Smarter drugs to save lives

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The development of basic research in cellular and tumour biology has been a prerequisite for the new types of targeted cancer treatments currently being implemented on a wide scale. Maya Stål Söndergaard is one of the patients who have already been treated. "I am extremely grateful", she says.

Bild på Maya Stål Söndergaard.It has been five years since the day Maya Stål Söndergaard first felt a strange lump above her left breast. She had recently began working, following maternity leave with her second daughter. She has just received a new managerial position within her job at Region South Fire and Rescue Service. In other words, she had her hands full at the time, and then the lump suddenly appeared.

"Initially I broke out in a cold sweat, but since I'm quite rational I figured it was nothing to get worked up about and that there was probably a natural explanation" she says.

She found information on the internet suggesting that it may be an inflamed mammary gland, but that you should always get suspicious lumps checked by a doctor.

The doctor at the medical centre found an additional lump in the breast and referred her to the Breast Clinic at Lund University Hospital for a mammogram, ultrasound and biopsy.

"When I laid there during the ultrasound, looking up at the ceiling, I began to feel a little worried for the first time. I don't know if it was something they said or did but I don't think it was, just more the feeling of 'what if it is something after all?'"

A third lump was found during the ultrasound.

Maya Stål Söndergaard is used to dramatic situations. Before she was promoted to manager, she served as Fire Safety Engineer, which meant being in charge of and leading the rescue operations during major fires and traffic accidents.

But when she was summoned to the medical centre the very next day and the doctor told her that she had cancer in all three lumps, she broke down.

"I was in total shock. I hadn't expected that at all. It was really strange. At first I thought that it was still probably not real cancer. 'Is there any chance that it's benign?' I asked, grasping at straws. So of course I started to cry and I was in a state of extreme shock" she says.

A more aggressive form of breast cancer

It turned out that she had a form of breast cancer that was HER2-positive and which had spread to the lymph nodes under her left arm. This form of cancer is more aggressive, the fatality rate is higher and the victims are often younger than with other breast cancer.

The positive news was that there was a brand new drug that had proved to be very effective against HER2-positive breast cancer, the oncologist, or cancer doctor, at Lund University Hospital told her.

He could not see any metastases, but could not rule out the possibility that there were microscopic amounts distributed in the body. He therefore wanted to start treatment without surgically removing the tumours in the breast, in order to see how the cancer cells responded to the treatment.

Maya Stål Söndergaard first received three cytostatic treatments that were three weeks apart. This was followed by a combination of the new drug trastuzumab (Herceptin) and another cytotoxic drug for the same length of time.

"Admittedly, it was tough to have the tumours remain for the 18 weeks I received chemotherapy. But at the same time, it was psychologically important to me to be able to feel the lumps get smaller" says Maya Stål Söndergaard.

Her cancer responded very well to the treatment.

In normal cells, there is a balance between the signals for growth and the signals for deceleration of growth. That balance is disrupted in cancer cells.

Bild på Arne Östman"A common feature of all tumours is that they exhibit changes in the genes that encode proteins that dictate growth control. It can either be mutations that activate growth-stimulating genes or mutations that inactivate growth-inhibiting genes" says Arne Östman, Professor of Molecular Oncology at the Department of Oncology-Pathology, Karolinska Institutet.

Proteins that stimulate growth in the cells are known as growth factors and it is common that the genes for these growth factors or their receptors have mutated with the cancer and that they are excessively produced.

HER2, or "Human Epidermal Growth Factor Receptor 2", is a receptor on the cell's surface that is involved in the cell's signalling concerning growth and cell division. With HER2-positive cancer, there are too many of these receptors, which means that the signals for cell growth in the cells are too strong and the tumour therefore grows uninhibited.

Herceptin is an example of the new targeted cancer drugs, whose effects are specifically targeting a receptor which has been identified thanks to new research in cellular and tumour biology.

The cornerstones of the cancer treatment remain the older methods: surgery, chemotherapy or radiation (see fact box at the bottom). However, these have several limitations, both in terms of effectiveness and severe side effects. The dream for all cancer researchers is therefore to find something that can replace the older treatments. They have not got there yet, but the new targeted cancer drugs constitute a further strengthening of the cell-destroying effect.

New targeted cancer drug

In the past decade, there have been more than a dozen new target specific cancer drugs that either target the actual growth factor or its receptors on the cancer cell. And more are on the way. Research has shown that there are more than fifty versions of receptors through which growth factors can signal. This means more opportunities for developing new drugs and there is a large number of new preparations in the corporate pipeline.

