Factoring in frailty and age to improve pancreatic cancer treatment

(Press-News.org) While some risk factors for cancer can be mitigated through lifestyle choices such as diet or exercise, aging is not one of them. In the case of pancreatic cancer, it also can limit treatment options if a patient is too frail to be safely treated with surgery or other alternatives.

Scientists at the NCI-Designated Cancer Center at Sanford Burnham Prebys Medical Discovery Institute would like to expand options for these patients with personalized treatments. Many stand to benefit from a therapeutic strategy that factors in age. The average age of a patient diagnosed with pancreatic cancer is 70, and nearly two-thirds of cases are in people over the age of 65.

“Too often, frailty prevents patients from being able to withstand conventional chemotherapies as well as surgery, and often there aren’t other viable options,” said Cosimo Commisso, PhD, the deputy director of the institute’s cancer center and a professor in the Cancer Metabolism and Microenvironment Program.

“As a field, we need to rethink how the therapies that we're developing work for a frail population and an aging population, because that's the vast majority of patients.”

In a new study published November 7, 2025, in Cancer Research, Commisso and his colleagues advanced the possibility of age-based pancreatic cancer treatment by investigating how aging affects cancer cells and the environment surrounding them.

The research team began by comparing the progression of pancreatic cancer in mice that were about two months old and mice that were more than a year and a half old. The cancer cells implanted into the mice were genetically identical, yet the older mice had faster-growing tumors and more cancer cells spreading into other tissues to form metastases.

“It was clear to us that aging was accelerating cancer progression as the primary tumors were larger, and the metastases were larger,” said Priyanka Gupta, PhD, a staff scientist in the Commisso lab and lead author of the manuscript. “It shows the limitations of using young mice to test drugs and model diseases that mostly affect older patients.”

The scientists hypothesized that the change was due to aging altering the tumor microenvironment, the neighborhood of immune cells, connective tissue, blood vessels and a sea of proteins and carbohydrates that cancer cells hijack to avoid the immune system and support their growth.

The researchers began comparing the tumor microenvironment differences by studying gene expression in each group. Nearly 550 genes were either more or less expressed in the tumors of the young and older mice. The older mice’s gene expression indicated a decline in the function of T cells, one of the immune system’s primary tools for detecting and eliminating cancer cells. There also were fewer T cells found in the tumors of older mice.

This finding fit with the result of a follow-up experiment showing that the tumors in older mice featured more collagen, characteristic of a stiff tumor microenvironment that serves as a barrier blocking the entry of T cells.

“The presence of collagen is indicative of fibrosis near the tumors, which we found also was present in data from human patients with pancreatic cancer,” said Commisso. “We know that fibrosis is a driver of tumor progression and makes it harder to deliver drugs across different tumor types, including pancreatic cancer.”

The scientists also discovered that aging was associated with the remodeling of the jelly-like substance between cells called the extracellular matrix. This remodeling contributes to a more fibrotic tumor microenvironment, presenting further obstacles to T cells and promoting tumor metastasis.

“We then asked if it was possible to reverse this remodeling by restoring some of the characteristics in the tumor microenvironment of the older mice to what we observed in their younger counterparts,” said Gupta.

To test this, the scientists turned to cancer-associated fibroblasts (CAF), support cells surrounding the tumor that provide nutrition in the form of metabolites as well as growth signals. After implanting CAFs from young and older mice along with cancer cells, the researchers observed the effects on tumor growth and metastasis.  

“In the older mice, we saw a revitalization of the tumor microenvironment when implanted with the young CAFs,” said Commisso. “It reversed the metastasis that we saw in the older animals.”

In the future, it may be possible to trigger this revitalization in human patients using a drug or gene therapy. This could slow down the progression of the disease and make tumors more susceptible to other treatments, including immunotherapies that rely on the immune system breaking through a more porous tumor microenvironment.

“This study supports the paradigm shift I believe we need in the field of pancreatic cancer,” said Commisso.

“If we take a more patient-centered approach, we can use preclinical models that factor in age to better reflect who bears the biggest burden of this disease. And that will give us a better shot at discovering and developing therapeutics that get through clinical trials and FDA approval because they work in the patients that most need them.”

 

Priyanka Gupta, PhD, a staff scientist in the Commisso lab, is the lead author of the study.

Additional authors include Rabi Murad, Li Ling, Yijuan Zhang, Karen Duong-Polk, Weiliang Huang, Marzia Scortegagna, Swetha Maganti and Cheska Marie Galapate from Sanford Burnham Prebys.

The study was supported by the National Institutes of Health and National Cancer Institute.

The study’s DOI is 10.1158/0008-5472.CAN-25-1904.

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