Why is the incidence of early-onset colorectal cancer increasing globally?
Cancer Grand Challenges is a trailblazing research funding initiative taking on some of the toughest challenges in oncology by uniting a global network of oncologists. In this exclusive interview, we speak with Yin Cao and Andrew Chan who are co-leads for team PROSPECT, who are seeking to uncover the pathways, risk factors and molecules underlying early-onset colorectal tumors, with the aim of ultimately reversing the network of causal factors.
Yin Cao is a molecular cancer epidemiologist and Associate Professor at Washington University in St Louis and Alvin J. Siteman Cancer Center (MO, USA). Her lab leverages innovative methods to identify emerging risk factors, biomarkers and molecular pathways of early-onset cancers, with a particular emphasis on colorectal cancer.
Andrew Chan is a physician-scientist at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School. As a practicing gastroenterologist and molecular epidemiologist, he has developed precision cancer prevention approaches through translational research, which spans population cohorts to clinical trials.
What factors may be contributing to an increase in EOCRC?
Previously, we have shown that risk factors such as obesity, diabetes, metabolic comorbid conditions, prolonged sitting, poor diet, sugar-sweetened beverages, alcohol drinking patterns and birth via cesarean delivery, may contribute to the increase in EOCRC.
In PROSPECT, we will more deeply examine exposures to these risk factors throughout the life course and investigate novel risk factors (including environmental and social factors). We will also leverage molecular biomarkers to infer novel exposures and their potential mediators, such as the gut microbiome. Collectively, we broadly consider these factors as the exposome.
How will the team characterize the mechanisms underlying these conditions?
We hypothesize that multiple hits from the exposome across the lifespan will have a cumulative impact on tissues, which can be physiologically recorded, leading to the initiation and promotion of CRC at younger age.
To characterize mechanisms, we will follow up the risk factors identified through multiple diverse population-based cohorts to understand how they cause biological changes that increase susceptibility to, or drive the progression of, EOCRC. Insights and hypotheses from human data will be tested in innovative animal models and in vitro organoid models.
Can you elaborate on the disruptive, transdisciplinary approach being taken in this project?
Our first objective focuses on the lifelong impact of both established and novel risk factors, utilizing global and diverse cohorts. The second objective delves deeper, looking at causal mechanisms and biological networks through advanced chemical and functional profiling of human biospecimens, innovative life course animal models, and exploration of human-animal convergence. In our third objective, we will apply these insights to design and conduct precision trials, further testing causality.
What are the long-term goals of the PROSPECT project?
We hope to transform the conceptual framework that was used to identify risk factors, not only from traditional epidemiology to exposome epidemiology, but by strategically, biologically and rigorously integrating human and experimental studies, with an overarching goal to identify causal risk factors.
How do you envision these interventions could impact the trajectory of EOCRC incidence and prevention efforts on a larger scale?
In PROSPECT, we will set up two types of trials: precision prevention trials (in the US and UK) to explore if treating young adults with an increased risk of EOCRC with anti-obesity drugs or dietary interventions can interrupt the molecular pathways linked with increased risk; and community risk assessment trials (in the UK and India) to determine whether knowing one’s risk for EOCRC influences motivation to modify one’s lifestyle or pursue screening.
We hope our efforts, from identifying the causes and mechanisms of EOCRC, to developing clinical trials and interventions to reduce the burden of this cancer type, could not only advance the underlying drivers of EOCRC across the globe, but also pioneer precision-based cancer prevention for younger populations, a critical yet underserved area.
The opinions expressed in this article are those of the author and do not necessarily reflect the views of Oncology Central or Taylor & Francis Group.