Researchers from the University of Massachusetts Amherst and UMass Chan Medical School have found a novel approach to fight pancreatic cancer using mice in their latest study. The findings, published in Science Translational Medicine, reveal the combined benefits of a new nanoparticle drug-delivery system and tumor-targeting agents in activating an immune pathway.
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent type of pancreatic cancer, with a low five-year survival rate of only 13%, making it the third most common cause of cancer mortality.
A significant challenge in treating this cancer is the tumor’s microenvironment, which is dense and creates a barrier that restricts blood vessel growth and prevents immune cells from infiltrating the tumor.
“Drug delivery is incredibly difficult due to the complex structure of these tough-to-treat tumors’ surroundings,” explains Prabhani Atukorale, assistant professor of biomedical engineering at UMass Amherst and one of the co-authors of the study. She notes that this environment hinders the activation and entry of immune cells into the tumor.
According to Marcus Ruscetti, assistant professor of molecular, cell and cancer biology at UMass Chan Medical School and the other corresponding author, traditional therapies such as chemotherapy and even the newer immunotherapy treatments have had limited success in treating pancreatic cancer, which remains a challenge in the field.
In his previous work, Ruscetti found that two cancer drugs, MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib (referred to as T/P), can help develop blood vessels, thus facilitating better T cell and chemotherapy delivery into the tumor. However, the cancer manages to disguise itself, misdirecting the immune system into perceiving the tumor as just healthy tissue. As a result, more T cells do not lead to effective cancer clearance without proper activation.
This is where the researchers aim to integrate a clever strategy of their own. They focus on a pathway known as the stimulator of interferon genes (STING), which identifies viral infections within the body. “If we can mislead the immune system into believing there’s a viral infection, we can trigger a strong anti-tumor immune response for immunotherapy,” Atukorale elaborates.
Additionally, the researchers aimed to activate the TRL4 pathway to enhance the effects of STING activation. They utilize agonists—substances that can initiate a biological response—specifically targeting immune stimulation pathways. However, effectively delivering these immune-activating chemicals through the tumor’s dense environment remains difficult.
The researchers’ innovative approach involved encapsulating the STING and TRL4 agonists within specially designed lipid-based nanoparticles. This strategy provides several advantages, including a demonstrated efficacy in delivering the agonists deep into the challenging tumor microenvironment.
This design enables both agonists to be packaged together despite their tendency to repel each other, similar to oil and water. “This ensures they travel together through the bloodstream, reach the same target cells, and are absorbed simultaneously by those cells,” Atukorale explains.
“We utilize biocompatible, lipid-based materials to encapsulate drugs that have complementary mechanisms, even if they’re not typically compatible. Our engineering capabilities allow us to integrate various functionalities to ensure they reach their intended targets,” she adds.
The synergistic combination of the two agonists with the T/P treatment proved successful: tumor necrosis and shrinkage were observed in eight out of nine mice. “Remarkably, two mice exhibited complete responses, meaning their tumors disappeared entirely, which is unprecedented in this model,” asserts Ruscetti. “This has never been achieved before.”
Although further research is necessary since tumors returned after treatment cessation, Ruscetti views the results as a promising advancement toward a potential cure.
“This strategy could extend beyond pancreatic cancer to treat other cancers, requiring a combination therapy approach targeted to both the tumor and the immune system,” he states. Potential applications of this research may benefit patients with various cancers, including certain types of colon, lung, liver cancers, and cholangiocarcinoma (bile duct cancer).
Prabhani notes that this modular design encourages easily personalized therapies for patients. “It operates like a plug and play system,” she remarks. “We can adjust the ratios of agonists, drug combinations, and targeting molecules while using the same foundational platform. This flexibility may enhance the translational aspect of our approach, tailored individually because many cancer therapies necessitate personalization.”
Lastly, she emphasizes the significance of collaboration between the two UMass institutions, stating, “This system’s development is streamlined when you bring together diverse, complementary expertise across disciplines.”
