Racing against the ebb
David Thomas. Image courtesy of Broad Communications
Despite what he and his colleagues are accomplishing, David Thomas is impatient. As an associate researcher at the Broad Institute, Thomas has made progress in developing a model system for testing the toxicity of cancer drugs before they reach humans and is finding ways to study a critical syndrome associated with cancer. But as a doctor who cares for patients, Thomas is restless.
“No matter how much success you have, no matter how much progress you make, you’re always impatient,” he said. Thinking about his patients in the palliative care service at the Dana-Farber Cancer Institute, Thomas said, “On a pretty frequent basis, the progress that we need to make and the potential impact that we can have are very clear. It’s not a theoretical issue at all.”
One of the urgent needs that Thomas sees is the ability to manage cachexia, or the wasting syndrome associated with many cancers. Cancer patients with wasting syndrome lose weight and their muscles wither; despite doctors’ best efforts, they cannot gain their body mass back. Using an intravenous drip, a doctor can try to directly supply a full day’s worth of calories and nutrients – protein, fat, and all of the required components – that a healthy person would need to gain weight, but a patient with cachexia will continue to melt away. Approximately one-quarter of cancer patients die from cachexia.
Searching for cachexia’s cause
Cachexia can leave a person so frail that doctors are forced to stop cancer treatment. “It’s very clear from the patients that I take care of on a regular basis that wasting syndrome continues to go on, despite therapies, and this can actually be the therapy-limiting process for patients,” Thomas said. “There’s a real driving need to understand this better and devise therapies that can be truly effective and thereby continue to keep the window open so that patients can get other disease-controlling therapies as well.”
Despite doctors' best efforts, cancer patients with
cachexia begin to waste away. Image courtesy of
Currently, researchers in the Cancer Program at the Broad are working on a model system to shed light on the cause of cachexia. The researchers want to be able to examine different tumors to see what genetic characteristics are general across different cachexia-causing tumor types and what mutations may be unique to certain kinds of cancer. They are developing a way to graft cachexia-causing tumor samples onto mice.
“We’ve had some success in creating models that a lot of people thought we would never be able to do,” Thomas said. “When we launched the cachexia project, the default response we were getting was that this is not going to work.”
The interplay between tumor and host could hold critical information about the causes of cachexia. The researchers are beginning to apply many of the core Broad technologies to the problem. Working with the Broad Institute’s Proteomics Platform to catalog proteins and the Broad’s Metabolite Profiling Initiative to catalog small molecules, they will be able to determine what the tumor produces and what the host produces in response.
Thomas describes the technological tools available at the Broad as one of the things that make it thrilling for him to be here. “This is an enormous project and we’re just on the front-end phase of it, but I think it’s a very clear example of the kind of thinking that allows you to say, ‘We’ve got the tools, let’s apply them to a critical and fiendishly complex medical problem in a tractable way.’”
Thomas joined the Broad less than three years ago after hearing Todd Golub, director of the Cancer Program speak at Yale. “I was hungry to be in a place that cultivated careful multi-disciplinary thinking and scientific approaches into large-scale problem solving,” said Thomas. “The other reason I came to the Broad is that I really felt that there’s this closeness of bringing cutting-edge genomic technologies to patients and the bedside.”
Improving the process of cancer drug discovery
Human liver cells. Image courtesy of
In addition to his research on cachexia, Thomas is involved in another Cancer Program project. As companies develop a new drug, they must find ways to test the drug’s effectiveness and its side effects. Cancer drugs are intended to kill tumor cells, but they can also harm healthy cells and, potentially, the patient. Novel compounds are scrutinized, but sometimes these compounds’ toxic effects escape detection until they reach clinical trials and are given to human subjects.
In addition to endangering clinical trial participants, this means that companies have invested an enormous amount of money into a failing drug. Researchers may therefore restrict their research to less financially risky compounds, meaning that potential areas of drug discovery are neglected.
“Our goal is to improve this process and expand back out the areas the drug companies would be willing to invest in,” said Thomas. “It’s been a hard topic to crack open, but I think novel thinking and the novel capacities, technologies, and scientific approaches of the Broad (make us) uniquely positioned to take on a project like this and make some headway.”
Thomas and his colleagues want to be able to detect a drug’s toxic effects long before it reaches a human subject by perfecting a model system that uses a life-like tissue sample and precise genetic tools. For help with this, they turned to Sangeeta Bhatia’s lab at MIT. The Bhatia lab had developed a method for culturing human liver cells in the lab in a way that preserved the cells’ functional abilities. Learning how to culture these cells was a critical step in the project’s development. “We were very fortunate to be in this hub of biomedical innovation and we were able to partner with a team across the street at MIT who had been spending their careers developing a physiologically relevant, in vitro model system,” said Thomas.
The first organ that interacts with whatever humans ingest -- including drugs – is the liver. Enzymes in the liver breakdown medications, but some compounds can disrupt the finely tuned genetic machinery that turns on and off these enzymes. Typically, drug manufacturers look at a handful of these enzymes; Thomas and his colleagues want to look at every drug-metabolizing enzyme expressed in the liver. The researchers’ list of enzymes is approaching one hundred.
Using technology available at the Broad, the researchers can look at hundreds of genes to determine what genes certain compounds change. They are working to develop a detectable “signature” – a pattern of gene changes unique to toxic drugs.
The research group involved in this project is modest in size. At a recent presentation, a senior pharmaceutical executive asked Thomas how many people have been working on this project and for how long, because the scale of the early results were already significantly beyond what the industry was doing in the field. “I was shy to say that it’s really just a couple of us who have been at this for a couple of years,” said Thomas. “But that’s within the context of the Broad, the context of having MIT and Harvard and enormous intellectual resources, enormous technological resources, and the enormous spirit of collaboration that makes this kind of rapid discovery work possible.”
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