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Neurobiology of Brain Tumors
- Introduction
- Biology of Brain Tumors
- Nomenclature and Grading of Tumors
- Types of Brain Tumors
- Molecular Biology of Brain Tumors
- Clinical Applications of Biological Research
- Potential Therapeutic Implications
Chapter 1: Introduction
Jeffrey Bruce: Thank you. Good morning to everyone. We're going to talk today about brain tumors, and I'm going to divide this lecture up by first giving a little bit of a clinical overview of brain tumors, followed by a description of the classification of brain tumors. This is kind of a confusing area mostly because of the nomenclature that's involved. We'll follow that by a discussion of the molecular biology of brain tumors, and then some applications of this knowledge of molecular biology.
As an overview, brain tumors are the second leading cause of cancer among children. This is a disease that tends to affect young people, not so much children in general, but young people for the most part. It is the third leading cause of cancer death among people from 15 to 54 years old, and there are about 17,000 new cases per year. Unfortunately the most common brain tumor, glioblastoma, is a highly malignant tumor. Patients rarely survive beyond one year, and treatment with radiation and surgery still leaves with a limited prognosis.
Where do gliomas come from, what causes gliomas? This is a question that patients ask all the time. Well the fact is nobody really knows what causes them, it's not the type of correlation you can make with lung cancer. We know that lung cancer is caused by smoking. Gliomas, there's no real correlation. There's some very indirect evidence that there may be some viral factor, some unusual viruses such as SV40 and cytomegalovirus. There is a very small increase in gliomas in patients who work in the rubber industry or petrochemical, although these studies haven't really borne out any direct correlation. There is some evidence that radiation can induce these tumors to a certain degree, and there are clearly some very rare types of familial tumors that can occur in families, so are therefore a genetic basis.
Now primary brain tumors, which is what we are really talking about today—as opposed to secondary brain tumors—primary brain tumors are tumors that actually begin in the brain, as opposed to a secondary brain tumor, which is a metastatic tumor that's come from somewhere else, but primary brain tumors include glioblastomas, astrocytomas, and meduloblastomas, which we're going to talk about a little bit.
Clinically, just like most things in life, it's the location. It's like you can have two seemingly identical townhouses, one of them in a small Midwestern town that costs $250,000. If you put that in San Francisco, it's a $1.5 million townhouse. Brain tumors are like that. If you happen to have a brain tumor in the frontal lobe, unilaterally, probably not a big deal, you'd tolerate it pretty well from a symptomatic point of view. But if it's in the speech and motor area in the dominant hemisphere, then you're going to be unable to speak, you may have a hemiparesis—so the location is critical. Many patients present with seizures. Anything that irritates the cortex is capable of causing seizures. And other patients present with generalized increased intracranial pressure. As the tumor grows it expands. The skull is a limited volume, so as the tumor expands you get an increased intracranial pressure, which can lead to headaches, nausea, vomiting, and other general symptoms of increased intracranial pressure.
One of the features of gliomas, and one that makes them difficult to treat, is the fact that they are highly invasive, and they're invasive in low-grade tumors and high-grade tumors. Here you see at autopsy a typical brain tumor. It looks pretty well circumscribed; however, if you were to look microscopically in the white matter here, you would see malignant tumor cells that have spread and invaded into the surrounding brain. And this is similar to the pathway that we see embryonically as the brain is forming: glial cells move and migrate. In fact, this is a picture from one of our laboratory studies done in collaboration with Peter Canoll here. These are brain tumor cells on a living brain slice that have been labeled with a fluorescent dye; and what you can see, this is time-elapsed photography, is that these cells are migrating along this plate here. That's what they do in the brain. And because they migrate, it makes it difficult if you're trying to remove a tumor at surgery, because even if you remove the bulk of the tumor, you're still left with these invading tumor cells. If you look at the results from surgery, you see that there's a modest benefit of surgery. Patients who have a biopsy only live less long than patients that have an aggressive surgery, but the difference is really not that great, and that has to do with the fact that these tumors invade.
Clinically when we're operating on these tumors we use stereotactic localization—this wand is correlating to the MRI scan, so where you place the wand will show up on the scan and allows you to localize where a specific tumor is, and minimize the damage in taking it out. Likewise, the ability to map on the brain—these are electrodes that are placed along this patient's speech and motor area, so during awake surgery you can monitor the function of that part of the brain. The patient is awake, you can ask them questions, and you can determine where the eloquent area of the brain is and avoid that with your surgery.
