Imatinib (Glivec) - the story of a game changer in discovering new drugs for cancer
Glivec, or its chemical name Imatinib, was first approved for the treatment of chronic myelogenous leukaemia (CML) in 2001. It was extremely successful at treating CML and it was soon tried successfully with other cancers such as GIST (gastrointestinal stromal tumour). It was even described as a “wonder” or “miracle” drug, a phrase very rarely heard in medicine.
Some of the best science tells a fascinating story and although today Glivec has encountered a few problems, the story of its discovery is a powerful example of how deep understanding of cancer can lead to effective new medicines.
“Brutal and ineffective” treatments.
For most of the 20th century anyone who developed the rare blood cancer chronic myelogenous leukaemia (CML) had a very poor prognosis. Standard chemotherapy was unpleasant and ultimately unsuccessful. The first attempts at treatment were poisonous arsenic solutions. Radiotherapy was given to ease the symptoms of an enlarged spleen. Then came the cytotoxic drugs, busulfan and hydroxyurea in the 1950s which dangerously reduced the numbers of white blood cells in the body. Interferon-alpha in the 1980s could often lead to remission and in a handful of cases affected cells disappeared. Unfortunately interferon alpha also has significant side effects.
As the twentieth century drew to a close, something better was urgently needed.
The differences between normal cells and cancer cells are the key to new drugs.
For all cancers, researchers worldwide are working to understand the biology of cancer cells. Cancer cells often have many changes that make them different to normal cells. Finding and understanding these differences can give researchers new ways of making cancer treatments. This is called targeted therapy. This story for CML goes back over sixty years and starts with that iconic piece of equipment, the microscope.
In the 1960s a scientist was studying the cells of people with CML closely under the microscope and noticed something unusual about the chromosomes. Chromosomes are the X-shaped structures that the cell uses to package its genetic material up for transport during cell division. A healthy human will have 46 chromosomes in pairs. In several patients with CML, one of these chromosomes was far shorter than expected, but at the time we didn’t know enough about how genes and chromosomes worked to explain what this meant. However, this shortened chromosome was named after the place where it was discovered and became known as the Philadelphia chromosome and will be very familiar to anyone with, or studying CML.
As science learnt more about genes and chromosomes, the significance of the Philadelphia chromosome was eventually uncovered.
Chimaeras – from Greek mythology to discovering modern “monsters”.
The chimaera of ancient Greek myths was a fire-breathing lion, with a goat’s head on its back and a snake’s head for a tail. The joining of the different animals created something that has features of the originals as well as something new -the fire breathing.
This is a little like what happens with the Philadelphia chromosome in CML. When new cells are required by the body to grow, repair or to fight an infection, the parent cells will effectively double in size, then divide into two. As part of this process it makes a copy of all the genetic material (DNA) and packs it into chromosomes that get shared evenly between the two daughter cells.
Occasionally this process doesn’t work so well. Bits of chromosomes can break off and get swapped with other bits of chromosomes. Sometimes it’s harmless, sometimes it’s disastrous for the cell and the cell dies, but sometimes it creates something new.
In CML the short Philadelphia chromosome turned out to be the result of a swapping event. A piece of chromosome number 9 is swapped with a piece of chromosome 22. The new thing that was created by this swap is called Bcr-Abl (pronounced bee-cee-ar ay-bel). And if we can allow ourselves to continue with the comparison to the Greek chimaera, Bcr-Abl is very much a fire-breathing monster.
What is this thing that has been created, why is it a problem and how can we stop it?
It starts with DNA:
At this point we need to think about genes and what they do. The DNA in our cells contains the genes (instructions) for several thousand different protein molecules. These instructions are written in a simple four-letter code in the long chains of the DNA. If part of one set of instructions is swapped with another, the result will be something new. Just like starting to make one lego model, then someone swaps in the instructions for a different one. You get a mix-up or a chimaera.
What are enzymes?
Most of the proteins that are made according to the instructions in your DNA are enzymes. Enzymes are proteins that are essential for all of the chemical reactions in our bodies. They help chemical reactions to occur by bringing the individual components together, or by making it easier to break other molecules apart. These reactions happen in a specially shaped cavity in the enzyme called the active site. Once the reaction has happened the new substances are released and the enzyme is free to help another reaction of the same type.
If an enzyme is part of an important process such as cell division, it must be tightly controlled so there is not too much or too little growth. To do this, the enzyme may have extra sections that act as controllers or regulators.
Bcr and Abl and the Philadelphia chromosome.
