Obesity, which has reached alarming levels in the United States, may soon surpass smoking as the number one cause of preventable cancer. The U.S. Centers for Disease Control and Prevention links excessive weight with increased risk of developing 13 types of cancer. That’s why understanding how to best treat obese cancer patients is essential.

Monjazeb is collaborating with a team of UC Davis researchers to unlock the role obesity and its related hormone leptin play in radiotherapy resistance. Their studies may have major clinical implications and could help advance personalized medicine

Personalized care for obese cancer patients

Monjazeb’s work focuses on understanding cancer holistically. He says research has not paid enough attention to the patient’s metabolic profile. Monjazeb and his team are looking at how obesity diminishes the radiotherapy response. They believe that what patients eat and the level of inflammation in their body may affect their cancer treatment.

“It is important to really know your patients and understand cancer in their specific context. Tailoring radiotherapy strategies to a patient’s metabolic parameters can improve patient outcomes,” Monjazeb said.

Radiotherapy resistance

For radiotherapy to work, it needs to directly kill cancer cells and trigger the immune system to clear out the damaged cells. The success is based on its ability to cause DNA damage and destroy the tumor cells as well as stimulate the immune system’s response to that damage.

Radiotherapy resistance appears when patients have less tumor shrinkage and higher cancer recurrence rates after radiation.

“Our preclinical data show increased tumor resistance to radiotherapy in obese mouse cancer models. Clinical data also demonstrate that obese cancer patients are more resistant to radiotherapy and have higher rates of cancer recurrence,” Monjazeb explained.

“Some researchers have hypothesized that this resistance is a matter of physics, as it’s just harder to deliver radiation in larger patients, which may be true. But we think that there is a biological difference between cancers in obese patients and those in lean patients and the way that cancer responds to radiation,” Monjazeb added.

How does obesity affect radiotherapy?

The team’s previous studies showed that obesity could alter the growth, spread, and survival of cancers. They showed that the obesity-linked adipokine leptin could influence cell death and post-survival pathways of cancer cells.

Adipokines are cell-signaling molecules produced by the body’s fat tissue. They play a key role in regulating the body’s energy and metabolic status, inflammation, and obesity. Leptin, a recently discovered adipokine, is highly elevated in obese patients.

Research has shown that the immune system plays a role in how tumors react to radiotherapy. Obesity can make cancer patients more resistant to radiation by causing immune dysfunction. It may suppress the adaptive T cell response in the tumor microenvironment, impairing the immune response to cancer.

“The microenvironment surrounding the cancer cells provides nourishment for the tumor. Obesity can help feed this environment and protect the cancer cells,” said immunologist William Murphy, a co-investigator on the study. “Obesity potentially helps tumors adapt and become resistant to radiation in a nutrient-rich environment. It can also result in greater inflammatory responses, allowing the cancer to spread more as well as suppress immune attack.”

Murphy is a distinguished professor and vice chair of dermatology with a joint appointment in the Department of Internal Medicine, Division of Malignant Hematology/Cellular Therapy and Transplantation.

Studying obesity’s effect on radiotherapy

The team will study the links between obesity and radiotherapy using mouse models. They’re using genetically identical mice with genetically identical tumors. The only difference is that some mice are on a high-fat diet, making them gain weight. They will compare the efficacy of radiotherapy in the lean versus the obese mouse models.

They will also study radiotherapy in immunosuppressed mice to look at the direct effects of obesity on the tumor itself. The team will also evaluate how obesity and leptin signaling within cancer cells and the tumor microenvironment influence resistance to radiotherapy and immune responses.

Future directions

In the future, they hope to study different tumor models and explore avenues to reverse radiation resistance in obese patients.

“It is possible that certain strategies that we may come up with to try to make cancers more radiation responsive will work both in obese and lean patients. These strategies may just have a more profound effect on obese patients since these mechanisms are more in play,” Monjazeb said.

Monjazeb also received a supplemental diversity grant for $257,739 to support the work of doctoral graduate student Logan Vick. Diversity supplements provide funding to individuals from backgrounds that are generally less represented in the sciences. Vick is a researcher in Monjazeb’s and Murphy’s labs at UC Davis Medical Center.

Other collaborators on this project include radiation oncologist Jian-Jian Li, physicist Julian Perks and the Department of Radiation Oncology