Researchers on the University of Massachusetts Amherst and UMass Chan Medical School have demonstrated in mice a brand new method to combat pancreatic cancer. The study, published in Science Translational Medicine, outlines the synergistic effects of a novel nanoparticle drug-delivery system to activate an immune pathway together with tumor-targeting agents.
Pancreatic ductal adenocarcinoma (PDAC) is probably the most common type of pancreatic cancer. With a dismal,13% five-year survival rate, it’s the third leading reason for cancer deaths.
One major challenge is the microenvironment surrounding the tumor. This environment is characterised by dense tissue making a barrier across the tumor that inhibits blood vessel formation and blocks immune infiltration.
“Drug delivery is a big challenge resulting from the architecture of those difficult-to-treat tumors’ microenvironment,” says Prabhani Atukorale, assistant professor of biomedical engineering at UMass Amherst and certainly one of the corresponding authors of the paper. She adds that the environment also blocks the activation of the body’s immune cells and their penetration into the tumor.
“Pancreas cancer, unfortunately, doesn’t reply to most conventional therapies like chemotherapy, and even immunotherapy, which has revolutionized a whole lot of cancer therapy within the last 10 years,” says Marcus Ruscetti, assistant professor of molecular, cell and cancer biology at UMass Chan Medical School, and the opposite corresponding creator.
Ruscetti’s previous research demonstrated that two cancer drugs (MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib, or T/P) can promote blood vessel development, enabling greater T cell (in addition to chemotherapy) delivery into the tumor. Nonetheless, the cancer “tricks” the immune system into considering that the tumor is just an everyday, healthy clump of cells. Because the T cells aren’t activated, simply having more of them present won’t clear the cancer.
Here’s where the researchers need to implement a trick of their very own. The primary pathway known as the stimulator of interferon genes (STING) pathway. STING recognizes viral infections within the body. “If we are able to trick the immune system into considering that there’s a viral-type infection, then we harness a really robust anti-tumor immune response to usher in for tumor immunotherapy,” Atukorale explains.
The researchers also desired to activate the TRL4 pathway since it boosts the results of STING activation. They use agonists, that are any chemicals that may trigger a biological response; on this case, in immune stimulatory pathways. But getting these immunity-triggering chemicals through the tumor’s microenvironment remains to be a challenge.
The researchers’ solution: encapsulating the STING and TRL4 agonists in a novel design of lipid-based nanoparticles. The nanoparticles have several advantages. First, the research demonstrated that they’re highly effective at delivering the agonists into the difficult tumor microenvironment.
The design also allows each of the agonists to be packaged together — a challenge since these two mix in addition to oil and water. “It ensures that they’re carried inside the blood circulation together, they reach the identical goal cell together and are taken up together by the identical goal cell,” says Atukorale.
“We’re using biocompatible, lipid-based materials to encapsulate drugs that functionally work together, but do not like to be next to one another, after which we’re in a position to use engineering capabilities to construct in various functionalities to direct them where they should go,” she says.
The synergistic effect of the 2 agonists plus the T/P therapy proved effective: eight out of nine of the mice saw tumor necrosis and shrinkage. “And we had two mice that had complete responses, meaning the tumors completely went away, which is pretty striking,” says Ruscetti. “We have never seen that on this model before.”
There remains to be work to be done since the tumors returned after the mice were taken off of the treatment, but Ruscetti says it remains to be a really encouraging step toward a cure.
“For those who transcend pancreas cancer to other cancer types, you would like a mixture therapy to focus on the tumor and to focus on the immune system,” he adds. “This can be a technique to give you the chance to try this.” Treatments for cancers like PDAC that may very well be derived from this study include mutations of colon cancer, lung cancer, liver cancer and cholangiocarcinoma (cancer of the bile ducts).
Prabhani adds that the modular nature of this design allows for therapies that could be easily personalized for patients. “It’s form of plug and play,” she says. “We will tailor the agonist ratios, the drug mixtures, the targeting molecules, but keeping essentially the identical platform. That is what is going to make it hopefully translational, but additionally tunable on a per patient basis, because a lot of these cancer therapies must be personalized.”
Finally, she nods to the facility of collaboration between the 2 UMass institutions, saying, “The sort of system is definitely built when you’ve complementary, but multidisciplinary and cross-disciplinary, expertise.”
