For rare cancers, it is important for scientists to go directly to patients, patient groups, and private foundations for research funding.
—Brian P. Rubin, MD, PhD
Epithelioid hemangioendothelioma is a rare and devastating vascular sarcoma that affects between 100 and 200 people, mostly young adults, each year in the United States. The cancer may arise as a solitary lesion but more commonly presents with metastatic involvement, usually in the liver and lungs. When confined to soft tissue, mortality from epithelioid hemangioendothelioma is between 13% and 18% but increases dramatically to 40% and 65% when it is found in the lungs and livers, respectively. Although localized epithelioid hemangioendothelioma can be surgically resected, currently there is no effective therapy for systemic disease. And because the cancer is so rare, public funding for research is scarce, making the development of targeted therapies difficult.
However, in 2011, Brian P. Rubin, MD, PhD, and his colleagues reported that a gene fusion was found in over 90% of the epithelioid hemangioendothelioma tumors they examined.1 This characterization is changing the understanding of the molecular pathways in epithelioid hemangioendothelioma and is leading to potential therapies for this cancer.
The ASCO Post talked with Dr. Rubin, Professor and Vice-Chair of Pathology; Director, Soft Tissue Pathology; and Director, Bone and Soft Tissue Pathology Fellowship Program at Robert J. Tomsich Pathology & Laboratory Medicine Institute and Department of Medicine Genetics at the Cleveland Clinic and Lerner Research Institute, about how characterizing the gene fusion in epithelioid hemangioendothelioma is changing patient care; the prospect of more effective therapies for patients with this tumor type; and why research in this rare cancer is difficult to pursue.
Genetic Translocation Specific to the Disease
How is your characterization of the epithelioid hemangioendothelioma gene fusion changing patient care?
In epithelioid hemangioendothelioma, a genetic translocation involving chromosomes 1 and 3 results in the fusion of a gene known as WWTR1 (or TAZ) to a gene known as CAMTA1 in almost all epithelioid hemangioendothelioma tumors, and that told me that all cases of epithelioid hemangioendothelioma are oncogene “addicted” to this gene fusion. We developed a fluorescence in situ hybridization (FISH)–based bioassay for the diagnosis of epithelioid hemangioendothelioma and found the gene fusion in 90% to 95% of the tumor tissues we examined—and not in other tumors—so we know that this translocation is absolutely specific to this disease.
The immediate result of developing a FISH-based assay for WWTR1-CAMTA1 fusion is it is a wonderful diagnostic test and allows pathologists to confirm a diagnosis of epithelioid hemangioendothelioma, which can be confused with carcinoma and other epithelioid vascular neoplasms.
The second result of our finding is it has allowed us to create cell-based biologic models of epithelioid hemangioendothelioma, which we can use to devise therapeutic strategies to treat these cancers, which are essentially untreatable.
One of the reasons so little research is being done in epithelioid hemangioendothelioma is because these cell lines do not exist and cell lines are very difficult to develop, especially in these rare cancers, where you might only have one or two chances a year to obtain a fresh tumor for culture. Discovering the gene fusion gave us a tool to move forward with manufacturing an epithelioid hemangioendothelioma mouse cell line by expressing the WWTR1-CAMTA1 gene fusion in the mouse cell line. So even though the cell line isn’t an epithelioid hemangioendothelioma biologic model, it is closer than anything we have had before to study epithelioid hemangioendothelioma.
MEK Inhibitor Under Study
As a result of the epithelioid hemangioendothelioma cell line you developed, are you testing new therapies for this type of tumor?
Yes. We have been studying a MEK inhibitor, trametinib (Mekinist), which is having great efficacy in our cell-based model. The drug is already approved by the U.S. Food and Drug Administration for melanoma, so we are also using it off-label on a couple of patients. It is a tough drug to take, with severe rash being one of the side effects, but one patient has been on the drug for 6 months and is showing a great response.
With a lot of rare cancers, it is tough to do clinical trials, so a lot of drugs are used off-label in an experimental fashion, because there is no therapy for these patients.
Unclear Natural History
Is epithelioid hemangioendothelioma largely a fatal disease?
It is an interesting disease. With this cancer, essentially half of patients will present with widespread metastasis, including literally hundreds of tumor nodules, but some of these patients have stable disease. They can live for decades with a disease that looks like it should kill them. In fact, many patients are told, “You are going to die in 6 months.”
I think this disease is different from other cancers in that some patients can have widespread metastasis but not die because even though there is widespread metastasis, in some of these patients it is not an aggressive cancer. And that’s because the first genetic event that caused the cancer to develop is essentially a very prometastatic gene. It is the genetic changes that happen later in epithelioid hemangioendothelioma that cause it to become aggressive.
We don’t know the natural history of the disease completely, so although some patients survive for a really long time, other patients will progress rapidly and die within months.
And currently, you cannot tell which patients will maintain stable disease and which ones will develop aggressive epithelioid hemangioendothelioma?
That’s right, and it is a major research question for me right now.
Effective Therapies ‘Around the Corner’
How hopeful are you that there will be new effective therapies for epithelioid hemangioendothelioma?
I think we are going to have new therapies for epithelioid hemangioendothelioma, and they will be very effective. This cancer is addicted to the WWTR1-CAMTA1 fusion protein, which is a transcription factor. There is no doubt in my mind that this mutation is the cancer target, so we can target that protein either directly or indirectly, for example, by hitting it with a MEK inhibitor, because we believe that most of the activities of the transcription factor run through the MAPK pathway. But ideally, we want to develop a therapy that attacks the transcription factor directly, and one of the problems with that is researchers haven’t developed techniques to do that yet.
If we can figure out a way to target either the WWTR1-CAMTA1 protein or something highly related to that translocation, we may not be able to cure these patients, but we will be able to control their disease, even in aggressive cases.
I think what we could soon achieve with epithelioid hemangioendothelioma is disease stabilization in patients who have very rapidly developing disease, and cures for the cancer are going to be around the corner.
Research Funding Challenges
With your discovery of the translocation, will funding for this rare cancer be easier to obtain?
The National Institutes of Health (NIH) said it would probably fund my research if I could produce epithelioid hemangioendothelioma cell-line models, but as I explained earlier, growing and making cancer cell lines in these rare cancers when you do not have fresh tumor for culture are not trivial.
The bottom line is that if the NIH is going to make having a biologic cell-line model that is relevant to the cancer you are studying a prerequisite for funding, rare cancers are never going to be funded at high levels, and that is the current state with epithelioid hemangioendothelioma. What I have found is that patients and their families are willing to support this work, because they realize it is not being funded on a national level.
Grassroots fundraising has become very important to my laboratory, and we have raised $150,000 from patients in the past year, which is on the level of funding from an NIH Research Project Grant Program (RO1). So for rare cancers, it is important for scientists to go directly to patients, patient groups, and private foundations for research funding. I link to epithelioid hemangioendothelioma patients on their Facebook page, and many e-mail me with questions about their disease, and I am happy to help them.
Despite the difficulties of research funding, I like the personal aspect of working on a rare cancer, where I know so many of the patients directly. They are invested in what I am doing, and I am invested in helping them improve and prolong their lives. ■
Disclosure: Dr. Rubin reported no potential conflicts of interest.
1. Tanas MR, Sboner A, Oliveira AM, et al: Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med 3:98ra82, 2011.
Two years ago, my son was diagnosed with the rare vascular sarcoma epithelioid hemangioendothelioma, on which there is incredibly little reseach and knowledge (see here for more on this rare cancer). PubMed revealed a “characteristic” description: unpredictable behavior, no correlation with...