Chapter 2: Biology of Brain Tumors
I'm going to switch now to a little bit about the biology. There has been a lot of work in the past couple of years beginning to understand what causes these tumors, where they actually come from, from a cellular biology point of view. One of the biggest areas of discovery has been the fact that there are stem cells and progenitor cells in the adult brain. Originally it was thought that once the brain is developed that there was no plasticity, there was no capacity for cells to regenerate. Well that idea has really been found to be false, and the brain actually has progenitor cells and stem cells, even in adults. Now these progenitor cells of course have a greater function during development and during infancy, but if you start with a normal stem cell, the stem cell has the capacity to generate into either a neuronal progenitor or a glial progenitor. The neural progenitor becomes the neurons of the brain, the glial progenitors become the astrocytes, and the oligodendrocytes, which are the supportive elements in the brain. Now if something happens to the progenitor cell, whether it be from radiation, a carcinogen, whatever, that alters the genetic pattern of that glial progenitor; then it has the capability of turning into an astrocytoma, or an oligodendroglioma, some other type of tumor. And malignant degeneration occurs when you have the transformation from your neural stem cell to your glial progenitor cell, you have transformation so that's already tumorigenic; and then you add additional mutations, that turns the cell into a more highly malignant glioblastoma.
Now progenitor cells are found, as I said, in the human brain, mostly located in the subventricular zone, around the ependymal lining of the ventricle. These are the stem cells here. You can see them labeled. And progenitor cells act much in the same way that glioma cells do—they're migratory, they can move, and are therefore invasive; they have a diverse progeny, when these cells divide they can lead to other types of cells; they proliferate, they divide and proliferate. Biologically they have a relationship with blood vessels, they tend to travel along the blood vessel tracks. Likewise they have a relationship with the white matter tracts, they migrate and grow along the white matter tracts of the brain; and they can express a number of immature genotypes—the genes, particularly growth factor-related genes and oncogenes are highly expressed in these types of cells.
Chapter 3: Nomenclature and Grading of Tumors
The nomenclature that's used to describe astrocytomas gets a little confusing. And a lot of this has to do with the fact that some of the terms are very similar. If we look at the group of tumors that we call astrocytoma, this encompasses astrocytes that are tumors. Astrocytes are graded 1 through 4, depending on the degree of malignancy. The grade 1 astrocytomas are called pilocytic astrocytomas, these are relatively well differentiated. The grade 2, which are a little bit more pleomorphic, the grade 2 astrocytomas are simply called astrocytoma. That's where it gets a little bit complicated, because when you say "astrocytoma" that can mean the groups of all astrocytic tumors, or it can refer specifically to a grade 2 astrocytoma. At the same time the term glioma is used to encompass all of these astrocytic and glial-derived tumors. The grade 3 tumors are called anaplastic astrocytoma; and grade 4 astrocytomas are the most common, the most malignant, these are glioblastoma multiform.
The clinical features then correlate with the grade of the tumor. The low grade astrocytomas, grade 2 astrocytomas, these tumors have a relatively low mitotic index, they don't divide as rapidly. They do invade, they do have the capacity to invade into the brain, and they have a high rate of transformation, so that over time these low grade tumors can, in the course of about 5 to 10 years, these low grade astrocytomas can become high grade astrocytomas or glioblastoma. Alternatively, some patients present just with a glioblastoma, they don't go through the various grades before they're diagnosed and treated. The high grade or glioblastoma tumors proliferate rapidly, they're highly invasive, very angiogenic, a lot of vascularity, and one of the hallmarks is the fact that the tumors are highly necrotic. So the grading, how do you determine what grade a tumor is? Right now the standard way to do that is histologically: a biopsy or a piece of tumor taken at surgery is given to the pathologist, and they grade it. Based on the grade, that's the diagnosis that's given, whether it's grade 2, 3, or 4. The criteria that they use generally have to do with four main areas, and that is atypia, how atypical the cells are, how pleomorphic they are; mitosis, how many of the cells are actually dividing; endothelial proliferation, how much vascularity is present in the tumor; and the degree of necrosis, how much of the tumor has actually necrosed and become apoptotic.
