Dana-Farber Researchers Explore Strategies to Reduce Obesity-Related Cancer Risks
December 16, 2024
By Beth Dougherty
Headlines across the country recently reported that obesity rates in the U.S. had dropped over the past two years. Ever so slightly and not statistically significantly, but still, it was big news.
According to the Centers for Disease Control and Prevention (CDC), the obesity rate today is approximately 40%. The number has been rising steadily since 1990, when just 12% of the population was considered obese.
Obesity has long been linked to cancer risk and is a known risk factor for 13 different cancers, including breast, ovarian, colon, and pancreatic cancers. A recent study suggested that new and wildly popular weight-loss medicines such as Ozempic and Wegovy, generically known as semaglutide, a GLP-1 receptor agonist, are linked to a lower risk for a subset of these cancers. Together, these trends are a glimmer of hope when it comes to reducing the risk of cancer.
But the scales have not yet tipped against obesity-related cancer risk. Many questions remain. For instance, in the study of cancer risk among patients taking semaglutide, the population studied was taking the drugs to treat diabetes, not obesity. In addition, the study was retrospective, looking back on a collection of medical records, not an intervention being tested in a clinical trial, making it more of a hint at a possibility than a practice-changing revelation. Also, the way a person loses weight — via medicine, diet, physical activity, or a combination — could influence cancer risk, researchers have learned, because changes in eating patterns and exercise levels have many effects on the body, beyond obesity levels.
To learn more, Dana-Farber researchers are devising interventions concocted in the kitchen, the gym, and the lab and testing them in the clinic to learn more about how diet, exercise, and novel medicines affect the risk of cancer and recurrence.
Obesity is the second leading cause of cancer and it is preventable.
"Obesity is the second leading cause of cancer and it is preventable," says Elizabeth O'Donnell, MD, director of the Multi-Cancer Early Detection Clinic in the Centers for Early Detection and Interception at Dana-Farber. "But it is not easy to lose weight. Behavior change is hard. We really need to find ways to help our patients who are struggling to lose weight because they want to reduce their risk of cancer or relapse."
The Obesity-Cancer Connection
The potential link between obesity and cancer, despite the current headline news, is not new. Scientists were publishing papers linking obesity and excess weight to cancer since the mid-1970s. In 2015, the International Agency for Research in Cancer assembled an expert panel, including Jennifer Ligibel, MD, director of Dana-Farber's Leonard P. Zakim Center for Integrative Therapies and Healthy Living, to review the literature linking obesity to cancer risk. The resulting publication detailed the link between excess fat and the risk of 13 cancers. Ligibel also led an initiative through the American Society of Clinical Oncology starting in 2013 to review the research linking obesity and cancer, inform the public about these connections, and outline areas in need of research.
"There was a real need for this campaign to increase education among patients and providers," says Ligibel. "Most Americans didn't know about the connection between obesity and cancer risk. Even oncologists weren't thinking about obesity as a risk factor for cancer."
Given these findings plus the study results that linked the use of GLP-1 agonists with reduced cancer risk, it might seem tempting to jump to the conclusion that weight loss reduces cancer risk. But Ligibel urges caution.
"There's so much data that shows us that people who have healthier lifestyles and keep their weight in a more advantageous range have lower risks of cancer," says Ligibel.
But there is very little data showing that weight-loss interventions reduce cancer risk. That's not because tests of weight loss interventions for reduced cancer risk have failed.
Rather, says Ligibel, "We do not have trials that have actually tested the effect of weight loss — whether achieved through lifestyle or medications — on cancer risk."
Prevention studies are notoriously difficult to run. It might take a lifetime to study a population and determine if an intervention reduces the risk of cancer.
Instead of focusing on risk in the general population, Dana-Farber researchers have zeroed in on specific groups of patients who are overweight and have an unusually high risk of cancer.
Christina Dieli-Conwright, PhD, MPH
Diet, Exercise, and Cancer Prevention
Researcher Catherine Marinac, PhD, studies patients with an elevated risk of multiple myeloma, one of the 13 obesity-related cancers. She is specifically studying individuals with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma, which are well-defined pre-malignant conditions that precede the development of myeloma and confer a lifelong risk of progressing into overt multiple myeloma.
To determine if weight loss reduces the chances of an overweight or obese patient with MGUS progressing to myeloma, Marinac devised an intervention that she thought patients might be able to stick to. The intervention, a 14-hour nightly fasting regimen, aims to have patients avoid eating during times that are most out of sync with natural biological rhythms.
"It's a strategy to improve metabolic health and potentially lose weight," says Marinac. "Some of the postulated mechanisms through which obesity increases the risk of multiple myeloma include aspects of metabolic dysfunction."
In early data from the fasting study, fasting patients have reported weight loss and improved sleep. The team will also measure multiple blood biomarkers to examine changes in immune cells and plasma cells. They'll also track measures of body composition, particularly proportions of lean mass versus fat.
"Having lean muscle mass is so critical for preservation of functionality, particularly in aging patients," says O'Donnell, who is running a similar fasting-based trial in patients with a high risk of breast cancer and who, like Marinac, is interested in a wide range of potential weight loss interventions. "In a clinical trial focused on weight loss, there's usually a supportive team advising on nutrition and physical activity and guiding patients to safely use any weight loss medicine involved."
"I have a very strong appreciation for lean mass," says Christina Dieli-Conwright, PhD, MPH, an expert in a new field called exercise oncology. "When losing weight, that's not the tissue you want to lose."
