count and clonality will be able to more accurately predict patient outcome than currently existing approaches that are based on using disease stage only. We also hypothesize that measuring the TIL clones in T cells derived from blood following therapy will provide a method to accurately predict progression of CRC. Our hypothesis is supported by growing evidence that the presence of intraepithelial Tumor Infiltrating Lymphocytes (TILs) is strongly related to patient outcome in CRCs and many other diseases. Our opportunity to succeed is based on new technologies developed by our team. While current technologies for assessing TILs are not appropriate for use in a clinical setting, we will use new technologies developed by our team that can reproducibly and quantitatively measure the overall number and clonality of TILs in a specific sample. The assay Immunoseq quantifies rearranged T-cell receptor ? CDR3 chains. We will combine these measures with additional factors to derive a prognostic metric that can be practically used in a clinical setting. To derive our metric we will measure colon cancer biopsy sections and matched blood samples collected at two time points (baseline and 6 months) from 80 stage II and III colon cancer patients with at least two years of clinical follow-up.