Bcr and Abl are genes for proteins, which are also called Bcr and Abl. These names seem unusual, but they are short versions of much longer names that tell scientists more about what they do or where they come from. It doesn’t help us here to know the full names.
Abl is a very important protein in our cells. It is involved in cell division, cell differentiation (cells becoming specialised to do particular jobs), cell adhesion (where cells connect with each other), and repairing damaged DNA. All of these activities need to be kept under close control – cancer occurs when cells divide uncontrollably. The Abl gene includes the instructions for several control switches that form part of the normal Abl protein. These allow the cell to turn the activity of Abl up and down as needed.
Bcr has several roles in cells, but they are not relevant to this story. It’s what happens when it is fused to Abl that is important here.
When the swap happens to make the Philadelphia chromosome, the genes for Bcr and Abl are spliced together. The cut and join happens inside the Abl gene. Unfortunately some of the control switches for Abl get swapped out, effectively taking away the brakes. The Bcr part also brings with it an extra “on” switch – acting as an accelerator.
Just like a car with no brakes and the accelerator pressed down hard, Bcr-Abl can’t stop. In this case it can’t stop making cells divide. A serious problem indeed.
How can this runaway enzyme be stopped?
Abl and Bcr-Abl enzymes are kinases. These are families of enzymes that switch on other enzymes one after another in a chain that eventually leads to a cell doing something specific, such as dividing, or turning into a white blood cell. All kinase enzymes use a molecule called ATP which has to fit in the active site as part of the reaction.
Many drugs work by sticking or binding in the active site cavity of an enzyme and stopping the normal reactions happening. These drugs are called inhibitors.
A lot of work has gone into finding chemicals that bind to the active site of kinases instead of ATP. The idea being that the drug will get in the way, so ATP can’t get in and the enzyme can’t work. However, any inhibitor that affected all of the kinases in the body would be disastrous as it would essentially shut down all of the cells of the body. This was why scientists were initially wary of making drugs that affected these enzymes.
As we learned more about kinases we discovered that there are enough differences between them that it is possible to make drugs that only affect one or a very few kinases. Many drugs created over the last twenty years do just this.
“Druggable target” is a phrase created by scientists trying to discover new medicines. It is used to describe something biological, usually an enzyme or protein, that has the potential for a drug to bind tightly, affecting its activity, and have a beneficial effect for patients.
Bcr-Abl with its active site that bound ATP, the differences between it and other kinase enzymes and the well understood consequences of its runaway activity was most definitely a druggable target.
Turning science into medicine
When a druggable target has been identified by the scientific community, several pharmaceutical companies, biotech companies and scientists in government or charity funded labs such as the CRUK research centres will start looking for a suitable new drug. Many of these projects will fail as medicines because they can’t find quite the right chemical, it turns out to be poisonous, can’t get into the body or doesn’t work as well as hoped. The scientists involved still learn a lot about the biology they studied or the compounds they made, so the time and money isn’t entirely wasted. These results can be shared with other scientists in scientific papers.
When a project is successful the scientists who created that new drug get to tell their story and in this case it was the company Ciba-Geigy (now Novartis).
What did Ciba Geigy do?
What the scientists did was very typical for drug discovery companies at the time and much of the drug discovery process still works this way today. The decision to start a new drug discovery project can ultimately involve the investment of many millions of pounds with no guarantee of success. Many small scale projects are started to test scientists’ ideas and only when there is enough evidence that a project could succeed in becoming a new medicine will a company invest the resources needed to create a new drug. Glivec emerged from work that was originally done for a different aspect of cancer.
Making new chemicals to test.
Using the knowledge that was available about the types of chemicals, usually called compounds, that might work, they tested many thousands to see how they affected the Bcr-Abl enzyme on its own. Once they had found a few compounds that had an effect, they started to change them little by little, to see whether that made them better or worse at inhibiting or slowing down Bcr-Abl. To help with this they used computer models to help predict whether their changes made the next molecules a better fit.
They also tested them against the other kinase enzymes to make sure that they weren’t affecting them as well. A small number were affected but not enough to stop the project. In fact this is why Glivec works for GIST where it blocks a different kinase enzyme that has become mutated, also causing uncontrolled cell division.
The most promising of these compounds needed a few extra changes to make sure it could easily dissolve in water and be absorbed by the body. This new compound was STI571, which was eventually named Imatinib, its chemical name or Glivec, its trade name. Although it was not named Glivec until later in its development, it will be referred to as Glivec for consistency.
How does it affect cells?
