by Jeffrey Bruce, MD
Can you imagine the day when a vaccine can excite your body’s immune system to make a brain tumor disappear? How about designer drugs that are specially fashioned for each person’s tumor? What if you could avoid all of the unpleasant side effects of chemotherapy by delivering drugs directly into the tumor where they are needed without first traveling throughout the body? Clever ideas for combating brain tumors once considered fantasy are now becoming reality. With recent advances by clinicians and researchers, the prospect for new and better treatments for brain tumors has never been greater.
Approximately 40,000 brain tumors are diagnosed each year in the United States, with about 15,000 being the most malignant type, known as glioblastoma. Brain tumors are particularly serious because they are often found in younger, healthier people and can profoundly affect everyday function and lifestyle. Nobody knows what causes brain tumors, even though a fair amount of research has been done in this area. It is generally known that radiation can cause brain tumors, but beyond that, other causes are unknown. Other possible causes, such as cell phones, head injury, occupational hazards, and electromagnetic waves, have been investigated but have not clearly been shown to cause brain tumors.
The last two decades have seen the explosion of new insight into understanding tumors at their most fundamental level.
The current standard of care for a newly diagnosed person with glioblastoma is a six-week course of radiation along with a chemotherapy drug called temozolomide. Newer methods allow radiation to be contoured to the tumor to avoid damage to adjacent brain structures. Temozolomide has been found in recent years to be the most effective chemotherapy available for brain tumors and is appealing because it can be taken orally and has few side effects. Although the combination of radiation and temozolomide has improved the long-term outcome for people with brain tumors, better treatments are needed since the tumors invariably grow back. It is clear that, although all brain tumors have some characteristics in common, no two tumors are exactly alike, and even the cells within a tumor have differences. These differences limit the effectiveness of most treatments and are the focus of current research into new brain tumor treatments.
The last two decades have seen the explosion of new insight into understanding tumors at their most fundamental level. This means that sophisticated tools and strategies are available that allow scientists to peer into the genetic machinery that causes a tumor cell to grow and divide. One of the biggest advances has been The Cancer Genome Atlas, which analyzes the molecular and genetic material in a large number of glioblastomas. These studies have provided insight into the molecular biology of tumors, and they have been used to identify specific subgroups and categories of tumors.
The ability to better classify subtypes of tumors has been useful for predicting how individual tumors are likely to behave. New understanding of the molecular pathways that lead to tumor growth is being used to choose possible targets for specific designer molecules that can be assembled specifically to block growth mechanisms in tumor cells. All of this means that someday it will be possible for each person’s brain tumor to be analyzed in such a way that multiple targets for anti-tumor drugs can be individually designed based on features unique to that person’s tumor. Currently, molecular targets include those that cause tumor growth (proliferation), expansion of blood vessels that are needed for tumor growth (angiogenesis), or those that enable the tumor to invade into the brain (migration). Already, the knowledge of brain tumors at a molecular level has led to special tests that can be done to predict which people are likely to have the best response to radiation and temozolomide.
One of the most promising new areas of brain tumor research is the field of immunotherapy.
Additionally, these new findings are being applied to better understand how tumor cells originate, including whether stem cells or progenitor cells are responsible as tumor initiating cells. Further studies may provide knowledge that will allow direct targeting of these cells at an early stage before the growth is out of control.
To complement the development of new drugs, additional studies are being done to improve the way that drugs are given. Most of the drugs available today are given in a pill form or intravenously, which means they have to travel through the entire body before they get to the brain. Their effectiveness is limited because the brain has a special lining, called the blood-brain barrier, that makes it difficult for most drugs to get into the brain. This means that the chemotherapy drugs, which must be given at high doses in an effort to overcome this barrier, have the unfortunate side effect of causing more toxicity and damage to other parts of the body. To make chemotherapy treatments more effective, investigators are looking at ways to overcome the blood-brain barrier and allow the drugs to enter the brain more efficiently.
A relatively new and improved method called convection-enhanced delivery is a simple system by which a drug is pumped through a catheter placed directly into the tumor. The brain acts like a sponge allowing the drug to flow through the catheter and penetrate into the tumor and surrounding brain. This allows very high concentrations of the drug to be given without any of the side effects normally associated with chemotherapy. The good news is that this delivery system can be useful for nearly any type of drug, including new ones being developed.
On a completely different front, one of the most promising new areas of brain tumor research is the field of immunotherapy. Immunotherapy uses the body’s own immune system to fight the tumor. Normally, the immune system is designed to keep away “foreign bodies,” such as viruses and bacteria that cause everything from the common cold to pneumonia. When these infections are encountered, the immune system is stimulated and activated to get rid of the infection. A similar phenomenon happens when a tumor begins to grow. The tumor has features causing it to be recognized as a foreign invader by the immune system, which then excites the immune cells in the body to destroy the tumor. The problem is that the immune response is relatively weak, and generally, the tumors grow faster than the immune system is able to slow them down.
Most of the research done in immunotherapy is designed to find ways to stimulate the immune system further in the presence of a brain tumor. This can take the form of vaccines or antibodies that are specifically designed to attack parts of the tumor surface. Vaccines take advantage of the fact that specific parts of the tumor surface are recognized by the immune system as foreign. The vaccines are designed in ways that enhance this interaction between the foreign components on the surface and the immune system itself. Additionally, certain drugs, such as interferons, which work by improving all aspects of the immune response, are being tested.
Among other new areas of emerging therapies for brain tumors is gene therapy. This involves engineering specific genes that are then delivered back into the tumor by either a virus or other direct mechanisms. Genes can be designed to block tumor cells from dividing or can restore parts of the cell that are designed to cause self-destruction when the tumor cell’s internal machinery goes awry.
Despite these advances, problems can occur when trying to make these new treatments work. Some of the treatments are only partially effective and limited in their ability to work consistently. Much of it has to do with insufficient understanding of what constitutes a tumor cell and what makes it grow. The good news is that the tools for examining these problems are more readily available and useful than ever. In addition, some of the top scientists in the country are examining these problems. Whether it is gene therapy, vaccines, new “targeted” chemotherapy, or some combination of these, it is likely that new advances will be occurring in the next few years.
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Dr. Jeffrey Bruce is the Edgar M. Housepian Professor of Neurological Surgery, vice chairman of Academic Affairs, director of the Bartoli Brain Tumor Research Laboratory, and co-director of the Brain Tumor Center at Columbia University Medical Center in New York, NY.
This article was published in Coping® with Cancer magazine, January/February 2011.