When you look histologically then you have in this upper corner here, these are the pilocytic astrocytomas, or so-called grade 1. They can have a fair amount of vascular hyperplasia and cellular pleomorphism, but are generally a low grade tumor. The pleomorphic xanthroastrocytomas in the grade 2, these are just the same types of variance to a grade 2 astrocytoma. These are somewhat cellular, and the cells are a little bit pleomorphic. But then when you get to the grade 3 astrocytomas, you see the cells are much more heterogeneous, much more pleomorphic, and much more abundant. Then if you look in the bottom two frames, this is glioblastoma, you can see how cellular that is compared to the other tumors; and you get this so-called palisading necrosis here, this pattern of palisading; and you also have the vascular hyperplasia, you see these prominent blood vessels throughout the tumor. So this is how the pathologists use these criteria to grade the tumor and to give a clinical diagnosis to the patient.
Angiogenesis bears particular mention because this is a prominent feature of these tumors, and therefore contains a fair amount of clinical significance. At surgery you can see, this is a glioblastoma on the surface of the brain, you can see the abundant vascularity in the surrounding brain, you see some thrombosis of tumor vessels, you see necrosis. This is a highly vascular angiogenic tumor, in fact they're among the most angiogenic tumors found anywhere in the body. They have the highest concentration of endothelial cells, and not surprisingly the degree of angiogenesis will correlate with post-operative survival and the degree of anaplasia. And particularly in children, if you measure the amount of microvascular density, this will correlate with the time to recurrence and the time to progression and death in children with this type of tumor.
Chapter 4: Types of Brain Tumors
Now just to briefly give a background on the different types of tumors. Astrocytomas are low-grade astrocytomas or grade 2 astrocytomas. This is near the more benign, less malignant spectrum of gliomas or astrocytic tumors. These tumors are generally slow growing and infiltrating, found mostly in the fourth decade. Here you can see this tumor and you can see they don't enhance much with contrast. They look fairly well demarcated, but again you have the same degree of invasion. Here's a different tumor, but you can see how this tumor is not very discrete but it's filling the white matter throughout that hemisphere. The clinical presentation will depend on what part of the brain is affected. The treatment for this is surgery, and in some cases radiation. It's sort of a controversial area whether radiation is effective against these low grade tumors. Patients generally survive about four years, and they do better if they're a little bit younger when they're diagnosed.
Anaplastic astrocytomas or grade 3 astrocytomas, these are highly infiltrating tumors, also found at a peak incidence of around the fourth decade. Clinical presentation depends on where it's located, which part of the brain is affected. Treatment for this is surgery and radiation. All of these patients get radiation, and their average survival is about two years.
Glioblastoma multiforme is the most common primary brain tumor. It's highly malignant, highly invasive, highly infiltrating. The tumor cells are capable of disseminating through the subarachnoid space all throughout the cortex. This tumor tends to occur in a little bit older population. And the clinical presentation again depends on the location. You can see how pleomorphic, how heterogeneous these tumors are, and that's part of where the term glioblastoma multiforme comes from—the multiforme refers to the fact that these tumors are so heterogeneous and there are many different types of cells that are contained within the tumor. Unfortunately even with aggressive surgery, radiation, and chemotherapy, the average survival is rarely beyond a year.
Just to clarify again the nomenclature, we talk about glial tumors or gliomas in general, that refers to any tumors that are derived from glial cells, so that can be astrocytes becoming astrocytomas, oligodendrocytes becoming oligodendrogliomas, or ependymal cells becoming ependymomas, and choroids becoming choroid papillomas. So these encompass all of the glial tumors or gliomas. Then the question is where do the different subtypes of tumors, oligodendrogliomas, astrocytomas, come from? Again going by the stem cell theory, they appear to begin from a neural stem cell that has the capability of becoming a neuronal progenitor or a glial progenitor. Again, the neural progenitors become tumors of the neurons or meduloblastoma, while the glial progenitor cells can differentiate into oligodendrogliomas or astrocytomas. Any of the glial types of tumors probably arise from these glial progenitor cells. But because they have multiple abilities to differentiate into different types of cells, that's theoretically where these different cells types come from.
