EHE Research

Dr. Brian Rubin

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EHE had been completely understudied until 2011 when world-renowned pathologist and medical researcher Dr. Brian Rubin at the Cleveland Clinic assumed a leadership in EHE research.

Letter from Dr. Rubin to Patients:

Dear EHE Foundation members,

My name is Dr Brian Rubin and you are probably aware that I am leading an international effort into Epithelioid Hemangioendothelioma (EHE) research from the Cleveland Clinic in Ohio. Research into EHE worldwide is at an early stage and little is known about this frequently aggressive and lethal cancer. As many of you know, tumors associated with EHE can arise in the liver, lungs, bones, lymph nodes, skin and soft tissues and often involve multiple sites (i.e. patients present with widespread metastasis). EHE has an indolent (dormant) state and an aggressive state, when tumors grow rapidly, and exhibit destructive behavior. EHE can also quickly change from the indolent state into its aggressive state with little or no warning. In short, EHE is entirely unpredictable.

There are many questions about EHE to which the answers are not known. It is not known what biological and physiological factors predispose a person to EHE, what dictates whether a patient will suffer from the indolent or aggressive state, or what triggers its change from indolent to aggressive. The natural history of the disease is not fully understood, which means it is currently not possible to forecast for patients what they can expect at any stage.

Overall, what is clear is that there is still a huge amount we need to discover and understand about this disease. That is why the research I am undertaking at the Cleveland Clinic into EHE is so important. It is this research that will lead to the answers to these key questions, and will eventually enable us to manage EHE and design and administer treatment regimens that will halt and even reverse the progress of the disease within a patient.

My discovery of the specific gene fusion associated with EHE tumors was a very significant breakthrough that has enabled the development cell-based biological EHE models that have enabled research that was not previously possible. My first paper on the biology of the EHE gene fusion, which used these biological EHE models was just accepted at the prestigious journal Oncogene. This is the first paper to describe the biology of EHE and another landmark in the field. However, I am far from finished.

My immediate ongoing research focus is comprehensive and involves four major areas:

  1. Development of cell and animal-based model systems. I am actively trying to grow EHE cells in culture. If you know of anyone who might be having EHE tissue resected for any reason, please let me know – I can use it to make EHE cell cultures. I also have a genetically engineered EHE mouse model under construction. This is particularly important as it may allow the generation of an inexhaustible supply of EHE cells available to study the biology of EHE and to test therapies, which would in turn have an enormously positive impact on the research programme.
  2. Diagnosis. I am developing molecular tools that take the guesswork out of diagnosing EHE, providing pathologists tools to objectively classify tumors as EHE.
  3. Prognosis. In collaboration with colleagues at Cornell University Medical College, I am studying the genetics of EHE to understand which tumors will progress and which won’t. This is a fundamental question that is key to the management of EHE. I am also working with researchers at the Translational Genomics Research Institute (TGen) to try and detect circulating EHE tumor DNA in the blood of EHE patients in order to determine when tumors are progressing or whether or not patients are responding to therapy.
  4. Treatment. With a lot of rare cancers, it is difficult to do clinical trials, so drugs are used off-label in an experimental fashion, because there is no other recognized therapy for the patients. I mean to change that by picking drug targets based on my mechanistic research and work with oncologists to do clinical trials. My research group is already studying one inhibitor, trametinib (Mekinist), which is having very beneficial effects in our cell-based model. It is a tough drug to take, with severe rash being one of the side effects, but one patient has been using the drug off-­label for six months and is showing a great response. We are hoping to start a clinical trial of trametinib in EHE very soon.

There is no doubt in my mind that the EHE gene fusion is an important therapeutic target. We can target it either directly or indirectly, for example, using an inhibitor, to try and block the genes that are produced by the EHE fusion, such as we are doing with trametinib. We are also devising strategies to screen additional therapeutic targets and to develop therapies which target the EHE fusion directly. Finally, we are also exploring immunological-based therapies, which have the potential to cure EHE. Immunotherapies have recently shown great promise in other tumor-types and we hope to engage this cutting edge area of research.

Our work at the Cleveland Clinic will I hope also encourage, and combine with, EHE research being undertaken in other research establishments around the world. I have undertaken a number of collaborations including with researchers at Cornell University Medical College, MD Anderson Cancer Center, The University of Michigan, Baylor Medical College, the University of Washington, the Mayo Clinic, the French Sarcoma Group, Boston Children’s Hospital, the Broad Institute, and TGen. I am also trying to establish collaborations with colleagues at the Royal Marsden Hospital in London. I am open to and encourage collaboration to increase our expertise and ensure that research is not being unnecessarily duplicated, that results are shared, and to ensure we make the greatest progress possible from every dollar of funding we receive and spend.

I cannot promise that certain results will be delivered, or that results will be achieved at set intervals. Research by definition is uncertain and unpredictable. However, what I can promise is my continued focus and dedication to finding answers to the many questions we all face relating to EHE. At the Cleveland Clinic, I have recently managed to secure a small two-year development grant from the National Cancer Institute to help fund my activities but it will take a lot more work, and funding to defeat EHE. I continue to rely on private donations to progress, and that is why a group such as The EHE Foundation is so important. I know that the EHE Foundation has initiated a significant fund-raising program, for which I am hugely grateful. I will combine the funds raised by the Foundation with grant funding I secure from other sources, and thus hopefully get to the answers and progress we all want quicker.

Please accept my sincere thanks again for your interest and support.


Dr. Brian Rubin