Eric Holland, Director of the Brain Tumor Center (BTC), is both a neurosurgeon and a laboratory investigator. In his laboratory, he studies the molecular changes that occur in glioblastoma, the most common and aggressive type of brain cancer, as well as other brain tumors.
His research is focused on developing mouse models of brain cancer that mimic the behavior of the disease in patients. While working as a postdoctoral fellow at the National Institutes of Health, Dr. Holland participated in the development of a gene transfer technique known as RCAS/TVA, which uses a bird virus to deliver tumor genes into specific cells in mice. This technique is now used extensively to study not only brain tumors, but a range of different types of cancer.
In this interview, Dr. Holland, who joined Memorial Sloan-Kettering in 2000, discusses his career as a physician-scientist.
What was the state of glioblastoma research when you first entered the field?
The standard treatment had not changed for decades. It was surgery, followed by radiation and chemotherapy, and it was not very effective for most patients. But in the 1990s, there began to be a lot of analysis of these tumors to try to identify mutations and to try to categorize the tumors based on these mutations. Still, not a lot was known up until about ten years ago.
What has changed in the past ten years?
A lot has happened. One thing is that we’ve begun to determine which of the mutations we found previously in these tumors can actually cause the disease, and which of them simply characterize it. Much of this work was done in my lab, using mouse models to study the result of different genetic changes.
Another finding, which is the subject of ongoing debate, is the concept that not all the cells in these tumors behave the same way, and that some of them are more like stem cells. Stem-like cells are more resistant to therapy, which would help explain why these tumors are so hard to treat.
Arguably the biggest series of events in the past decade has been the categorization of these tumors by molecular criteria, which allowed us to realize that glioblastoma is not one disease, but actually several diseases. Having information about the gene expression and mutational profiles of these tumors allows us to categorize them into groups that have similar biology.
Do you think the treatment of brain tumors will evolve to the point where patients receive different therapies depending on the genetic profiles of their tumors?
The best historical parallel to this is leukemia. At one point, all leukemias were treated as the same disease. All patients got the same treatment, and no one responded very well. Then researchers realized that there were actually multiple different diseases and that they responded to different therapies. Real success in certain subsets of leukemia has come from being able to give someone the most correct diagnosis.
There are many centers around the country, including the BTC here at Memorial Sloan-Kettering, that are trying to put glioblastoma tumors into functional groups based on specific genetic changes. This would allow us to give patients a more detailed diagnosis and has implications for predicting survival. It also would allow us to find the best clinical trials for them based on which drug they are more likely to respond to. We’re not there yet – no one is – but Memorial Sloan-Kettering certainly has a lot of projects aimed at this effort.
In addition to running a laboratory, you’re also a surgeon. What role does technology play in the operating room?
The technology that we use, both functional magnetic resonance imaging (fMRI) and intraoperative MRI, allows us to be as safe as possible when we are operating, especially in areas of the brain involved in language, movement, or other critical functions. We are able to map out these areas prior to surgery, so that while we’re operating we can look at the MRI scans and we know which areas to stay away from.
But for Memorial Sloan-Kettering, the real issue isn’t even having the technology. Our edge is the expertise with which we use it. To have good surgical outcomes, you need the right people with the right experiences and training, both in the operating room and postoperatively. That’s what makes our team as strong as it is.
What types of brain tumors other than glioblastoma are the focus of laboratory research within the BTC?
There is a large group interested in studying metastatic disease [cancer that starts in other parts of the body and ends up spreading to the brain]. Much of this work is being led by Joan Massagué. The questions that he and others in the BTC are asking is what kinds of genes are expressed in primary tumors that drive the cells to colonize other sites – not just in the brain but other organs as well.
As we learn more about the biology, we may find therapeutic targets so that we can attack those cells. We may also be able to use gene signatures to determine which patients are more likely to develop brain metastases. There’s a fair amount of work going on to understand how these metastatic tumors interact with the brain around them and why they are resistant to standard therapies that are effective against the primary tumor.
How has the establishment of the BTC helped advance brain tumor research?
The BTC administration helped us write proposals for many of the grants we have received. As a result, BTC members are now participants in several large, multicenter collaborative efforts and consortiums. These include the Mouse Models of Human Cancer Consortium, which promotes modeling of tumors in mice and the technology that is required to do that, and the Tumor Microenvironment Network, which focuses not on tumor cells per se but the environment they live in and how that drives and regulates the formation and growth of tumors. Another one is the Physical Sciences–Oncology Consortium, which has increased collaboration between physical science and biology and the outcome of which has been advances that would not have otherwise happened.
The BTC also has brought together leading experts, people from many areas of Memorial Sloan-Kettering who are interested in different aspects of brain tumor research as well as in related areas. Because of the organization of the BTC and its collaborative nature, we’re in a position to capitalize on findings that show up in our own labs or the labs of any of our collaborators. And ideally, looking into the future, we’ll potentially be able to bring them into clinical utility sooner than almost anyone else.