Why is targeting the stroma important in advanced metastatic pancreatic cancer?

FAQ Library published on June 13, 2017
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Tanios Bekaii-Saab, MD, FACP
Co-Leader, Gastrointestinal Cancer Program
Mayo Clinic Cancer Center
Senior Associate Consultant
Division of Hematology and Oncology
Mayo Clinic
Phoenix, Arizona
Why is targeting the stroma important in advanced metastatic pancreatic cancer?

Welcome to Partners in Pancreatic Cancer. I am Dr. Tanios Bekaii-Saab. I am frequently asked, “Why is targeting the stroma important in advanced metastatic pancreatic cancer?” Overall, pancreatic cancer is one of those cancers that seems to depend quite significantly on the stroma, and there is the step of a love-hate relationship with the stroma. In other words, the stroma seems to have some beneficial aspects and some detrimental aspects to targeting this cancer which makes it quite complex. When we talk about stroma, we are talking about multiple components in the stroma. Pancreatic cancer is unique. It forms around itself this fortress composed of fibrous tissue of immune suppressive cells, the cells of the immune system that actually are detrimental. They suppress the immune system. A very low blood supply, low oxygen, etc., makes it very tight and very aggressive. For many, many years, actually for a few decades, we have tried very hard to find ways to attack the stroma, modulate the stroma, in a way that hopefully makes our treatment more effective, including future immune therapy and others. There were attempts at the beginning to use these agents called MMPs (matrix metalloproteinase inhibitors) with a hope to destruct the stroma and that was not very helpful. The phase 3 studies did not suggest much benefit from these agents. The next attempt was mostly with these hedgehog inhibitors which were thought to have a similar effect on the stroma and to allow, essentially, the modulation of the stroma and to allow chemotherapy to do a better job with the cancer. Again, that ended up being, in some instances, not beneficial, and others actually ended up being detrimental by doing this. We are getting near an era where we are looking at agents that destruct the stroma a little bit differently; agents like PEGPH20 that specifically target hyaluronic acid (HA). What this does essentially, in simple terms, is HA is very important to the composition of the stroma, and disrupting HA and breaking down HA will essentially make the tumor more penetrable, so more likely for the chemotherapy to reach its target and kill pancreatic cancer cells. There is a lot of excitement around this agent, PEGPH20, that is being developed in pancreatic cancer. Interestingly, the early phase studies suggested that perhaps in an unselected patient population, meaning if you treat all-comers with pancreatic cancer with the combination of standard chemotherapy plus PEGPH20, the benefit is small. However, very interestingly, when we actually look at tumors and find those tumors that express higher levels of HA, so higher levels of the target, those patients seem to benefit more significantly from the combination than those with a lower expression of the target.  That led to the embarkment on a phase 3 study looking at the combination of standard chemotherapy with gemcitabine and nab-paclitaxel plus/minus the agents of PEGPH20 in those patients who express high levels of HA. In other words, the therapy is targeted specifically to those patients who are most likely to benefit from the treatment. This is ongoing.

With that excitement in mind, there was a recent study from SWOG that was stopped early because of a futility analysis. The study included the backbone regimen of FOLFIRINOX. It was phase 2 randomized study with or without PEGPH20. That study seems, at least from preliminary understanding, that it was negative, meaning in other words, PEGPH20 did not seem to add much benefit to FOLFIRINOX. It is certainly a disappointment. However, it is important to note that the study itself did not select for patients with high levels of HA, which means it was unselected. SWOG does have access to the tissue from most of the patients which hopefully will help us understand whether HA level selection certainly could have turned the study into a more positive study. Nonetheless, we are eagerly looking at the gemcitabine and nab-paclitaxel plus/minus PEGPH20 study to complete in the hopes that this will help us understand the role of this agent in patients who have been selected for HA high levels. I would thank you for viewing this activity.

Last modified: June 12, 2017
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