We begin life as a bundle of embryonic stem cells, which divide and differentiate until you have all the various cell types required to make the many tissues and organs of the human body. In adulthood some stem cells remain to maintain the body's diverse cell types during growth, injury and aging. These adult stem cells are less adaptable than the embryonic stem cells which can form any tissue type, adult stem cells exist in multiple sets each specialised for maintaining a particular tissue types. Tissues that have been identified to contain stem cells include bone marrow, blood, brain, muscle, skin and liver. Most other tissues are also likely to contain stem cells, but their number is tiny in comparison to the normal cell population and this makes their identification difficult.
In recent years it has become evident that cancers also have tiny populations of stem cells that produce the main body of the cancer. During cancer treatment, the chemotherapy drugs and radiation therapy are often highly successful in reducing the size of the tumor, and often the cancer seems to be totally cured. However, several months or years later, the cancer often returns. This could only happen if a population of cancer cells survived the therapy, that population is likely to be very small, small enough not to be seen by a surgeon or a radiographer, it could even be a single cell. These cells are thought to be the cancer stem cells, indeed it has been shown that the cancer stem cells are highly resistant to radiation death, and are often resistant to chemotherapy too.
It would seem to make sense that cancer originates from adult stem cells that have mutated to form cancer stem cells. Adult stem cells are constantly copying their DNA and dividing to produce a specialist cell and a replacement stem cell to maintain the stem cell population. They divide like this constantly throughout your whole life to maintain your body. Each time the DNA is replicated it is vulnerable to copying errors, and over a lifetime may acquire mutations in tumor suppressor genes, inactivating the genes that control cell growth.
If current chemotherapy drugs are not effective against the cancer stem cells, it is because the majority of cancer research to date has been performed using cancer cells which are more than likely the product of the stem cells, but not the stem cells themselves. This means the drugs have been developed to be effective against the body of the tumor, but may not be targeting the cancer stem cells that drive the growth. While destroying the main body of a tumor is still useful in alleviating the pain and problems of having large masses interfering with the organs, the cancer stem cells will also need to be targeted to achieve a true cure.
Much work is currently underway at research institutions around the globe to better identify these cancer stem cells, their genetics and molecular mechanisms. For example this week the pharmaceutical giant Eli Lilly began a collaboration between its Singaporean Centre for Drug Discovery and Singapore's National Neuroscience Institute and Institute for Clinical Sciences. This collaboration has the aim of utilising newly isolated brain tumor stem cells to discover new drugs that will be effective in targeting the stem cells that cause brain tumors.
Meanwhile in Cincinnati, researchers at the Cincinnati Children's Hospital Medical Centre have recently been exploring the involvement of cancer stem cells in neuroblastoma, a cancer of the nervous system. They are also experimenting with a potential virus therapy. This virus is a specially modified herpes virus that could target neuroblastoma stem cells and kill them by infection.
Efforts in recent decades have given us hundreds of chemotherapy drugs of varying effectiveness. But until now we have been measuring their success against the general tumor mass and not on the cancer stem cells. With greater understanding of the biology of cancer stem cells we will be able to target them specifically and ensure the whole tumor is treated. This should improve the survival of cancer patients and reduce the rates of relapse following therapy.
Showing posts with label targetted therapy. Show all posts
Showing posts with label targetted therapy. Show all posts
Tuesday, 17 February 2009
Saturday, 17 January 2009
Targeting Therapies
Getting your drug therapy to the tissue that you want to treat is easy, the body's circulatory system is perfect for that. The problem occurs when the drug gets into other tissues and causes side effects, a long list of which can be found on the information sheet supplied with any drug.
There are a multitude of different ways of specifically targeting certain tissues or cells, and many new ways being developed with the use of new nanotechnology. One such method is being developed at the City University of New York. Here the drug is attached to a mesh of fatty acids, making it inactive. This mesh will disperse around the whole body like any other drug, but could be designed so that the drug can be detached from the mesh by an enzyme that is only present in the tissue being targeted. In this way the drug is only released in its active form at the desired location, thus limiting the chances of the drug getting into other tissues and causing side effects. This is in very early development and has yet to be proven outside of bench-top experiments, there is undoubtedly still a lot of work to be done to make this method work, but it shows us the kind of thinking going on in this area at the moment.
Here's some background to a different problem. DNA encodes the 'blueprints' for all the proteins your cells need to do their business, it is like the master copy. When the cell needs to make a protein it uses a slightly different chemical called RNA to make a copy of the gene, the cell then uses that copy to construct the protein. Many copies are made and transmit the message of how to construct the protein to the cellular machinery. When a cell is making a protein that it isn't supposed to, it can often cause disease. In the lab it is possible to block the RNA message by designing small segments of interfering RNA that stick to the RNA message. As the cellular machinery works its way along the message, making the protein as it goes, it reaches this interfering RNA segment and can't read the message anymore because it is blocked out and so the protein is never completed. Inject this interfering RNA into the body however, and you'll find it is destroyed pretty quickly in the blood before it ever reaches where it supposed to.
