Richard White, M.D., Ph.D.
I obtained an M.D. and a Ph.D., and am trained in both medical oncology and basic science research. My interest in cancer goes all the way back to medical school, when I was rotating at a small hospital in upstate New York and was completely amazed by what I saw: young people dying from metastatic cancer with essentially nothing real to offer them. By the time I began my oncology fellowship at the Dana Farber Cancer Institute in Boston several years later, I was sure that we must be improving, but I was wrong. On my first day of fellowship training, we were shown a graph of survival from metastatic cancer going back to the 1960s, and it was remarkable how little we had progressed. Patients, on average, were living a few months longer, but when you looked at the overall survival curves several years after diagnosis, we were doing amost next to nothing: most patients with metastasis were dead within 3 years.
After my clinical fellowship, I began to search for postdoctoral research positions, a "prelude" to starting my own research group in the future. And I was very clear about two things: 1) I wanted to study metastasis, and 2) I wanted to study it in a way radically different than what had been done over the past 50 years. It is for those reasons that I chose to do my postdcotoral training in Leonard Zon's lab at Children's Hospital Boston and the Harvard Medical School: he was starting to study cancer using zebrafish, a model very well known for its incredible genetic toolbox, ability to study drugs, and capacity for "seeing" what was happening due to imaging technologies.
The zebrafish, for me, seemed like the perfect way to study the question I was interested in: why does metastatic cancer kill you? Conceptually, there are two ways to go about the problem. First, you can make educated guesses about potential mechanisms, and then test each of those mechanisms to see if they kept the animal alive with their cancer. Second, you could simply study huge numbers of animals, identify the rare ones that are able to live with their cancer, and then figure out why that animal is able to do so. Both approaches are completely practical in the zebrafish, becasue I can study somewhere between 100,000 and 200,000 fish at a time. Statistically, my likelihood of finding a few that are completely tolerant of their tumor is very high, far higher than if I were trying to do this type of study in a mouse.
For all of these reasons, in my own lab at Memorial Sloan Kettering Cancer Center, I am studying how metastasis kills the zebrafish, and why some animals are completely tolerant of their cancer and do not die from it. This is with the expectation that what we find in the fish is broadly applicable to all species that die from cancer.
Metastasis is the process by which cancer cells disseminate from one part of the body to another. When we talk about cancer as a fatal disease, it is really metastasis we are discussing: it is responsible for over 90% of cancer deaths. Decades of investigation have revealed startling details into how cancers form and what molecular changes promote metastasis. Despite this, almost no attention has been paid to the ultimate consequence of cancer, which is how do metastatic cancer cells kill the host? My laboratory uses a small tropical fish called the zebrafish to study this problem. Although at first glance it might seem odd to use a fish to study metastasis, this fish develops cancer and ultimately dies from it. Importantly, the fish is transparent, allowing us to understand how tumors start and ultimately disseminate. Because of its remarkable capacities for genetic manipulation, drug studies and imaging, my laboratory is trying to understand the mechanisms by which cancer cells kill their host organism.
To do this, we will study highly metastatic melanoma cells in our transparent zebrafish. These cells invariably form tumors that lead to the death of the host animal within 4-6 weeks due to mutli-organ dissemination. The goal of this project is to identify zebrafish strains which still develop tumors, but do not die from those tumors. We will then determine the genes that allow the animal to live with their tumor. By essentially studing animals "tolerant" of their tumors, we will uncover the specific mechanisms by which most animals die from cancer.
Because death from metastasis cuts across all species, we hope that what we learn in this fish will allow us to discover methods to allow humans to live with their cancer cells, rather than dying from those cancer cells.
Why is this important?
The vast majority of cancer treatments aim to kill cancer cells. Chemotherapies act to simply kill cancer cells faster than normal cells. More modern "targeted" therapies aim to kill cancer cells due to specific genetic vulnerabilities. In all cases, these approaches are thwarted by resistance to the drugs, likely because we try to kill billions of cells which are incredibly adaptable and aim for their own survival.
