What could GLP-1s have to do with oncology? Potentially “everything,” according to Deborah Phippard, chief scientific officer at the mid-sized CRO Precision for Medicine.
Blockbuster drugs like Novo Nordisk’s Ozempic and Wegovy and Eli Lilly’s Mounjaro and Zepbound are so versatile in their effects that they could play a role in cancer as well as in diabetes, weight loss and cardiovascular conditions, Phippard said.
“These are some of the most complicated drugs I’ve seen in my career because they do so many things,” Phippard said. “The G protein-coupled receptor that a GLP-1 agonist binds to is at the top of so many different pathways, and there are so many downstream effects that feed back in.”
The FDA’s August approval of Wegovy for the liver disease metabolic-associated steatohepatitis, or MASH, is a testament to the drug’s ability to improve a condition by targeting underlying risk factors like weight — while also treating the disease through mechanisms the regulator acknowledged are not “fully understood.”
For the same reasons, GLP-1s could impact cancer patients as well, Phippard said.
“If you’re obese and diabetic, you are at higher risk of any number of cancers, which is well-documented,” Phippard said. “Pancreatic, endometrial, ovarian and colorectal cancers in particular have been found to be driven by insulin resistance, so controlling obesity should theoretically take cancer incidents down.”
Beyond the benefits of weight loss to reduce cancer risk, the Swiss-army knife nature of GLP-1s could overlap with different pathways that govern how cancer forms and spreads from an immunological standpoint, she said.
“Looking at the function of specific T cells, NK cells, macrophages, dendritic cells, all of those functions you can demonstrably show change with a GLP-1 agonist,” Phippard said. “The MAP kinase pathway, the NF-kappa B pathway, VEGF — GLP-1 is upstream of all of these.”
The data around these pathways and the comorbidities associated with them is “messy,” Phippard acknowledged, but understanding clinical outcomes for patients being treated for cancer who are also on a GLP-1 could reveal actual effects.
GLP-1s and cancer therapy
Early research has shown that GLP-1s could potentially help overcome chemotherapy resistance, which would theoretically improve outcomes for cancer patients, though Phippard again noted the exact mechanism “isn’t brilliantly well understood.”
And with GLP-1s’ documented effects on the immune system, the drugs could also play a part in making PD-1 immunotherapies like Merck & Co.’s Keytruda or Bristol Myers Squibb’s Opdivo more effective, Phippard said.
“If you look at immune cells in an obese person, they don’t work that well and aren’t very healthy, but a GLP-1 can help,” Phippard said. “I’m always a little hesitant at that because the immune system is very complicated and massively redundant, but we should explore these areas further.”
Earlier in pharma’s GLP-1 era, some concerns that the drugs are linked to thyroid or pancreatic cancer arose, according to MD Anderson Cancer Center. But subsequent studies haven’t confirmed that connection.
Still, physicians are careful not to jump into the deep end with GLP-1s in an oncology setting, particularly with pancreatic cancer patients or those already suffering from nausea and vomiting, which a weight loss drug could exacerbate. Muscle loss is also associated with long-term GLP-1 use, which could make patients more frail over time.
“Pancreatic, endometrial, ovarian and colorectal cancers in particular have been found to be driven by insulin resistance, so controlling obesity should theoretically take cancer incidents down.”
Deborah Phippard
Chief scientific officer, Precision for Medicine
Clinical studies for cancer are where GLP-1s could make a difference in how patients respond to certain drugs. With nearly 12% of all Americans having taken a GLP-1, the odds of patient overlap with clinical trials are growing, Phippard said, and researchers need to better understand those implications to ensure accurate data.
“We’re right at the beginning of how we work this out, but I think you’ve got to run a clinical study looking at this with a separate statistic even in its own right,” Phippard said. “I don’t think we’ll ever be able to pull it entirely apart, but I’m not planning on retiring anytime soon.”
A standalone oncology treatment?
As for whether GLP-1s would ever be considered a cancer treatment, that’s well down the road, Phippard said.
“We are not remotely close to a GLP-1 alone for cancer treatment,” she said. “There may be one or two patients who start a GLP-1 for whatever reason, and their immune system picks up, but that’s an anecdotal n of 1.”
But as a combination treatment alongside chemotherapy or immunotherapy, GLP-1s are a possibility.
Currently, “combo therapies are happening by accident” with patients both on a GLP-1 and undergoing cancer treatment at the same time, Phippard said. And companies like Lilly, which has a foot in both the diabetes and obesity market as well as oncology, could start thinking about the clinical opportunities without having to buy new assets.
“I’m expecting to see this coming out at all the big cancer meetings over the next five to 10 years,” Phippard said. “This is starting to buzz in the community.”