"Yes, I would imagine that a series of new drugs that target growth factors, their receptors or signal proteins will appear in the next five years. We cannot guarantee that any of them will be very much better than what we have today, but they will be equivalent and can be used for other patient groups" says Arne Östman.

However, the wide variety of growth factors and receptors that enable the many new drugs also complicate the treatment, especially in metastatic cancer where several different cancer cell types have had time to develop in the tumour.

Put simply, a developed cancerous tumour is described as a collection of cells, where 80 per cent of the cancer cells have a specific mutation. The other 20 per cent have instead other mutations. When the treatment targets the predominant cell type, the tumour first shrinks because the treatment is effective against the majority of cells. But when they die, the other cells still remain. And these cells do not respond to the treatment. In a way, cancer has become resistant to the treatment.

"We see a rapid effect on the tumour which stops growing for a while, three months up to one year, but then it returns. In the case of the specifically targeted treatments, such resistance is a reality, especially for disseminated cancer. This means that the hope that you would be able to cure a disseminated disease with a single targeted treatment is small. What we now hope to do is use combination treatments or sequential therapy, where we first use one drug and then another" says Arne Östman.

Even though Maya Stål Söndergaard's cancer had spread into the lymph nodes under her arm, it still does not count as a disseminated cancer, her doctor explains. She was lucky to discover the tumours before they had spread any further.

After 18 weeks of drug treatment, she underwent an operation. Her left breast and the lymph nodes under her left arm were removed. Following the operation, the doctor explained that the cancer was gone and that she was healthy. All subsequent treatment was aimed at preventing a the cancer from returning.

She stayed on Herceptin for the next year, and two months after the operation she underwent five weeks of radiation therapy involving daily doses, Monday through Friday.

After some time, she was given the opportunity to participate in a study presented concerning one of the upcoming drugs. It was a substance called neratinib which, much like Herceptin, targets HER2 receptors but also several other receptors for growth factors such as HER4 and EGFR, or "Epidermal Growth Factor Receptor".

Maya Stål Söndergaard had read about the known side effects of the substance, but she figured that if the treatment could help her, she was prepared to put up with a lot. And it turned out to that she had to put up with a lot indeed. The treatment caused disorders of the gastrointestinal tract resulting in diarrhea.

"It took two days from when I took the first pills. Then it came, and lasted off and on for the whole year. I sometimes ask myself; How did I survive? But I had made my decision. Partly for my own sake, in the case it was a great drug, but partly also for others. It is important to help research new things" she says.

Exploit hypoxia in the fight against cancer

As research techniques and modern genetics have evolved, it has become possible at the basic research level to better identify what is actually happening in both the cancer cell and its surroundings. This has, among other things, resulted in the idea that it would be possible to combat cancer with hypoxia.

Cancer tumours grow rapidly, so much so that they do not have time to create new blood vessels that supply the cancer cells with oxygen. This leads to an oxygen deficit, or hypoxia, in the tumour. All cells have protection against hypoxia consisting of what is known as hypoxia-inducible transcription factors, HIF, which alter the functioning of the cells so that they can manage with significantly less oxygen than normal.

It was here that Randall S. Johnson, newly appointed Professor of Molecular Biology and Oxygen Physiology at Karolinska Institute, began his research on hypoxia in tumours.

"We thought that the HIF gene might be important for cancer development. And it was! We could see that when we modified the gene in mice, it resulted in reduced tumours" he says.

Researchers have subsequently developed drugs that inhibit the cancer cell's ability to form new blood vessels, called angiogenesis inhibitors, and other researchers are working to develop HIF inhibitors, both with the idea of trying to "strangle" the tumour completely. However, it now seems that many tumours instead become more aggressive and increase their propensity to create metastases if the oxygen deficit becomes too great.

"Therefore, the opposite strategy has been launched instead. The idea is that if we improve the blood vessel network inside the tumour and then treat it with conventional anti-tumour drugs that previously had difficulty in reaching into the tumour due to the lack of blood vessels, the efficiency of the drugs can increase. And in some cases, this has proven to be the case" says Randall S. Johnson.

He admits that a cancer treatment which initially helps the tumour grow is controversial, but he believes that the future lies in exploiting both the tumour cells and the normal cells found in and around them in the best possible way.

"We need to better understand the interaction between tumour cells and normal cells, and use that knowledge to make both new and existing drugs more effective" he says.

Today, there are a few substances in clinical phase I that target hypoxia in cancer tumours, but Randall S. Johnson believes that these should most likely be viewed as test balloons in the constant interplay between basic research and applied clinical research.

"In many cases, clinical research reveals something that basic research must go back to and try to understand better" he says.

There is probably a long way to go before there are drugs on the market that make use of the knowledge on hypoxia in cancer tumours.