A very different way of trying to treat cancer is to "teach" the body to live with the cancer cells. In this paradigm, we would not aim to kill cancer cells; instead we would teach the normal cells of the body how to avoid dying in response to the cancer cells. Although initially this sound unappealing, we all live with cancer cells at some point in our lives - our bodies are constantly generating mutated pre-cancerous cells, but these cells rarely kill us. Our studies in the zebrafish aim to identify specific genes and pathways that allow the animal to live with widely disseminated, metastatic cancer, without negatively affecting survival of the animal. Although we cannot always extrapolate from a fish to a human, we feel that by discovering these basic mechanisms of cancer tolerance, we can rapidly apply this knowledge to human patients with metastatic cancer. The ultimate goal is two-fold: 1) understand the basic mechanisms underlying why the body can sometimes live with cancer, and 2) can we identify drugs that can educate any person to become "tolerant" to their cancer without affecting their survival?
Who will benefit?
This study is aimed squarely at patients with metastatic cancer. Our initial studies will focus upon metastatic melanoma, but we believe that the underlying principles that regulate why organisms die from disseminated cancer will apply to most solid tumors such as pancreatic, breast and colon cancer, for example.
BudgetFeatured funders of this work include: NIH New Innovator, Melanoma Research Alliance, Albina Co., Inc. Consano crowdfunding donations will be used as follows:
Progress On Our Project
Our Consano project centered on the question of “why does cancer kill you”? This is a very difficult question to answer, since cancer can exert a multitude of effects on the body, and induces changes in metabolism, blood flow and brain function. In this sense, cancer is truly a “systemic” problem – it doesn’t only affect the organ in which the tumor is present.
With this systemic concept in mind, we decided to use a cancer model that allows us to study the entire organism at the same time. Since this is impossible to do in humans, we chose to use a transparent fish called the zebrafish to do this study. We have created a special variant zebrafish called casper which allows us to “see-through” the body of the fish to identify how the tumor cells are moving and spreading through the body. Since many of the principles of cancer growth are the same in both animals and humans, what we find in the zebrafish has surprisingly direct relevance to patients with cancer.
Our studies so far have pointed us in a very new direction for the lab. What we realized fairly quickly at the start of the project is that once a cancer cell metastasizes to a new place, it undergoes a dramatic change in its shape and appearance. An example of a cancer spreading is shown in the video below – the tumor cells are labelled with a green fluorescent protein, and you can see how it starts in one place and rapidly moves throughout the rest of the fish: https://youtu.be/kBc26ZH7RrU
This change in appearance is linked to a whole slew of changes in the genes that are expressed in the cancer cell. What we determined is that all of these changes in the cancer cell are dictated by the cells surrounding the cancer cell – it is the new environment that the cell finds itself in that determines what happens to it. These surrounding cells - which are sometimes called stromal cells or microenvironmental cells – are not cancerous themselves, but act to support the cancer cell.
These observations led us to ask what exactly these stromal cells were and what they were doing. One of the most striking observations we’ve made so far is that a high proportion of these supportive stromal cells are made up of adipocytes, or fat cells. These are the cells that all of us have throughout our body and normally act to supply energy to our muscles or brain when we exercise or when we haven’t eaten in a long time. And what we found is that the tumor cells can specifically use these fat cells as their source of energy. They essentially divert the energy from your normal muscles or brain cells, and instead shift that energy into the tumor cells.
We think this explains numerous aspects of why cancer is so deadly. The tumor cells interact with the surrounding normal cells, and “steal” an important energy source for their own growth. This allows the tumor cells not only to succeed in growing, but may also deprive the rest of the body of the energy it needs for daily activities. Over time, the cancer cells win out, and this is no longer compatible with life. It is like a competition between the tumor cells and the rest of the body, and the tumor cells win by taking over their surrounding stromal cells.
One question that we are now addressing is whether we can block this interaction between the tumor cells and the fat cells. We have identified some very specific ways that these two cells interact and have begun to identify chemicals that can interfere with it. This would be a truly exciting avenue for cancer therapy – don’t go after the tumor cell itself, but instead go after the way the tumor cell interacts with its environment. These studies are ongoing but we think is going to be a very promising way to figure out why cancer kills you, and hopefully do something about it.
Through all of this, we have been very lucky to have been funded by Consano’s efforts and all of the donors who helped out. The Consano grant has helped us to secure further funding from other agencies such as the National Institutes of Health, essentially acting as an “amplifier” of our funding efforts. We are very excited with the ways in which this project has moved, and look forward to the next several years to continue towards our goal of stopping cancer in its ability to kill patients.