Spotlight on the Research of Edward R. Smith, MD, Neurosurgeon at Children's Hospital Boston

By Tammy Gilson

The Brigham and Women’s Hospital and Children’s Hospital Boston share a joint neurosurgical training program that creates a unique close association between these world-renown institutions and affiliates Harvard Medical School and the Dana Farber Cancer Institute.  As a result, multidisciplinary teams from across these institutions are able to seamlessly care for patients from infancy through adulthood and easily exchange ideas and share vast clinical and research resources to ensure the very best outcomes for our patients. This relationship is critically important for pediatric patients diagnosed with neurological diseases, as many related problems are present for life, with broad reaching effects. In addition to treating these young patients, Edward Smith, MD, a leading neurosurgeon at Children’s Hospital Boston, leads groundbreaking research into the molecular mechanisms of tumorigenesis and angiogenesis in the central nervous system. Dr. Smith shared his exciting findings at MAD 2009, and recently sat down with the BSF.

BSF:   What led to your interest in pediatric neurosurgery and journey to Children's Hospital Boston?

Dr. Smith: Growing up in Southeastern Massachusetts, my best friend was diagnosed with a brain tumor in his first year of high school.  He underwent a number of operations and treatments – including care at Children's Hospital Boston.  He passed away my freshman year of college, but his example of how to face an illness with courage inspired me.  I decided that I wanted to try to do what I could to help cure children with brain tumors.  It has been a bit of a dream come true for me to arrive at the present time, when I am fortunate to be working at the very hospital I looked to when I was younger, with both a clinical practice and a laboratory effort focused on helping kids overcome these terrible tumors.

BSF:  Many of the brain tumor challenges seen by the faculty at Children’s Hospital Boston are quite different from those seen in adult patients. Can you provide some insight into the challenges associates with treating children with brain tumors - as well as the challenges specific to advancing research necessary to improve brain tumor treatments and quality of life (post-treatment health challenges)?

Dr. Smith: Obviously, one of the greatest issues with treating children with brain tumors is that the patients are children – that is, they are young and may not always have the cognitive skills or maturity to understand or discuss what is happening to them.  This communication gap can make identifying problems and administering treatments more difficult than it might be in adults.  In addition to these developmental and social issues, the biology of many pediatric brain tumors is unique.  For example, there are several tumor types, including medulloblastoma, where early diagnosis and an aggressive surgical removal can substantially improve outcomes.  This means that even small advances in early diagnosis or surgical techniques may provide exponentially improved results as compared to other adult tumors.  This is especially important because many of the adjuvant treatments for brain tumors used in adults – such as radiation and chemotherapy – can have deleterious effects on the developing and growing child that may not be as important in fully grown individuals.  As pediatric neurosurgeons, we have to weigh the immediate benefits of an intervention against the risks of side effects distributed over a much longer life as the child grows up.  These long-term risks include secondary cancers caused by radiation treatments, growth problems, hormone insufficiencies and problems with brain and cognitive development.  However, these are challenges gladly tackled if they mean that we keep children alive and healthy for longer and longer times!

BSF: We know that childhood brain tumors are the second most frequent malignancy of childhood and the most common form of solid tumor - has the outcome for children with primary CNS tumors improved in the last decade? What is the future outlook for this diagnosis?

Dr. Smith: Overall, the outlook for many pediatric brain tumors has markedly improved over the past decade.  New chemotherapeutic regimens, better targeted radiation treatments, improved surgical techniques (including minimally invasive operations and image guidance), remarkable imaging and increased understanding of tumor biology have all helped children with these tumors.  Several success stories, such as germinomas, some medulloblastomas and pituitary lesions have been encouraging.  However, these advances only highlight the immense amount of work that remains to be done.  Anti-angiogenic drugs like Avastin, novel MRI techniques like functional imaging and enhanced surgical tools like endoscopy have only come after years of hard work, research and innovation by dedicated scientists and clinicians.  The challenge is now for clinician-scientists to focus on these tumors.  Fortunately, the benefits of work focused pediatric tumors can have application to many types of tumors, including adults.

BSF:  Can you provide an overview of your research into the role of urinary biomarkers in brain tumor detection and the relevancy of your exciting work for patients?

Dr. Smith: Brain tumors are the most common solid cancer of childhood and currently the leading killer of children after trauma. In adults, despite little change in mortality rates, the number of brain tumors is steadily climbing, with the caseload of surgeries for brain tumors increased by 53% over the past 12 years. One of the most difficult issues in treating brain tumors is a lack of effective methods of screening for novel or recurrent disease.  In short, we need an early detection system for brain tumors. In other organ systems, progress has been made in the detection and follow-up of tumors through use of biomarkers. 

One of the most promising targets for identification of useful brain tumor biomarkers is to look for molecules that are present in many types of tumors.  In particular, we are interested in molecules that help brain tumors to grow new blood vessels (angiogenesis) and to spread into the surrounding brain (extracellular matrix remodeling). Our lab has a well established record of identifying and analyzing these types of molecules, particularly in urine.  The use of urine is appealing due to its ability to be collected cheaply, easily and non-invasively. The use of urinary biomarkers offers a number of advantages particularly relevant to brain tumors.  Current methods of brain tumor diagnosis and follow-up rely on infrequent clinical examinations and expensive radiographic studies (such as magnetic resonance imaging; MRI) that also often require sedation or anesthesia in children.  In contrast, urine collection can be done frequently, without sedation and is relatively inexpensive.  Biomarkers provide a method of tumor diagnosis that relies on metabolic activity; a different – and complementary – approach to the current method of visual evaluation made with imaging studies.  Collection of urine specimens is easy and non-invasive, avoiding the difficulties and risk inherent to lumbar punctures and venipuncture – especially important with children.  Urine collection can be done locally and mailed, saving families travel to tertiary care centers.  We intend to expand this research, which has been successful with many other tumors–redirecting techniques already validated in other organ systems–to now include the study of brain tumors.

In the long term, our goal is to develop a urine test – similar to an over-the-counter pregnancy test – that may help to identify new tumors or detect recurrence.  The advantage of early detection, coupled with a non-invasive test (no needles, no blood, no sedation), would allow frequent, cheaper screening and may complement existing techniques, such as MRI.  This is especially great for kids (who don’t like needles or who need sedation for scans), for folks who don’t live near a major hospital (they could mail in urine samples and avoid long trips) or – potentially – for monitoring response to therapy and predicting outcomes.  Ultimately, the information gathered from these biomarker profiles – a urine test – could help doctors design “tailored therapies” specific for each patient based on their unique tumor fingerprint. 

This work has progressed to the point where it has been published and is poised to begin widespread study at our institution.  Although not a BSF project, this is the kind of work that dovetails with the excellent work already done by BSF investigators, such as complementing enhanced imaging techniques or potentially increasing the application of genetic analysis.  Overall, we are very excited about the progress being made in brain tumor research at Children's Hospital Boston and Brigham and Women’s Hospital, made possible – in large part – by visionary organizations such as the BSF.