Ralph DeBerardinis, M.D., PhD, Director of Genetic and Metabolic Disease Program at Children’s Medical Center Research Institute at UT Southwestern, talks about a new discovery that could someday stop the spread of cancer.
Interview conducted by Ivanhoe Broadcast News in July 2016.
This project that we’re talking about today is a joint project between UT Southwestern and Children’s Medical Center, is that right?
Dr. DeBerardinis: The Children’s Research Institute or the CRI is a joint venture between the The University of Texas Southwestern Medical Center and Children’s Health, Children’s Medical Center, the Pediatric Hospital. In effect everything that we do here is a joint project. The project is paid for with funds from the lab that partly come from Children’s, partly come from Federal sources and partly from foundations and private donors.
Tell me about your degrees, how many different degrees have you got?
Dr. DeBerardinis: I have an M.D. and a Ph.D. in Cellular Molecular Biology, both from the University of Pennsylvania.
Tell me what we’re doing here, this is a complicated story but it has to do with identifying pathways and how cancer cells move right? Give me the headline of what you guys have found here and what’s significant about it.
Dr. DeBerardinis: Metabolism is like the operating system of all the cells in the body. All the things the cells do, the way they make energy, the way they grow and divide are all regulated in some level by metabolism. These are all the processes in the cell that make energy and consume energy. You can think about it as a big circuit board. Whenever the cell changes its biology, its metabolism changes as well. If you think about a normal cell that becomes a cancer cell, a lot of the biological properties of that cell become reprogrammed in order to allow the cell to be a cancer cell. Some of the biological properties that get reprogrammed are metabolic activities. The metabolism of a cancer cell is different than the metabolism of normal cell. We’re very interested in that idea because it suggests that if some of these metabolic activities have become reprogrammed, some of them might be targetable. In other words you might be able to develop a drug that would inhibit an energy producing pathway specifically in the cancer cell and therefore kill the cancer cell and treat the cancer. That’s the overarching view of what we study in the lab.
Just explain a little bit of like the metabolism, like when we talk about people we think about their energy level somehow being their metabolism, is that correct?
Dr. DeBerardinis: Yes. Let’s say you just ate lunch and you’re digesting the food, what’s going to happen to the basic constituents of the food, the proteins, the sugars the fats etc? They’re going to go to the liver and they’re going to be converted in to energy. That energy is going to be used to drive all the activities of the body. That’s metabolism.
That happens in every cell?
Dr. DeBerardinis: Every cell has its own form of metabolism and metabolism is extremely dynamic and highly responsive to other biological processes, including the process by which a normal cell becomes a cancer cell. Most cells in the body are not actively dividing. When most cells in the body encounter sugar, for example, they burn it up to make energy. One of the things that makes a cancer cell very different is that they use sugar to make building blocks so that they can make a new cell. We ultimately want to understand all of the metabolic processes that allow cancer cells to be malignant. That is, we want to know which metabolic activities allow cells to survive when they should otherwise die, and which allow them to grow when they should stop growing. These are the processes that kill cancer patients.
Dr. DeBerardinis: A single cancer cell in your body would be harmless; it’s when the cells grow and divide at a high rate that problems arise. But even so, most cancer patients don’t die because of the primary tumor. They die when some cells break away from the tumor, go to another part of the body and establish a new tumor there. That’s called metastatic cancer, and that is often lethal. We’re very interested in the metabolic activities that allow a cell to become metastatic. We’re interested in understanding all of the metabolic challenges that cancer cells face during the journey towards establishing a metastatic tumor. The very first step in the process is the act of breaking away from the original tumor. That’s what we studied in this project.
What did you find, I know it’s an ongoing process but did you come up with a conclusion that helps you?
Dr. DeBerardinis: This was very a focused study. We wanted to know in the situation where a cancer cell loses its attachment to a Petri dish, what metabolic challenges does it face and how does it deal with them? We found a several processes that were interesting and possibly helpful in understanding the challenge of forming a metastatic tumor. The most important one relates to the fact that when cancer cells lose attachment they undergo a form of stress called oxidative stress. Molecules called reactive oxygen species accumulate very rapidly and are toxic to the cell, preventing it from growing. When reactive oxygen species get too far out of control, the cell will just die. We realized that many of the cells after losing attachment were able to survive and actually grow and divide and make new cells. What we did was to discover the pathway that allows cells to deal with these reactive oxygen species.