The next step was to test whether Glivec affected the Bcr-Abl enzyme in cells from people with CML. It was also tested in normal cells to see if it had any unwanted effects. Finally Glivec was tested on cells with other cancers to see if it had any effect on them.
Fortunately, no significant unwanted effects were seen and Glivec did affect Bcr-Abl in the environment of real cells. Most importantly, Glivec slowed the growth of CML cells and in some cases, almost all of the CML cells stopped growing. They also found that Glivec stopped the growth of cells from a rare gut tumour called GIST (gastrointestinal stromal tumour) which eventually led to it also becoming a treatment for that cancer . It turned out that the effect on GIST was through Glivec affecting another, similar enzyme.
From cells to animals to humans
A whole body is much, much more complicated than cells growing in a dish. The scientists at Ciba-Geigy had to answer a lot more questions before their drug could be tested in humans.
What happens to Glivec in the body?
When cells grow in a laboratory the amount of drug they are exposed to can be closely controlled, so it is at its most effective concentration. Getting the same effect in the body is not so easy. As with all new medicines, Glivec was studied to understand how it gets into, spreads through and is removed from the body.
The drug has to survive the digestive system and enough of it be absorbed into the blood to be effective. This can be avoided by using an injected form, but this is more unpleasant and inconvenient for patients.
It has to last long enough in the body so that you don’t have to take the drug more than a couple of times a day. Your liver is where most drugs get broken down and it can remove all traces of a drug in a few minutes. It also has to get to the part of the body where it is required. Some parts of the body are difficult to get drugs into. For example, the brain has a protective barrier that stops many drugs from getting in, whilst other tissues like cartilage have no blood vessels, so drugs have to make their way in through the fluid surrounding it.
Sometimes small changes are needed to the drug to make it stable and effective. It was found that Glivec was most effective if it included a salt called a mesylate. Glivec is produced as imatinib mesylate which is the name you would see on a packet of Glivec tablets.
How much? How often?
The dose needed to get the required effect in humans was worked out using animals such as mice so it could be scaled up for humans. Although mice and humans are obviously different species they have been used in drug discovery for many decades and it is well understood how results in mice can be used to make accurate predictions about how much is needed to give humans. This information was used to set the starting doses for the clinical trials on humans.
Is it safe? Are there side effects?
Safety is one of the highest priorities for scientists at all stages of a drug’s development. Scientists are constantly checking that the drug is safe, including at doses far higher than is needed to be effective. Organs and tissues from the mice used are studied for changes that could be caused by the drug. Side effects are often seen, they can sometimes be understood because of the way the drug works, sometimes they are harder to explain. If the drug being studied has so many harmful or unpleasant side effects they outweigh the benefit of taking it, then it will not move into human trials or be licenced as a medicine. How much is acceptable depends on what condition the drug treats and how long it will be taken for.
Does it Work?
Knowing Glivec was safe and present in the body is clearly not enough. It had to be shown to be effective against CML, the cancer caused by the Bcr-Abl enzyme. Mice don’t get CML, so they had to be given something that was as close to the disease as possible. To do this, mouse cells were changed to have the Bcr-Abl enzyme. These cells were injected into special mice that would not reject them. This is called a mouse model of cancer.
The affected mice were given the drug and monitored for the presence of the cancer cells. The scientists found that Glivec reduced the growth of the tumours in a “dose dependent fashion”. This means that as the amount of the drug was increased, it was more effective. No effect was seen on mice that had been given cells modified to have a different type of cancer gene. The loss of tumour cells was almost certainly due to the effect on the Bcr-Abl enzyme.
Some thirty years after the first observations were made of unusual chromosomes in the cells of patients with CML, a drug that targeted the product of that mutation was ready to be tested in humans.
What Happened Next?
Like all new medicines Ciba-Geigy had to apply for permission to test Glivec in humans. In order to do this they had to submit an enormous amount of evidence to show that they were as sure as they could be that Glivec was safe and potentially useful as a medicine along with detailed plans for how they would carry out the trials safely and ethically.
To learn more about the clinical trials for Glivec and how clinical trials are carried out in general please read our article on clinical trials.
Conclusion.
The Glivec story shows how understanding cancer can find features that can be exploited to create new medicines. Glivec revolutionised the treatment of CML and GIST as well as being used to treat other conditions that share the same features. Today there are problems around the development of resistance to Glivec, but this has spurred further research and understanding into how cancers evolve and new medicines to treat it.
However, it is ultimately not about the science, it is about the patients. What was once a devastating disease now has 90% of patients still alive five years after diagnosis. And that is the best story.