Calando Pharmaceuticals in California are testing in humans a kind of Trojan-horse system where the interfering RNA is packaged inside a nanoparticle studded with a molecule called transferrin. They chose this molecule because cancer cells are abnormally rich in receptors for that molecule, and when they detect it on the particle they will take the whole particle inside the cell. The acidity inside the cell is different to the blood, and this causes the particle to burst, releasing the interfering RNA into the cell where it can do its job. This technique is very promising as it can relatively easily be modified to target any receptors and deliver interfering RNA to all sorts of cells, not just cancer cells, and could potentially be adapted to deliver regular drugs.
A third approach is to make the cells produce the drug themselves. Viruses exist by infecting cells and making them produce all the proteins it needs, the virus just brings along the appropriate genes and the cell does all the work. Viruses are also very specific about the cells they infect, which is half the work already done for us. They are already being used selectively infect cancer cells, thereby killing them. Companies such as Oncolytics, Genelux and others are carrying out trials of this method. Viruses or artificial virus-like particles can be designed to deliver a gene for a specific enzyme that makes an active drug out of an inactive 'pro-drug' that is injected normally. This means the infected cell becomes a kind of drug factory at the precise location the drug is required, minimising the exposure of the rest of the body to that drug.
In ways such as these the treatments of the future will have a much reduced range of side effects, while at the same time being more effective and improving the quality of life of people suffering from chronic diseases.
There are a multitude of different ways of specifically targeting certain tissues or cells, and many new ways being developed with the use of new nanotechnology. One such method is being developed at the City University of New York. Here the drug is attached to a mesh of fatty acids, making it inactive. This mesh will disperse around the whole body like any other drug, but could be designed so that the drug can be detached from the mesh by an enzyme that is only present in the tissue being targeted. In this way the drug is only released in its active form at the desired location, thus limiting the chances of the drug getting into other tissues and causing side effects. This is in very early development and has yet to be proven outside of bench-top experiments, there is undoubtedly still a lot of work to be done to make this method work, but it shows us the kind of thinking going on in this area at the moment.
Here's some background to a different problem. DNA encodes the 'blueprints' for all the proteins your cells need to do their business, it is like the master copy. When the cell needs to make a protein it uses a slightly different chemical called RNA to make a copy of the gene, the cell then uses that copy to construct the protein. Many copies are made and transmit the message of how to construct the protein to the cellular machinery. When a cell is making a protein that it isn't supposed to, it can often cause disease. In the lab it is possible to block the RNA message by designing small segments of interfering RNA that stick to the RNA message. As the cellular machinery works its way along the message, making the protein as it goes, it reaches this interfering RNA segment and can't read the message anymore because it is blocked out and so the protein is never completed. Inject this interfering RNA into the body however, and you'll find it is destroyed pretty quickly in the blood before it ever reaches where it supposed to.
Calando Pharmaceuticals in California are testing in humans a kind of Trojan-horse system where the interfering RNA is packaged inside a nanoparticle studded with a molecule called transferrin. They chose this molecule because cancer cells are abnormally rich in receptors for that molecule, and when they detect it on the particle they will take the whole particle inside the cell. The acidity inside the cell is different to the blood, and this causes the particle to burst, releasing the interfering RNA into the cell where it can do its job. This technique is very promising as it can relatively easily be modified to target any receptors and deliver interfering RNA to all sorts of cells, not just cancer cells, and could potentially be adapted to deliver regular drugs.
A third approach is to make the cells produce the drug themselves. Viruses exist by infecting cells and making them produce all the proteins it needs, the virus just brings along the appropriate genes and the cell does all the work. Viruses are also very specific about the cells they infect, which is half the work already done for us. They are already being used selectively infect cancer cells, thereby killing them. Companies such as Oncolytics, Genelux and others are carrying out trials of this method. Viruses or artificial virus-like particles can be designed to deliver a gene for a specific enzyme that makes an active drug out of an inactive 'pro-drug' that is injected normally. This means the infected cell becomes a kind of drug factory at the precise location the drug is required, minimising the exposure of the rest of the body to that drug.
In ways such as these the treatments of the future will have a much reduced range of side effects, while at the same time being more effective and improving the quality of life of people suffering from chronic diseases.
Friday, 9 January 2009
A Little Help from Man's Best Friend
My last post suggested that some new drugs don't make it to market because the existing trials process doesn't provide critical information that can be used to optimise the trial design and reveal the true potential of the drugs being tested.
A change in the existing trial process would have serious legal and ethical issues to contend with, and so is unlikely to occur. It can however be supplemented in such a way that streamlines the process, more accurately determines the effect of a cancer drug and can reduce the time to market. That solution is dogs. These are not your typical animal experiments, such as the rat or mouse models of cancer, in which the animal often lacks a fully functional immune system and the cancer itself is a cross-species 'xenograft' implant. Its fairly easy to see how these models do not accurately represent the type of cancer that occurs naturally in the body, and that's where the dogs come in.
