Breakthrough Understanding in Pancreatic Cancer Therapy

Transcription

1 Breakthrough Understanding in Pancreatic Cancer Therapy Recorded on: May 28, 2013 Sunil R. Hingorani, M.D., Ph.D. Associate Member Fred Hutchinson Cancer Research Center Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Hello and welcome to Patient Power, sponsored by the Seattle Cancer Care Alliance. I'm Andrew Schorr. You certainly know that pancreatic cancer has been one of our deadliest cancers, and finding effective treatment has been difficult. Helping lead the way in new research is our guest today-- that is Dr. Sunil Hingorani. He's an associate member of the Fred Hutchinson Cancer Research Center, and he sees pancreatic cancer patients at the Seattle Cancer Care Alliance. Dr. Hingorani, welcome back to Patient Power. It's my pleasure. Dr. Hingorani, you've been leading the way in research for this deadly disease, pancreatic cancer, and I know you lost your own father to pancreatic cancer. Where are we now in looking for effective treatment for this disease? Certainly. It is true that pancreas cancer has been notoriously difficult to treat. In fact it has a level of resistance to chemotherapies that is unusual when compared to other cancers, and even other solid tumors that can tend to have similar kinds of mutations, or changes in the DNA, and

2 can also be aggressive. Interestingly, when you purify pancreas cancer cells, remove them from a tumor, and study them in the laboratory, they are responsive to many of the chemotherapies we do use for other tumors. However, when you give those same drugs to patients, and try to treat the tumor that's in the body, we find that essentially none of the drugs work very well, at all. And so we've puzzled over this, and one of the findings that we've made over the last several years, is that pancreas cancers actually decrease or shut down the blood supply to their tumors as opposed to most solid tumors which increase the blood supply. And they also erect different kinds of barriers that prevent drugs from getting in. One of the really surprising findings is that it may be that the primary mechanism of resistance, in pancreas cancer, is that the drugs never penetrate sufficiently into the tumor bed. And so the approach we have taken is to try to, first understand what those barriers are, and then to develop strategies to overcome them, which might then enable drugs to distribute more freely in the tumor, and hopefully see the kinds of responses we'd like to see when treating patients. Dr. Hingorani, every June there is the big American Society of Clinical Oncology meeting, ASCO, and at the 2013 meeting you have the results of a Phase I study of something called PEGPH20, where it can be combined with chemotherapy for pancreatic cancer. Tell us about the study and the study results. Yes. The Phase I study, that we just completed, was designed to test this combination strategy, but of course in the very first phase of trials you're actually just trying to find what the right dose is of the novel agent to give. What's the side effect profile, and how high can you take the dose and have the patient still tolerate it well. However, along the way, since we are physicians and we are taking care of patients, we also do take note of any responses that we see. And the strategy that we've used is to take an enzyme that has been modified so that it will last in the circulation for an extended period of time, and see if that enzyme can begin to chew its way through the barriers, these walls that the tumor erects, and once that's done, to then follow with chemotherapy and see now if the chemotherapy can do its job more effectively. And what we found primarily again, and we now know the right dose to give in combination with chemotherapy of this enzyme, and we have seen that when we do that, it would appear that these very same chemotherapies, that essentially did not work at all previously, do seem to give us responses that are encouraging. 2

3 Dr. Hingorani, I know neither you nor I want to create false hope for patients, but could this new treatment, you're looking into, represent a game changer, or what some might call a breakthrough in the treatment of pancreatic cancer? Well, of course those of us who take care of patients as well, we always hesitate to use too much hyperbole. We've been humbled many times by this cancer. However, I can tell you that certainly from our own standpoint, our own conceptual thinking, this is a new way for us to think about the tumor. It's a new way to understand why the tumor is so resistant to therapy, and in the end, the proof is in the pudding, so to speak. Namely, with combining this agent we will see whether or not chemotherapy does in fact work more effectively once it can get into the tumors. I can tell you that the results from the Phase I trial were encouraging enough that we have already moved on to a randomized Phase II trial testing this hypothesis in a much larger cohort of patients, and doing it in a rigorous fashion where half the patients will get the best chemotherapy we have available today, and the other half will get that same combination chemotherapy but together with the enzyme. And we hope that the results of this study will actually answer the question definitively of whether this strategy is the right one to pursue. Share with us the benefits that you see for patients. Well, as I mentioned, what we're hoping to find in the beginning, the first sort of tell-tale sign would be that blood vessels have opened up and you can actually deliver more blood and presumably, therefore more oxygen and nutrients, as well, to the tumor. Now, we have ways of measuring how well, or how much blood flow is going into tumors, so we can get a sense if the enzyme is having that effect or not. Now, it may seem counterintuitive that one would want to increase the blood supply to a highly aggressive tumor, and therefore increase its ability to get oxygen and its ability to get glucose, and perhaps in many settings that would be paradoxical. However, we know that these tumors have actually accommodated themselves. They have evolved so that they're perfectly happy with low levels of oxygen, and with lower levels, perhaps of conventional nutrients that most cells and most tumors use. 3

4 We think the primary difference in increasing this blood supply is actually the ability to flood the tumor with chemotherapy, which it previously was completely shielded from, because the chemotherapy was very effectively going into other parts of the body, and essentially not at all into the tumors. The hope is that by increasing this blood flow you increase the delivery of chemotherapy, and the tumor cells may not be sufficiently prepared to resist that chemotherapy from the beginning, which is what we thought they were doing previously. Dr. Hingorani, as you move forward with your research, and of course we wish you all the best with it, what is your hope for pancreatic cancer patients? Well, hope is the key word. I think for a long time this is the type of cancer that, in patients and physicians and scientists alike, have made it difficult for people to feel hopeful, so our approach has been, first of all, to understand this tumor as deeply as we can, and to try to create opportunities and circumstances so that we can treat it at least as effectively as we've been able to treat many other solid tumors. As a very first step it would be nice to really know which of the chemotherapies are the best to treat this tumor, because I would argue that it's quite possible over the last 15, 20 years that all of the drugs that have failed in patients may have actually failed because they never got in, which means we weren't really asking the question we thought we were asking when we gave those treatments to patients. Really from the very start, we have an opportunity now for figure out what happens when you do get these various chemotherapies in, and it may be that drugs that we have on the shelf right now, that we've used in many other cancers for many years, might actually provide significant improvements in survival if they're able to get in at high enough concentrations. I'm hopeful about that possibility. I'm also hopeful about other aspects of the understanding of this cancer that has emerged from these kinds of studies. Like some of the central dogmas that we have about cancer biology and about pancreas cancer, as well, have been overturned by these studies, and when you just simply look at the problem from a different perspective, and in some cases flip it on its head, there's a lot about this tumor that becomes understandable, and understanding is the first step to, I hope, its undoing. 4

5 I am hopeful now in a way that I really haven't been for many years, and I think the next few years are going to see dramatic differences in the way we think about and the way we treat this cancer. Dr. Sunil Hingorani helping lead the way in pancreatic cancer research at the Seattle Cancer Care Alliance, thank you so much for being with us, and your devotion to patients. Thank you. It was my pleasure to be here. A very devoted man to helping find more effective treatment for pancreatic cancer. I'm Andrew Schorr. Remember, knowledge can be the best medicine of all. Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. 5