Researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center have recently described a new method for obliterating brain cancer cells by using a surprising combination of drugs.
When the Cancer Center team combined lovastatin, a therapeutic agent commonly used to lower cholesterol levels, with cyclopamine, they noticed an impressive reduction in the number of medulloblastoma cells in a tissue culture.
Together, the two treatments were able to eliminate 63 percent of medulloblastoma cells, compared with between 15 and 20 percent of cancer cells when acting separately.
Medulloblastoma is a solid tumor that grows in the back of the brain between the brainstem and cerebellum. It is the most common brain tumor found in pre-adolescent children, especially those between the ages of four and eight.
Current therapies for medulloblastoma are highly toxic and only minimally effective in treating the cancer. For children less than three years old, the prognosis is usually very poor.
Cyclopamine was first recognized in the 1950s as a powerful teratogen, a toxin that causes fetal and birth defects by causing severe damage to chromosomes in developing tissues. The name "cyclopamine" refers to the sheep born with one eye on a pasture contaminated with the toxin in the late 1950s.
Recently, cyclopamine has been recognized as an effective anti-cancer agent after it was observed to actively block the necessary cell proliferation pathways in various cancers.
The Hopkins researchers believe that the cyclopamine-lovastatin treatment was effective due to its disruption of the cell growth cycle. Cancer is primarily characterized by unchecked cell division and growth.
Specifically, cyclopamine is thought to block the "hedgehog" pathway, a cellular pathway known to direct excessive cell reproduction. By blocking this pathway, cyclopamine weakens cancerous cells, allowing them to be targeted by lovastatin.
Although lovastatin is known to effectively reduce blood cholesterol levels by stimulating cholesterol uptake into the liver, there is also evidence that it is able to protect proteins that encourage cancer cells to undergo programmed cell death, known as apoptosis.
The therapeutic value of statins in treating melanoma, a deadly skin cancer, is also being studied.
The Hopkins team found a link between the genes related to the cell growth pathway in the medulloblastoma cells and other known cancerous cell signals. One such signal is Bcl-2, which is associated with a type of lymphoma. Bcl-2 is overproduced by cancerous cells in order to prevent cell death.
As scientists explored the link between Bcl-2 production and the hedgehog cycle, it became apparent that cyclopamine blocked both processes, causing tumor cells to eventually die.
Although the combination of cyclopamine and lovastatin has not been tested in animal models or in a clinical setting, the Cancer Center team is optimistic that the complementary actions of these drugs will successfully kill tumor cells in young patients.
The research team was led by Charles Eberhart, M.D., Ph.D., an associate professor of pathology, ophthalmology and oncology.
The research was funded by the National Institute of Neurological Disorders and Stroke and will be published in the January issue of the American Journal of Pathology.
Explainer: cancer and sonic hedgehog
Development of an embryo depends on a precisely orchestrated series of steps. Each tissue must develop in a particular way, at a particular time and place. Every cell line needs to divide and mature until there are just enough cells of that type, and then cell division needs to slow down to sustain healthy tissue. Cancers occur when this last step fails.
One of the chief conductors of this process is the hedgehog pathway, named for the spiky appearance of fruit flies that lack the hedgehog protein. Vertebrates have three closely related hedgehog proteins called sonic hedgehog, desert hedgehog and Indian hedgehog. The three operate in a complex choreography of time and place to control almost all aspects of vertebrate embryonic development.
Hedgehog serves as an all-purpose activator of cell division pathways, pushing the progenitor cells in which it is expressed to continue dividing and maturing. It operates by activating a variety of downstream genes that control the cell cycle and specific traits, such as the development of hair follicles in mammals or of wings in flies, depending on where and when it is expressed.
Because it can be secreted to neighboring cells, it also controls patterns in the development of tissues, such as the appearance of two symmetric sides of a body. These patterns can be quite complex: sonic hedgehog is responsible almost single-handedly for directing the folding of the neural tube, which becomes the brain and spinal cord in vertebrates.
When these proteins are aberrantly expressed after they are needed, cell lines grow out of control. At least one cancer, medulloblastoma, has been linked conclusively to alterations in the hedgehog signalling pathway. In these patients, sonic hedgehog continues to be active in the brainstem for the first several years of life, causing extensive proliferation of native stem cells that are the progenitors of mature neurons in that area.