Dieli-Conwright runs the first exercise oncology lab at Dana-Farber and is testing exercise interventions that focus on a range of cancer outcomes. For instance, some exercise programs aim to help patients before they begin treatment to improve their ability to tolerate debilitating medicines. Other interventions occur during treatment with an aim to stave off toxicities such as cognitive declines from chemotherapy. She also has interventions that focus on overweight and obese patients with an aim to improve metabolic function.
"We are seeing that patients who are exercising during, before and after treatment are feeling better and are happy to have found supportive care that's not a drug," says Dieli-Conwright.
Phone a Friend
Scientists have also found mounting evidence that excess weight influences the risk of cancer recurrence. In breast cancer, for instance, observational studies suggest that patients who have obesity at the time of their breast cancer diagnosis have worse outcomes. Their cancer is more likely to recur and be harder to treat.
Ligibel has designed a first-of-its-kind large-scale study, the Breast Cancer Weight Loss (BWEL) trial, to determine whether participating in a weight loss program after a breast cancer diagnosis can reduce the risk of cancer recurrence in women with a body mass index (BMI) in the overweight or obese range. Women in the study are randomized to receive a weight-loss intervention plus health materials or health materials alone. The intervention is a telephone-based coaching program focused on reducing calories and increasing exercise.
Ligibel recently reported that patients who were assigned to the weight loss group lost almost six percent of baseline body weight at one-year as compared to patients in the health education program. Additionally, the group receiving the weight loss program had increased their weekly exercise from a median of 10 minutes a week at baseline to 110 minutes a week after six-months of study participation. Investigators also found that more exercise was a predictor of more weight loss.
"People primarily lose weight through caloric restriction. But exercise is incredibly important for maintenance of weight loss," says Ligibel, who expects to report results of the intervention's effect on outcomes in 2025.
Bruce Spiegelman, PhD (left) and Edward Chouchani, PhD
We want to understand exercise at a molecular level. Could we use these molecules to create new therapeutics — not to replace diet and exercise but to precisely harness and amplify their effects?
Molecular Workout
Exercise has long been known to promote health and wellness. But what is it actually doing in the body?
Dana-Farber cancer biologist Bruce Spiegelman, PhD, asks this exact question in his lab. He induces exercise, primarily in mice, and then captures the molecules produced during and immediately afterwards and learns what they do.
"We want to understand exercise at a molecular level," says Spiegelman. "Could we use these molecules to create new therapeutics — not to replace diet and exercise but to precisely harness and amplify their effects?"
To do this, he uses an old technology for a novel application. He sets a centrifuge at 600 RPM to spin tissues collected from fat and muscle. The process pulls out the molecules nestled in between cells — those that were excreted or shed from fat and muscle tissue in response to exercise — and scientists can examine them using modern mass spectrometers, looking for interesting signals.
"These new mass spectrometers are transformative technology for our entire field of metabolism," says cancer biologist Edward Chouchani, PhD, who trained in Spiegelman's lab and now does similar work in his own Dana-Farber lab. "These instruments have, for the first time, allowed us to catalog with unprecedented depth what's coming in and out of biological systems."
The technique led Spiegelman's lab to discover the first novel molecule regulated by exercise, a hormone called irisin. This molecule is produced by muscle in response to exercise. Research shows that it interacts with tissues across the body and has effects typically associated with those of exercise. For instance, irisin preserves the life of neurons but induces the death of cancer cells.
Recently, Spiegelman has found that irisin slows the progression of triple-negative breast cancer, one of the more difficult forms of the disease, in mice. His studies also suggest that it has positive effects in mouse models of neurodegenerative diseases, such as Parkinson's disease.
"We would like to get this into the clinic for early-stage breast cancer and neurodegenerative diseases," says Spiegelman.
To support that goal, he and Ligibel have launched a clinical trial funded by the Breast Cancer Research Foundation to study how irisin, other biomarkers, and healthy breast tissue change over time and with exercise in healthy women at an increased risk of breast cancer due to breast density. Industry collaborators are also working to find ways to improve the drug-like qualities of irisin so it might be tested in human clinical trials for patients with triple negative breast cancer.
Exercise and Metabolites in Cancer Prevention
Chouchani has also used mass spectrometry to link a metabolite called succinate to exercise.
"Everyone learns about succinate in medical school," says Chouchani. The metabolite is produced in every cell in the body and helps transform energy from sugar and fat into ATP to power the cell.
Chouchani discovered, however, that its role is much broader than that. Succinate is released when cells become acidic. This can happen during exercise, for example, in muscle cells as lactic acid is produced. But cells also become acidic in unhealthy scenarios, such as with cancer and obesity, which results in insufficient oxygen, called hypoxia, inside a tumor or fat cells.
Further, in a healthy organism, succinate is released and cleared in spikes, says Chouchani. "That release is important for how the muscle and other tissues respond to exercise."
But in unhealthy tissue, such as with obesity or cancer, succinate release becomes chronic. "It goes up and stays up persistently for weeks, months, even longer," says Chouchani. "Chronic succinate elevation is not good. It can cause tissue fibrosis, is pro-inflammatory, and is associated with poor prognosis."
Chouchani is currently investigating ways in which this knowledge could be translated into a therapeutic. One idea is to target the receptors succinate interacts with in a way that blocks the negative consequences of chronic succinate. Such a therapeutic could potentially interfere with the development of non-alcoholic fatty liver disease (NASH), which increases the risk of liver cirrhosis and liver cancer.
"This work is still in the early stages," says Chouchani, "We are still learning."
Scientists and physicians agree that maintaining a healthy weight and getting regular exercise are good for many reasons. But today, tapping into 50 years of research into the link between obesity and cancer risk, they are focused on discovering exactly why weight and activity matter and using that information to design better interventions to reduce the risk of obesity-related cancers.