You’re finding the pathways and so the most basic question is this going to lead to better treatment of cancer?
Dr. DeBerardinis: Every treatment in cancer is intended to be directed against a particular target. What’s the oncogene that we can inhibit with a new drug? What is the part of the machinery that allows a cell to proliferate that we can target with a new drug? We want to develop drugs against metabolic pathways. You first have to know which pathways are being used. Now we know what pathway is used when cells lose attachment. One of the things that was a little bit surprising was that despite the fact that when cancer cells lose their attachment and they get a burst of reactive oxygen species, the species most directly related to growth suppression were confined to a specific part of the cell called the mitochondria. The cell is a little bit like an apartment complex. You can think of the reactive oxygen species as being a fire in the complex. The fire could occur in any one of the rooms in the complex. We realized that when cells lost attachment, the most important part of the fire was burning in the mitochondria, the part of the cell that produces energy The other part of the story is how the cells put out the fire. The way you douse the flames of reactive oxygen species is to use another molecule called NADPH. The basic puzzle for us was that the fire was happening in the mitochondria but most of the NADPH was in a different part of the cell called the cytoplasm. The pathway that we discovered in this paper links those two processes. Basically it’s a way to get the NADPH produced in the cytoplasm to the site of the fire in the mitochondria.
When people think of cancer they think of a lot of times the organ associated with the cancer, lung, breast, other cancers, just as ordinary citizens are we missing something about cancer? In other words are all those cancers different kinds of cancer or they all start as similar, are cancer cells all kind of similar and they just grow and attach in different parts of the body?
Dr. DeBerardinis: This is a very good question. I think the more we learn about cancer, the more we realize that there are no consistent rules across all cancers. The mutations that occur in a cell to allow a cancer to form have some similarity from tissue to tissue, but there are other mutations that only occur in a specific type of cancer. In as much as these mutations reprogram metabolism, it’s not only the mutation that matters, but precisely where in the body that mutation occurs That determines the precise manner in which the circuit board is rewired. One of the exciting things about this new pathway is that it seems to occur regardless of the tissue of origin, or regardless of where the tumor cell arose and regardless of which mutations are present in the tumor. When we initially observed the pathway, we went back to many different types of cancer cells, from the colon, from the breast, from the lung containing different combinations of mutations and we found a very consistent activation of this pathway as soon as all these cells lost attachment. That was exciting. The other thing that was exciting was that non-cancerous cells apparently can’t up-regulate this pathway. Most cells in the body are normal cells, and we think that they cannot activate this specific pathway that allows cells to deal with reactive oxygen species.
One of the things it seems to be pointing to while there are different types of cancer maybe a common area is the pathways?
Dr. DeBerardinis: Yes.
Like the way the cancer moves from one place to another and starts to re-colonize because you said that that’s what kills most people?
Dr. DeBerardinis: That’s true. Our hope is that this pathway is going to be relevant to many different types of cancer. Of course that needs to be tested is accurate animal models of cancer. But there’s precedent for this kind of idea. If you go back and look at the metabolic activities that allow a cell to grow and divide rapidly those metabolic activities are largely conserved from tumor to tumor. Evidence for this comes from the fact that patients with many different types of cancer can be diagnosed by an imaging technique called a PET scan. This type of imaging allows you to tell which parts of the body rapidly take up sugar and use it for metabolism. The reason this test is effective is that the ability to take up sugar is a fairly consistent feature of aggressive tumors.
On a day to day the research that goes in to it the cancer cells that are in the dishes are they identified as a specific type of cancer or identified as certain types of cells? You talked about different types of cancer so I guess it might change right?
Dr. DeBerardinis: We don’t think of cancer as one disease, we think of it as many, many, many different diseases. All of these different factors – the organ where the tumor arose and the specific genetics of the tumor – they all influence the biology of the cell to some extent. When we work with cancer cells in the lab, we try to be very specific about these factors. We want to know what mutations are present, what the tissue of origin was and even when those cells were in a tumor in a patient and exactly what they look like under the microscope. These all give us clues about the actual identify of the tumor cell.
Where do the cells come from, do they come from patients?
Dr. DeBerardinis: Every single cancer cell line we work with in the lab comes from a patient who had cancer.