Oligodendrogliomas then are tumors of the oligodendrocytes. These tend to be more slow growing, they're often calcified. Here you can see a patient with a tumor just adjacent to the motor strip. Generally these tumors are a little bit more well differentiated, so you try to remove them with surgery as aggressively as possible. And many times these patients can survive up to ten years or so. The histology is very characteristic, these sort of round cells with a central nuclei, almost looking like an egg yolk type of picture, fried egg.
Ependymomas tend to occur off the ependymal cells. Now the ependymal cells line the ventricles, fourth ventricle, the aqueduct, and so generally they're found in those area[s], mostly in the fourth ventricle. Because they're found within the ventricles they often cause a blockage of the spinal fluid and hydrocephalus. And these patients are also generally treated with surgery.
Meduloblastoma is a tumor arising from the neurons or neuronal cells, most commonly in the vermis of the cerebellum, and around the fourth ventricle. They arise from the neuronal precursors of the primitive ectoderm, more common in males, more common in children. These tumors can spread throughout the spinal fluid down into the spinal cord. They're often treated with surgery and either chemotherapy or radiation, with about a 33% ten-year survival. But also more common in children. So that's sort of the clinical histological background.
Chapter 5: Molecular Biology of Brain Tumors
I want to take the next period to talk about some of the molecular biology. This is the area that has sort of exploded in the last ten years or so, understanding the genes involved in regulation and in these tumors. And it all begins with a normal cell developing a mutation, and as these cells divide they acquire more and more mutations, so that by the time you have a malignant glioblastoma cell, you're seeing the end result of all of these different mutations. What the molecular biologists have tried to do is to try and categorize these different types of molecular biological changes that have occurred. Within glioblastomas and gliomas there's a pattern that begins to emerge, much like there are for other types of cancers. When you look at all types of cancers that are found, some of them have similar molecular biologic changes, but each type of tumor also has its own type of molecular changes that occur.
So the characteristics of primary brain tumors. If you look at what they do biologically, they proliferate without any kind of external signal, they just keep dividing on their own. They don't have any limits to their replication, they avoid apoptosis, and apoptosis is a built-in mechanism for the cell for it to die if something changes in the DNA or genotype. Most times if a normal cell is damaged, the cell just dies by apoptosis. A tumor cell is a normal cell that has become abnormal, but it doesn't die because it's lost that connection to the mechanisms in the cell that are designed to allow it to apoptose if it becomes abnormal. These tumor cells don't respond to external growth suppression, the drugs that are designed to block growth don't work very well. And, as we've pointed out already, these tumors are highly angiogenic and invasive.
If you start to look at some of the changes that are catalogued, again we talk about primary glioblastoma or secondary glioblastoma. Secondary glioblastomas are those tumors that are initially diagnosed as astrocytoma; they recur a few years later as anaplastic astrocytoma, and ultimately recur and are fatal when they become glioblastoma, as opposed to those patients that simply present with a glioblastoma. And some of the changes that occur molecularly in these different courses have been catalogued. The PDGF receptor in p53 are the first precursors to the astrocytoma. The astrocytoma then develops these different molecular changes and become anaplastic, loss of P-TEN, glioblastoma. And we're going to talk a little bit about some of the more important growth related and oncogenes in these types of tumors.
One of the more prominent ones is the PDGF or so-called platelet derived growth factor. This is a growth factor that's often important in connective tissue and glia to get them to grow normally, mostly during normal development and embryogenesis. The PDGF growth factor belongs to the tyrosine kinase family of receptors, and this is important because the tyrosine kinase pathway is an important pathway for growth in gliomas. PDGF is found in both low and high grade tumors. When it's overexpressed it's often associated with the proliferation of gliomas. In fact there is a model system now where Peter Canoll, who is one of the pathologists here, has a PDGF virus which if he injects that into a normal rat brain, the PDGF affects the normal progenitor cells and causes tumors in those animals.
The EGF receptor, the epidermal growth factor receptor, is an important growth-related gene. This also is involved with the tyrosine kinase pathway. This is the receptor for that. It's involved in the control of cell proliferation, through these signal transduction pathways, PI3K pathway; these are all pathways that are important in growth and proliferation, both for normal glial cells, but also in gliomas. It's the most frequently amplified oncogene in glioblastomas. Many of these tumors have hundreds of thousands of copies of this gene being overexpressed. And that overexpression correlates with the proliferation and the reduced response of apoptosis in those tumor cells.
