Kenneth Pienta is the Donald S. Coffey Professor of Urology and Oncology at Johns Hopkins University.
Kenneth Pienta: I am what you would call a classic physician scientist. I see patients with advanced prostate cancer one day a week. The rest of the time I spend trying to understand why prostate cancer spreads to the bone and new ways to attack that problem to help people.
Pauline Davies: You’ve just given a talk. What did you say?
Kenneth Pienta: What I said in the talk was that we need to understand cancer in terms of ecology, and ecological science. When cancer is in the body it exists as an ecosystem: It is one of the species that is interacting with often 30 different cell types in the body at any given time. Each of which can be viewed as a different species in that microenvironment in that ecosystem, interacting with the extracellular matrix, and the collagen and all of those other inorganic sides of the matrix. And the way for us to advance the field is to understand that we have to practice network disruption. We have to basically disrupt the ecosystem in multiple ways, not just by attacking the cancer cell but by targeting the other cells that are supporting its growth. I also demonstrated that, everyone is enamored with sequencing right now and we have sequenced hundreds of patients, their tumors compared to their normal DNA. We haven’t cured anybody by doing that, we’ve helped some people live longer but in general if you look at patients with solid tumors we’re only finding what we find an “actionable target,” meaning the driver mutation, the mutation that is pushing the cancer forward in about 15% of patients. And why is that? Well part of that is the heterogeneity around the different metastases in a patient. Gerlinger and colleagues demonstrated it in renal style and we demonstrated it in prostate many years ago that if you look at one site in the body that has some cancer and you look at another site, they are very heterogeneous. The cells once they get there continue to evolve and so what might work as a therapy on one side of metastases, won’t work on another one. Another problem that we have, and I quoted Smithers from 1962 when he said that you can’t understand a traffic jam by studying the inner workings of the internal combustion engine. Sequencing is really that; studying the inner workings of the engine. Its not taking into account everything that happens around that engine, all the different cars on the road, all the different drivers, the different road conditions and weather conditions and that’s the ecology. That’s the ecosystem. And traffic jams are only caused once in a while due to an engine breaking down, its usually something else; and that is exactly what we’re finding in cancer, through sequencing. We generate two terabytes of information on every patient and yet we’re only finding something to treat in 15%. So it really is bringing home the idea that there are multiple other factors that are involved. Then I went on in my talk to talk about cooperation and facilitation in parasitism in the ecosystem of the tumor and demonstrated how, by using a model system we developed, we can show that one cancer cell can parasitize not only other normal cells of the body to grow faster, it can also steal growth factors from other cancer cells and suppress other clones from growing. I also demonstrated another example, where two cancer cells actually help each other grow faster and actually create a more virulent tumor because they’re both there, two clones are there. Then, by understanding what they are feeding to each other we can actually disrupt that. I showed an example of one cancer cell giving another one IL-6, interleukin 6, and how we treat it with an antibody and it actually interfered with both of them growing; one more than the other but it was a clear example that cooperation is happening between cancer cells and we can disrupt that.
Pauline Davies: So lots and lots of interesting things to talk about more. First of all, it does seem to me that sequencing is becoming more common, isn’t it?
Kenneth Pienta: Yes, I believe that within 2 – 3 years, every patient will have their tumor sequenced. And in some cases we will find information that helps us treat them so that they live longer. But its not the only answer; its just a piece of the puzzle. It’s only one line on the network, where you’re disrupting cellular networks. We’re still going to have to disrupt nuclear networks, and local environment networks, and meta-community networks; and so I would not say we should stop sequencing because it is going to be cheaper than a CAT-scan. But we have to understand that it is not going to be the only answer.
Pauline Davies: You were mentioning that there is an ecology going on in a tumor. We understand from ecology in the world outside that if you disrupt something without understanding what’s going on in the system you can cause more problems. Are you not worried about disrupting stuff in a tumor that you’re might cause more cancer, or a more aggressive cancer or some other disease?
Kenneth Pienta: Well I think that we have to be smart about how we disrupt. For example if you use the mosquito analogy: It’s easier to drain the swamp than try to swat a million mosquitos. At the same time when you drain that swamp you can cause all the frogs to die; so we don’t want to do that. But one example that I give is the species of tumor associated macrophages. Macrophages come into the tumor environment because it’s a wound that does not heal. They actually facilitate the growth of the cancer by secreting matrix metalloproteinase enzymes and more vascular endothelial growth factor, and its been well demonstrated that they can be up to 50% of a tumor mass and they’re helping that cancer grow like mad. But in your normal body you don’t have any tumor associated macrophages. So for us to wipe them out very specifically will knock out a facilitative species without causing side effects.
Pauline Davies: The other thing that surprised me from what you said is that in only 15% of people with cancer you can identify the drivers for those cancers
Kenneth Pienta: Well, we are obviously studying this in great detail and it may be that, even with two terabytes of information, we’re not getting enough interrogation of the tumor to find that. Or it could be that cancer accumulates mutations in such a way that not one of them actually sticks out as the driver. So we are studying that hard and trying to understand if we need to increase the depth of our sequencing to pick up these multiple mutations that might be all contributing a little bit.
Pauline Davies: Have you enjoyed your experience working within the PS-OC and working with physicist and other physical scientists?
Kenneth Pienta: Yes, I have. I think its been an amazing experience because they really help in two ways. On the theoretical level, they can really help drive the math and the equations we need to set up models and then we make smart models instead of models that are irrelevant that we can then test in the real world, pre-clinically and clinically. On the applied physics side, the ability for them to help make measurements with fancy machines I didn’t even know existed; cantilevers that you push down on the cell that tell you exactly how much tension the cell has, and this one is more likely to metastasize than that one. That kind of technology actually helps inform us to try and understand cancer better. Then the whole microfluidics technology of trying to understand how to pull out cancer cells from the circulation and from disseminated sites. We can’t do that without the physics and engineering partners, which the PS-OC brings.
Pauline Davies: Is any of this changing your medical practice?
Kenneth Pienta: It is changing medical practice. For example, I have run clinical trials based on trying to interrupt cooperation between cancer cells and macrophages. Those trials were informed by understanding that there is this community. We are writing another protocol right now to treat oligometastases in patients with prostate cancer because we now believe, due to ecologic theory, that disrupting the communication between two sites of metastases by treating early may be very important which is something we never did in prostate cancer. We always waited until you had pain in a boney site before we would treat it. So it’s actually changing my practice actively.
Pauline Davies: Would you have done any of this without the PS-OC?
Kenneth Pienta: No, the PS-OC was really the catalyst for bringing this to fruition.