Those cancer cells are they harvested from living patients or sometimes from cadavers?
Dr. DeBerardinis: Essentially always from living patients.
To you what’s exciting in this particular study, what to you is exciting about it?
Dr. DeBerardinis: The most exciting thing by far is that this could be a new way to curtail metastasis in cancer patients. We’re studying that now in mice and if the results are promising, we’ll develop drugs that inhibit this pathway and advance to clinical trials.
That could be huge right?
Dr. DeBerardinis: We have no good way to suppress metastasis. Metastasis is what kills most cancer patients. This is tremendously exciting to me.
Give us some reason to be really hopeful about this research in terms of because it’s attacking metastasis.
Dr. DeBerardinis: Well, we’ve been treating tumors with chemotherapy for a very long time, and yet chemotherapy is not effective enough in eliminating the possibility of metastasis. We’ve known this for a long time. That’s always suggested to us that the biology of the metastatic cells must be fundamentally different in some way. Maybe because they have different mutations, maybe because some other aspect of the biology has been reprogrammed in a way that now allows them to escape from their primary site. What’s so exciting about this finding to me is that it suggests that even when you get down to the very, very basic level of the metabolic network, that circuit board that regulates the way cells make their energy, the way the cells deal with stress, the way they grow and divide, is completely different as soon as that cell escapes from the primary tumor. This gives us tremendous opportunities to further understand that biology and to develop ways to specifically kill those cells that are the most problematic.
What you have already come up with is going to encourage a lot of new research right?
Dr. DeBerardinis: At the very minimum what we’ve learned is that we need to really pay attention to the metabolic changes that happen during that critical transition. This should enable more research in our own lab and I hope will stimulate research from other good investigators as well.
Ultimately it could lead to some new drugs right?
Dr. DeBerardinis: That’s the hope. Either by targeting the metabolic pathway that we discovered or by targeting other metabolic pathways that allow the cell to deal with the stresses associated with being in the circulation. I do think that new drugs will be eventually developed out of this new knowledge.
If those new drugs can prevent metastasis what would that mean for cancer, fighting cancer?
Dr. DeBerardinis: If you look at the survival of most forms of cancer, aggressive forms of cancer that kill patients quickly versus less aggressive forms of cancer where patients can live with a tumor for a long period of time, the differentiating feature is really whether the cancer metastasizes. Once the cancer has metastasized, the overall outlook for the patient is usually dismal. Developing drugs that can inhibit that process would be completely transformative in the lives of cancer patients.
I know researchers like yourself you don’t jump to that blue sky easily do you. I mean it’s kind of against your nature.
Dr. DeBerardinis: Correct.
Well on purpose because you have to prove these things out.
Dr. DeBerardinis: Anybody who has worked in cancer biology for a period of years gets humbled by how complex the biological system is. How difficult the disease is, how complex every patient’s tumor is. So you’re right, we don’t jump to conclusions after an initial set of observations. But I think we’re all encouraged by the fact that every time there is a breakthrough in the understanding of disease biology, it opens up the possibility of targeting processes we never would have thought of targeting before, simply because we understand the biology that much better.
I used think about knowledge and what we know is what we don’t know, and then there’s what we don’t know that we don’t know.
Dr. DeBerardinis: That’s right.
This is part of where you’re getting in to some of that right, you’ve discovered a new pathway that maybe we didn’t even know was there right?
Dr. DeBerardinis: That’s exactly right. There was no reason to suspect this pathway was active. We knew something about reactive oxygen species and we knew something about NADPH. But the particular linking of these two pathways was a complete surprise to us. In fact it took us a couple of years to convince ourselves that what we were seeing was actually correct. There’s a lot that we don’t even know, and that’s partly because we haven’t known how to look. Now we know how to look and now we know what to look for.
I mean this is cutting edge stuff; it’s got to be pretty exciting. Even though your work moves at a snail’s pace.
Dr. DeBerardinis: The kinds of things that we can do now as opposed to five years ago – it’s a whole new ballgame. The types of machines that we used to analyze metabolism are getting more sensitive. They analyze more chemical compounds and they work faster. Now we can perform some of these experiments not in tissue culture but directly in cancer patients and analyze metabolic pathways in an actual patient’s lung tumor. This is something that ten years ago we never would have dreamed of.
END OF INTERVIEW
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