The angiogenic growth factors, it's not surprising that with a tumor that's so angiogenic that there are a number of different growth factors that are found. VEGF, or vascular endothelial growth factor, fibroblastic growth factor, transforming growth factor alpha, epidermal growth factor—these genes are induced by the hypoxia. Tumors in the brain as they grow quickly they lose some of their ability to efficiently transfer oxygen, and the tumor milieu, the microenvironment, becomes hypoxic, and all of these angiogenic growth factors are induced then by the degree of hypoxia that's present.
P16 is a gene that inhibits cyclin-dependent kinases which are involved in cell cycle arrest, or the so-called pathway of controlling apoptosis and cell cycle death. In many gliomas, the p16 gene is mutated or missing, so the cell doesn't have the capacity to apoptose when it senses the abnormal events or the injuries that are in the cell. The cell loses its ability to die very easily.
The tumor suppressor genes then are the genes that are making proteins that protects the body cell from becoming a cancer cell. Again, when a normal cell detects that there have been genetic changes or genetic injuries, the tumor suppressor gene[s] kick in and cause that cell to die. But if the tumor suppressor genes are missing, such as if you get a normal cell with an active p53, normally if there's damage to that DNA, the p53 pathway is stimulated and the cell will simply die. That what's happens normally. But in a glioma the p53, the so-called guardian of the genome, is mutated or missing. Up to 30% of glioblastomas have an abnormal p53. What happens is with a normal cell when it gets damaged if the p53 is inactive because it's either mutated or missing, then instead of the cell dying it switches into a phase where it just continues to grow and proliferate, and these cells become abnormal and they're the basis of your tumor growth with glioblastoma. The p53 and other associated tumor suppressor genes are very critical in trying to hold back the growth of these tumors.
The PTEN or the MMAC1 was actually discovered here at Columbia by Ramón Parsons. This is an important gene in glioblastomas. It's associated with a loss of genetic material on chromosome 10. It's a tumor suppressor gene. It's a phosphatase, meaning it removes phosphates from an enzyme, rather than most other oncogenes, which are kinases, they add phosphates. The loss of PTEN is associated with an altered PI3K pathway, and PI3K is one of the pathways involved in halting cell cycle and cell proliferation. In tumors that have lost PTEN they have higher degrees of angiogenesis, they're more invasive, and they become resistant to chemotherapy and radiation because that pathway, the PI3K pathway, that helps to kill the cell is abnormal; and so when you try to give drugs or radiation to kill the tumor cell it's able to become resistant to that because it's lacking the machinery to lead to its own self-destruction.
So how do these genetic changes, how do these oncogenes and growth-factor genes, affect the ability for these tumor cells to grow? Again, if we look at the low-grade to grade 3 to glioblastoma we see a correlation with the different features of malignancy; they become more prominent in the higher grade tumors, and again we see the acquiring of all of these different changes and growth factor and oncogenes that we just talked about.
When we talk about the so-called primary glioblastoma versus secondary—the primary glioblastoma being a patient that at diagnosis has a glioblastoma as opposed to a secondary glioblastoma which is generally a patient who's first diagnosed with an astrocytoma, comes back years later with a grade 3, and finally a grade 4. We see differences in these types of tumors. The secondary tumors generally, those patients have progressed through the changes, so they've had their tumor for a longer period of time; but we also see biological differences, a different age, different gender predilection, and more important, different changes in the molecular biology of these tumors, so they're clearly a different type of tumor, even though the end result, glioblastoma, histologically and clinically is the same.
Why is it important to understand the molecular biology? Well, getting a handle on these molecular changes has now led to the ability to begin to more accurately classify these tumors, because instead of looking at simply the histology and how the cells look under the microscope, we can begin to correlate these changes with the actual biology. If we have a fingerprint of the molecular biology, we can get a better handle on how aggressive this tumor is going to be, and potentially how likely it is to respond to specific therapies.
Chapter 6: Clinical Applications of Biological Research
In the last few years or so there have been a number of studies that have looked at taking the molecular biology, characterizing it, and correlating it with clinical factors. The first big area where this was done was in patients with oligodendrogliomas, and what they found is that when you look at the molecular changes in a group of patients with oligodendrogliomas, you had two groups of patients: one group that didn't do so well, and another group that lived fairly long. And in this group of patients you found better survival if they have a 1p chromosomal loss and intact CDKN2A, which is a type of gene. If you look at all oligodendrogliomas and classify them based on whether they have these characteristics or not, if they have them, they live longer, if they don't have them, they live less long. This was one of the first examples of where molecular biology and correlation with clinical factors became useful for clinicians.
