Pancreatic cancer has long had a poor prognosis due to its ability to aggressively spread and its inherent resistance to therapy. After years of little progress in treatment, two separate breakthroughs in understanding the biology of these tumors have placed two new potential therapies on the horizon.
The pancreatic cancer research program at Fred Hutchinson, led by Dr. Sunil Hingorani, is responsible for the discoveries. With both an M.D. and a Ph.D. in Cellular and Molecular Physiology, Dr. Hingorani studies the biological basis for pancreatic cancer's resistance. Research was historically difficult because the cancer is usually not diagnosed until it is already in a late stage. To better understand these tumors, Dr. Hingorani started by developing a live mouse model that allowed him to examine the disease from inception all the way through the advanced stages.
In the first prong of his double breakthrough, Dr. Hingorani discovered that pancreatic cancer creates a protective shield distributed throughout the mass. This shell-like tissue is similar to scar tissue. It contains fibrous cells embedded in a matrix composed in large part of hyaluronan (hyaluronic acid, HA). The shell creates pressure and flattens blood vessels, physically preventing chemotherapy drugs from reaching the cancer cells. Essentially, pancreatic cancer physically shuts down the drug delivery highway.
To remove the hyaluronic shell, Dr. Hingorani's team tested PEGPH20, an enzyme that breaks down HA. PEGPH20 was able to degrade the fibrous shell and allow the drugs in. Mouse studies of a combination drug protocol using this enzyme with chemotherapy showed excellent results, and moving to human clinical trials was fast-tracked.
Combination PEGPH20 therapy is now being studied in two separate clinical trials that began in 2013. The first, sponsored by Halozyme Therapeutics, is a Phase II study of PEGPH20 and gemcitabine with nab-paclitaxel in treatment of metastatic pancreatic cancer. Unfortunately, this first trial was put on hold in early April due to concern over possible blood clot issues. Both Halozyme and the FDA are currently evaluating the data. However, the second study, testing a combination of PEGPH20 and mFOLFIRINOX therapy, is still ongoing. To date, this Phase Ib/II study has not shown adverse effects.
The second prong, also discovered by Dr. Hingorani's team, involves pancreatic cancer's ability to elude the immune system. In February, 2014, Dr. Hingorani published his results: pancreatic cancer is able to attract and use cells that suppress the immune response. T cells, the basis for many of the new immunological anti-cancer therapies, are blocked by these suppressor cells.
Pancreatic tumors emit a protein that attracts suppressors, causing them gather and accumulate throughout the cancer mass. The result is a biological blockade of the body's immune system. Hingorani's team proved that if they depleted the suppressor cells in the tumors, the body's T cells were able to come in and attack the cancer.
The team is now working to develop a clinical protocol that blocks or removes the inhibitory cells and simultaneously delivers targeted anti-cancer T cells. Given the biological groundwork, such a combination therapy looks to hold great promise.
It is remarkable that two discrete causes of pancreatic cancer resistance were found within the course of just a few years. Understanding the biological underpinnings, crucial to development of new therapy approaches, is bringing hope for effective treatments of this difficult cancer.