Luebeck and his colleagues were able to bring mathematical models to this area, he said, by looking at the age of the tissue and backtracking to when a cancer and its precursor first arose.
“We were able to use statistical approaches to turn this information into a molecular clock,” he said. “When you find an adenoma in colon screening, the question has always been, ‘Is this going on to cancer? How old is it?’ Colorectal cancers presumably arise in adenoma, a polyp, but when did the adenoma (the one that makes the cancer) first arise? When should we screen? That’s the question that’s hard to investigate. There’s no epidemiology for that. However, cancer modeling can do this.”
Luebeck created a cancer model that showed that a founder premalignant cell that goes on to become cancerous can actually develop in the first decade of life.
The paper, published in 2019 in the journal Cancer Research, found that precancerous lesions ”can persist for decades before becoming cancerous,” data that suggests that “early dietary and lifestyle interventions may be more effective than later changes in reducing colorectal cancer incidence,” the authors wrote.
Can that information somehow be used to improve colon screening?
“We could start thinking about chemoprevention [taking cancer-preventive drugs], starting to screen people earlier, and having better instruments, more sensitive assays, that detect the precursors in which malignancies arise,” he said.
Modeling paths to esophageal cancer
Luebeck’s modeling and molecular clocks are considered for use in other cancers, such as esophageal cancer.
Over the last ten years, in collaboration with Fred Hutch physician-scientist Dr. Bill Grady and former graduate student Kit Curtius (now at UC San Diego), Luebeck created a DNA methylation clock for esophageal cancers that arise as a result of the condition Barrett’s esophagus, or BE.
“People have looked at smoking, alcohol, BMI, how often you have reflux symptoms, etc.,” he said. “They’ve stratified the risk by age, sex, race and all of that. But the critical information nobody was able to provide was: How long has this tissue been in place?”
"The idea that tissue aging somehow also plays a role in the initiation of a cancer was something that clicked with me.”
BE starts with injury to the tissue by acid reflux, or the more severe condition, gastroesophageal reflux disease, commonly known as GERD. But many people don’t know if they have BE, because it’s basically asymptomatic.
“Reflux or bile juices cause erosion in the lower esophagus and the tissue can turn into metaplasia [sometimes a precursor to cancer],” he said. “Roughly half the people who get esophageal cancers never had GERD symptoms.”
Only a fraction of people with BE actually go on to develop esophageal adenocarcinoma or EAC (about 5%). So those who are diagnosed with it are at risk of overdiagnosis and possibly overtreatment, while some of those who are not may develop EAC without a chance of an intervention.
Working with Curtius and his long-term Hutch collaborator Dr. Bill Hazelton, Luebeck developed a multiscale modeling framework, or molecular clock model, that plots the natural history of how GERD can progress to Barrett’s esophagus and eventually esophageal cancer. The results were published in 2016 and 2017.
“Does age really matter as a risk factor for cancer? The answer is yes,” he said. “There’s a clear correlation between age and cancer risk. The older the tissue is, the more stem cell divisions and the higher the number of mutational events that lead to cancer. Time is of essence.”
Since many people who develop EAC have no symptoms from Barrett’s esophagus, and since the U.S. Preventive Services Task Force doesn’t currently offer any kind of screening guidelines for it, Luebeck also hopes this work will enable clinicians to find a way to identify those at risk.
Perseverance and teamwork
Luebeck’s desire to continue clocking cancer — and collaborate with others at the Hutch determined to do the same — have kept him intrigued and engaged for more than three decades, years in which he’s seen “mind-boggling” progress in cancer research and technology.
“For me, the most enjoyable thing is the interaction with other people at the Hutch, the collaborations,” he said. “The brainstorming, just being exposed to ideas and the teamwork that comes from it. People have different strengths — in computer modeling or computer programming or in the medical field or genetics — we bring all these together.”
The result? Sky’s the limit.
“NASA is now requesting input into understanding the cancer risk from galactic radiation,” he said. “Why? Because we want to go to Mars. I find it all very exciting. Did you see [NASA rover] Perseverance land on Mars? ‘Dare do a mighty thing’: That was the message written on the parachute. I think that’s a great motto — even in cancer research.”
— By Diane Mapes, May 2, 2021