This led to a more recent finding in the New England Journal [of Medicine] where people looked at a clinical trial with these two drugs, erlotinib [brand name Tarceva] and gefitinib [brand name Iressa], and these are tyrosine kinase inhibitors; and the tyrosine kinase pathway, the EGF receptor which we've talked about here with an EGF receptor switched on, it runs through these tyrosine kinase pathways through the PI3K pathway, associated with PTEN, and all of these molecular changes are responsible for cell proliferation. The EGF receptor when it's overexpressed it stimulates tyrosine kinase, and in glioblastomas there are a lot of mutations to the EGF receptor, particularly the EGFR mutant, which causes the gene to be expressed all the time; and the receptor causes this pathway of proliferation to continue, and it obligates the cell to work along the PI3K pathway, so this pathway becomes dependent through the EGF receptor. Now the PTEN gene is able to inhibit the PI3K pathway, and so when the PTEN gene is missing, the cell becomes resistant to the signals coming from the EGF receptor. The details of this aren't important. What is important is understanding that these catalogued molecular changes can potentially correlate with a response to treatment. What they found in this article was that with these tyrosine kinase inhibitors, there were two groups of patients, one group that responded well, one group that didn't respond at all. They found that the group that responded well were those patients whose tumors had the mutant constitutively active EGF receptor, and also had the PTEN gene present. If those things were missing, the patients didn't have growth along these normal pathways, and so therefore they wouldn't respond to inhibition at that gene locus.
Another correlation of this has been in glioma therapy with temozolomide [brand name Temodar]. Temozolomide is a relatively recently used drug in gliomas that is found to be one of the few drugs that has any effect at all. The effect is still fairly modest. If you look at patients with glioblastoma that are just treated with radiation versus those that are treated with radiation plus temozolomide, you see there's a little bit of a survival advantage. And temozolomide is an alkylating agent, which means it causes alkylation at the level of the DNA, and this causes the DNA to be damaged. Again, if a cell is working normally, that DNA damage causes the cell to apoptose or to die. Temozolomide with radiation increases survival modestly from 14.5 months versus 12 months for patients without temozolomide. But interestingly, when analyzing the patients that do well with this type of tumor, they found that the MGMT, which is a type of gene also known as the 06-methylguanine-DNA methyltransferase, this is a DNA repair enzyme. When this enzyme has a promoter that methylated, the gene is turned off. And so you can imagine that the DNA repair is going to be important when you give an alkylating agent, because the alkylating agent is causing damage to the DNA. If that DNA repair gene isn't there you're going to have a worse response to your treatment. With methylation, meaning the gene is turned off, these patients have a better response to the temozolomide because the gene is turned off and you have less ability to repair the DNA, so the DNA becomes more damaged and the cell will die. You see the patients that have this methylation do much better with temozolomide than the patients that do not have this change.
Again, these details aren't important. What's important to remember is that we can now begin to correlate some of the molecular changes with a clinical response to treatment. And what this can lead to in the future are such things as DNA microarrays, and these DNA microarrays are a very complex, sophisticated method for analyzing large numbers of molecular changes that can occur. You take a tumor out and you process it, you look at the different genes that are expressed, and this gives you a readable pattern. Using sophisticated computer programs, you can categorize different groups of patients, and potentially correlate a group of changes with improved survival or other clinical factors. The way this can be used in the future is taking these group of patients with glioblastoma, all with different types of molecular changes, begin to separate out groups of patients with similar molecular changes, and determine whether one group of patients responds better to one type of therapy and another group may respond better to another type of therapy, if that therapy is based and targeted directly at those molecular changes.
Chapter 7: Potential Therapeutic Implications
What I want to finish up here with is just some potential therapeutic implications of these changes. By being able to catalogue and categorize these different molecular changes, this potentially can lead to some very new and highly directed treatments. Again, this complicated slide begins to look at all the different growth, proliferation, cell cycle pathways that are present in gliomas, and therefore become different targets. Each of these different areas is a potential target for a treatment directed specifically at that. And so the p53 gene, which we talked about, is something that again when it's missing the cell can't repair itself and it goes on to unregulated proliferation. But if you could take this gene, the p53 gene, and somehow put it back into the tumor cells so you restore the ability for the tumor cell to apoptose, you can have an effective treatment. This therapy is actually in clinical trial right now.
