A novel and generalizable organotypic slice model to evaluate stem cell potential for targeting pediatric brain tumors
In children, cancers are the deadliest of diseases and second only to accidents as the leading cause of death. Cancers of the brain are the worst. Our current forms of therapy for these diseases can best be described as brutal: brain surgery followed by administration of very high doses of very toxic drugs and exposure to high doses of radiation. The deadliest of the brain cancers are the malignant gliomas. All children with this type of cancer die and in all cases the course of the disease and its treatment are horrific. About two-thirds of children can survive the rest of the types of brain cancers but two-thirds of these survivors go on to have a recurrence of their cancer. Even more heartbreaking is the fact that those that do survive are usually left with lifelong disabilities.
It is clear that a new medical approach to brain cancers is needed.
Importantly, stem cells appear to be able to provide the basis for a new approach. That is, stem cells, because of their seemingly natural ability to seek out diseased tissue, could be used to deliver therapy directly to the cancer, lessening the reliance on the harsh treatment methods that we currently use, and increasing the chance of eliminating the cancer once and for all.
It is obvious that medical research on stem cells for the treatment of brain cancers is an important and necessary endeavor. The problem is that it is likely that, by doing this research in the usual fashion, it is going to take a very long time to come up with new therapies, perhaps decades. The usual fashion includes using animal models to test each therapeutic variation, each possible way of using different stem cells to treat different brain cancers. An additional and very troublesome problem is that once stem cells are introduced into the animal, they become very difficult to track as they blend in with the animal tissue, since they are not an organ and they are very small. So it becomes difficult to say, exactly, where the cells are going and what the cells are doing.
What we suggest in this grant proposal is that there is a new and much more efficient way to do this. By using living slices of rat brain that we can keep alive in the laboratory for many weeks, we can introduce stem cells into to these living “brains in a dish” and then watch the cells’ every move. In this way, we can try many variations on a theme in a relatively short period of time before actually moving into experiments in the whole animal. This allows us to much more quickly identify and abandon techniques that aren’t working and arrive at techniques that do. This also allows us to use far fewer animals for this type of research. Importantly, we believe that this approach to medical research lends itself to applications for a wide variety of other brain diseases and diseases of other organs of the body as well.
The malignant brain cancers comprise the leading cause of cancer death. Three decades of research have afforded little to allow us to change the outcome in these lethal brain cancers. For example, virtually all patients die after being diagnosed a diffuse brainstem glioma. Of the two-thirds of patients who survive at least 5 years after being diagnosed with any brain cancer, more than two-thirds go on to have a recurrence of their disease. Moreover, the treatments that these patients suffer can only be described as brutal and most of those that do survive are left with life-long consequences of the disease and its treatment, including disturbances in mental abilities, movement, and hormonal balance, which prevent them from re-entering the work force or, in the case of children, from ever entering the work force.
Overall estimates of the incidence of brain cancers in the United States show that about 20,000 will be diagnosed annually with about 2500 in California. The costs for the patient and family cannot be overestimated and should be clear, given the statistics above. The economic costs are also grim: repeated use of physician, inpatient, outpatient and laboratory services as well as lost future earnings and occurrence of secondary diseases incur costs of more than 1.5 billion dollars annually in California alone.
It is clear that California patients with brain cancers need a new therapeutic approach.
One promising approach is to use stem cell’s natural ability to seek out diseased cells, such as cancer cells. Since part of our current therapeutic approach involves administering very large amounts of very toxic drugs and radiation, we may be able to use stem cells to deliver these drugs directly, and only, to the cancer, thus sparing the rest of the body and brain of the damaging effects of these drugs. This not only would spare the patient from the ravaging effects of the treatment but also allow much higher effective drug concentrations at the cancer itself, resulting in a much more efficient destruction of the cancer cells.
Unfortunately, there is not, at present, a comprehensive and efficient way of assessing whether or not the stem cell can adequately perform this particular function in the living animal, which types of cancers might be best suited to this approach, when, in the cancer progression, it is best to institute this type of treatment, and whether or not repeated treatments might be appropriate.
The work described in this grant proposal is based on using a novel “brain-in-a-dish” method to answer these very questions. Given the applicant’s extensive training, the participation of established stem cell and clinical collaborators, and the demonstration of competence by way of work that has already been done, it is expected that the work will promote new clinical therapies for the brain cancers and will pave the way for using the techniques described for devising therapies for other brain diseases and injuries as well.