Study Identifies a Mechanism behind Pancreatic Cancer Treatment ResistanceResearchers have discovered a physical mechanism that prevents chemotherapy from reaching pancreatic cancer cells, as well as a way to reverse that mechanism. Dr. Sunil Hingorani of the Fred Hutchinson Cancer Research Center and his colleagues reported their results March 19 in Cancer Cell.
Pancreatic adenocarcinoma, the most common type of pancreatic cancer, is notoriously resistant to chemotherapy and radiation therapy, leading to an overall 5-year relative survival rate of less than 5 percent. Using mice with tumors that are genetically similar to human pancreatic adenocarcinomas, the researchers found that, as the tumors grow, a thick matrix develops and surrounds the tumors’ cells.
The matrix exerts tremendous pressure on the tumors—pressure that greatly exceeds the normal pressure found within blood vessels—causing the tumors’ blood vessels to collapse. This collapse prevents chemotherapy drugs in the blood stream from reaching the tumor cells.
Dr. Hingorani and his colleagues identified a substance called hyaluronic acid that forms a large part of this pressurized matrix. When they treated the mice with an enzyme called PEGPH20, which breaks down hyaluronic acid, the pressure within the tumors returned to normal, and the blood vessels regained their normal shape and function.
When the researchers treated mice with a combination of PEGPH20 and the chemotherapy drug gemcitabine, 83 percent of tumors within the pancreas shrank after only one cycle of treatment, and all tumors shrank after three cycles. Similar responses were seen in metastatic tumors. Mice that received the combination therapy survived almost twice as long as mice that received PEGPH20 plus a placebo.
“When able to penetrate the tumor bed, gemcitabine can indeed be an effective agent against this disease,” wrote the authors. An early phase clinical trial is testing the combination of PEGPH20 and gemcitabine in people with metastatic pancreatic cancer.