The ability to look at these new directed molecular biologics brings up another problem, and that is most of the molecular biologics are protein related or have to do with factors that don't lend themselves very well to drugs that can be given systemically. If you take a drug intravenously or by a pill, very little of it gets effectively into the brain. And so one of the areas that we're working on is a method of delivery where a catheter is simply placed in the brain and these drugs can be directed very precisely, right into the tumor itself. The brain is like a sponge, and as the drug is infused, it spreads throughout the brain itself, so you get very high concentrations, and this is very useful for these molecular biologic compounds which can only be manufactured in very small amounts.
Finally I want to talk about one of the more promising areas of treatment. This is an area that's not very useful clinically right now, but may be able to take advantage of everything we know about the molecular biology, and that is using an immune-based therapy, or immunotherapy, which is nature's evolutionary-derived strategy to eliminate tumors. When the immune system is involved in eliminating tumors it's very appealing because this type of strategy is very sensitive, very specific, it has a memory, and also has an ability to be manipulated so that it can optimize its response to the tumors. The role of the normal immune system—if you look at everybody's peripheral blood slide, if we took a specimen of blood from you and looked at it under a microscope, you would see mostly red blood cells, but you'd also these white blood cells or so-called lymphocytes. These circulate throughout your blood and are designed to look for infections and fight infections, but they're also designed to look for tumors, anything that's viewed as foreign, that's not supposed to be there, such as a bacteria, a foreign body, or a tumor. When these lymphocytes find this, they sort of become supercharged, like the old Pac-Man games—the lymphocytes sense something wrong and they become supercharged and go out and look for the foreign invaders, whether they're infections or tumors, and they seek to destroy them. The basis for this becomes being able for the immune cell to recognize that there's a tumor present. How does it recognize that there's a tumor present? Well, tumor cells all have their own fingerprint, and that fingerprint is a result of all of those mutations and molecular biologic changes that occur during the course of that tumor's development. What the immune system does is it looks at these changes and realizes these changes are abnormal. That's the first clue to the immune system that there is a tumor present that shouldn't be there.
One of the problems is if the immune system works that way, why do tumors still continue to grow? The reason for that is that the immune response that occurs in a patient with a tumor, although it's present it's not a very vigorous response, and partly it has to do with the fact that tumor cells have a lot of different ways that they suppress the immune response. They actively secrete cytokines that block immune responses, they trick the different components of the immune cell response into thinking that there is nothing actually there, and so in glioblastomas in particular, there's a lot of work showing that the microenvironment where the tumor is growing is a very immunosuppressive one.
This still leaves some hope for the future for vaccines. What these vaccines are designed to do is to look at the components of the tumor that are trying to camouflage it to the immune system. The tumor is trying its best to not be seen by the immune system. Vaccines take the proteins or the aspects of the tumor cell that will make it conspicuous to the immune system, and we try to amplify that. That's sort of like the ability to take those hidden aspects of the tumor cell and make them more conspicuous, and that's what the vaccines are designed to do.
In experimental results, here we have an experimental glioma placed under the skin of a rat, and the rat is then given a vaccine made of some of the abnormal proteins within that tumor cell. What happens over time is that the tumor will actually begin to disappear, and if you analyze it you'll find out that the tumor cells have disappeared because a massive inflammatory response has occurred that has been able to eradicate those tumor cells. So this kind of strategy actually works in an experimental setting.
For the future, I think what we're going to see is a correlation of the molecular characteristics of the tumor cell with the clinical behavior, and therefore with therapeutic targets, targets that are specifically derived to these molecular changes; and part of what people will be working on clinically is optimizing these strategies, both to get those drugs, those targets, right to where they need to be in the tumor, and perhaps looking at combination therapies, therapies looking at the multiple changes that occur, and hitting multiple targets in the tumor.
Despite all of this optimism the expectations are realistic. We know that chemotherapy and radiation for these tumors are not particularly effective. But I think with the new approaches based on the molecular biology, they're promising. There are a lot of clinical hurdles to overcome with this, but that's where the state of the field of clinical research is going.
Thank you for your attention.