In the USA up to 6 million pet dogs are diagnosed with cancer every year. Canine cancer is surprisingly similar to human cancer. Dogs get the same types of cancers as humans, they are genetically similar to humans and crucially, large scale genomic analyses of canine tumors have shown that there are no differences in the genetic mechanisms of the cancer. The other similarities in canines include their size and the fact that they possess fully functioning immune systems. The similarity between dogs and humans is so close that most existing drugs can be used to treat equivalent diseases in both species.
Naturally dog owners are keen to pursue any therapies that may prevent the death of their pet. Fortunately they can, in the USA the National Cancer Institute operates a network of animal hospitals, fully equipped with state of the art imaging technologies to accurately diagnose and monitor canine cancer. Similar work is carried out at the Roslin Institute in Scotland. These centres are used to test new therapies on the plentiful supply of canine patients following Good Clinical Practice guidelines and central reporting of dangerous side effects not too dissimilar to those in place to protect human patients.
The canine trials can start providing detailed information on the mechanisms of the drugs action before even the Phase I trial in humans starts. Information such as genetic profiles for which the drug is ineffective or blood markers that can be used to determine successful responses in advance of significant tumor reduction. These can all be translated to human systems and used to better design the human trials. These types of biomarkers are not often discovered until around Phase II of human trials, and are usually validated during phase III. Having them in place for Phase I is very useful as they can be validated in the early phases and used to optimise the later more expensive and time consuming phases. For example selective enrolment of patients who have the genetic or biochemical profile compatible with the drug would make the trial more decisive, while freeing other patients to pursue other therapies with more likelihood of success for them. Another benefit is instead of waiting years to determine the survival of the patient and therefore whether the drug was effective, biomarkers that provide advanced indicators of survival could provide that information in months, drastically reducing the length of the trial and therefore the costs.
Comparative Oncology such as this has the potential to give us a much more detailed understanding of the drugs we are testing and should help bring more new drugs to market and quicker. Cancer is a complex and diverse disease that will not be overcome by a single therapy alone, we will need to use combinations of therapies specifically targetted to a patients personal disease to attack it from several fronts. Therefore understanding each cancer type and each drug as much as is technically possible will be critical in determining potential drug synergies and creating successful recipes for treatment.
A change in the existing trial process would have serious legal and ethical issues to contend with, and so is unlikely to occur. It can however be supplemented in such a way that streamlines the process, more accurately determines the effect of a cancer drug and can reduce the time to market. That solution is dogs. These are not your typical animal experiments, such as the rat or mouse models of cancer, in which the animal often lacks a fully functional immune system and the cancer itself is a cross-species 'xenograft' implant. Its fairly easy to see how these models do not accurately represent the type of cancer that occurs naturally in the body, and that's where the dogs come in.
In the USA up to 6 million pet dogs are diagnosed with cancer every year. Canine cancer is surprisingly similar to human cancer. Dogs get the same types of cancers as humans, they are genetically similar to humans and crucially, large scale genomic analyses of canine tumors have shown that there are no differences in the genetic mechanisms of the cancer. The other similarities in canines include their size and the fact that they possess fully functioning immune systems. The similarity between dogs and humans is so close that most existing drugs can be used to treat equivalent diseases in both species.
Naturally dog owners are keen to pursue any therapies that may prevent the death of their pet. Fortunately they can, in the USA the National Cancer Institute operates a network of animal hospitals, fully equipped with state of the art imaging technologies to accurately diagnose and monitor canine cancer. Similar work is carried out at the Roslin Institute in Scotland. These centres are used to test new therapies on the plentiful supply of canine patients following Good Clinical Practice guidelines and central reporting of dangerous side effects not too dissimilar to those in place to protect human patients.
The canine trials can start providing detailed information on the mechanisms of the drugs action before even the Phase I trial in humans starts. Information such as genetic profiles for which the drug is ineffective or blood markers that can be used to determine successful responses in advance of significant tumor reduction. These can all be translated to human systems and used to better design the human trials. These types of biomarkers are not often discovered until around Phase II of human trials, and are usually validated during phase III. Having them in place for Phase I is very useful as they can be validated in the early phases and used to optimise the later more expensive and time consuming phases. For example selective enrolment of patients who have the genetic or biochemical profile compatible with the drug would make the trial more decisive, while freeing other patients to pursue other therapies with more likelihood of success for them. Another benefit is instead of waiting years to determine the survival of the patient and therefore whether the drug was effective, biomarkers that provide advanced indicators of survival could provide that information in months, drastically reducing the length of the trial and therefore the costs.
Comparative Oncology such as this has the potential to give us a much more detailed understanding of the drugs we are testing and should help bring more new drugs to market and quicker. Cancer is a complex and diverse disease that will not be overcome by a single therapy alone, we will need to use combinations of therapies specifically targetted to a patients personal disease to attack it from several fronts. Therefore understanding each cancer type and each drug as much as is technically possible will be critical in determining potential drug synergies and creating successful recipes for treatment.
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