Cancer is by far the hottest area within pharmaceutical research in the world right now. According to the U.S. pharmaceutical industry association PhRMA, there are nearly 1,000 new substances being developed in commercial clinical cancer research, which is run by pharmaceutical companies. To this you can add all the research projects being carried out in the world's academic institutions. Many of these substances and ideas will fall through along the way, but some of them will lead to new cancer drugs in the future.

The suicide gene

An intriguing example is the substance APR-246 developed by company Aprea, owned primarily by the research investment company Karolinska Development. It is a substance that restores the function of the p53 gene when this is inactivated by a mutation. The p53 gene is sometimes referred to as the "suicide gene" in popular science and is the most common mutation in cancer cells as far as is currently known. The mutation means that the cancer cells do not die as they should, divide uncontrollably and become resistant to cytostatics or chemotherapy.

An initial study of 22 critically ill patients with advanced blood or prostate cancer has just been published, showing that the substance is safe to give to people and has a predictable effect on the body. In 15 of the patients, the researchers could also evaluate the development of the cancer.

Bild på Sören Lehman."We saw that we can activate p53 in the tumour cells and that this in some cases led to a slowing of cell division and so-called apoptosis, a planned suicide. In two cases, we could also see a retrogression of the tumour disease" says Sören Lehmann, Docent at the Department of Medicine at Karolinska Institutet and Group Leader at the Karolinska University Hospital in Huddinge, who led the study.

The great potential with the substance, however, is to administer it in tandem with traditional cytostatics, as the activation of p53 can overcome the cancer cells' resistance to cytostatics.

"We have already seen in animal experiments that you can achieve very good combination effects from cytostatics and APR-246. What we see are called synergistic effects that can be likened to one plus one equalling three" says Sören Lehmann.

Our research is now proceeding with a phase II study where APR-246 will be administered in combination with cytostatics to patients with p53-mutated ovarian cancer over the next year. If successful, the substance will gradually be available as a drug, but this will take time.

"It will most likely take three to five years" says Sören Lehmann.

Another good example of how a discovery at the basic research level can reach all the way to the patients are PARP inhibitors, as first described by Thomas Helleday, Professor of Chemical Biology at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. Every day, over 10,000 single-strand breaks occur in a normal cell, meaning that one of the two DNA helix strands fractures. In the cell, there are a number of systems to repair such breaks, and typically these are repaired quite rapidly.

Congenital gene defect can cause hereditary breast cancer

Hereditary breast cancer is almost always due to a congenital defect in one of the two genes known as BRCA1 and BRCA2 as they cause type 1 and 2 breast cancer. The genes encode the proteins BRCA1 and 2, who both have a role in the repair of the DNA strand breaks. Since the genes are defective, the proteins are defective, and cannot repair the broken DNA strands that occur. This increases the risk of mutations that can cause cells to develop into cancer cells.

However, in all cells there is a type of "back-up" system called poly (ADP-ribose) polymerase, or PARP, which also has the task of repairing these errors. Thomas Helleday had discovered that, even if the reserve system was disabled, the breast cancer cells that had a faulty BRCA2 gene died, as they had suffered too many unfavourable mutations. Whereas the normal cells that had a functioning BRCA2 gene survived.

In a 2005 article in the scientific journal Nature, he was able to show that PARP inhibition effectively killed BRCA2-defective cancer cells without affecting normal cells.

The article sparked intense activity at universities and pharmaceutical companies around the world, and today there are over 100 clinical studies involving a large number of PARP inhibitors registered on the U.S. website

However, hopes surrounding the new treatment principle have faded somewhat and several pharmaceutical companies have scaled back their research in the area or simply put the projects on ice. The disappointment is evident in Thomas Helleday's voice when he explains why.

"The PARP inhibitors are unfortunately not a cure for cancer. They are certainly very effective at selectively killing hereditary breast cancer and ovarian cancer, but then the cancer develops resistance. The PARP inhibitors allow the patients to live on average one year longer" he says.

That said, another year of life is a long time for anyone who is affected, and even the target specific treatments for growth factor signalling have problems with resistances developing. It does not therefore seem like a legitimate reason for companies to suspend their PARP inhibitor research. Especially as it is hypothesised that women with the BRCA mutation could receive PARP inhibitors prophylactically to prevent the occurrence of hereditary breast cancer, instead of the current procedure involving the surgical removal of the breast.

Patents on the breast cancer genes BRCA1 and BRCA2

The provocative truth about the drug companies' waning interest in the PARP inhibitors is rather that an American company has patented the two breast cancer genes BRCA1 and BRCA2, and charges 3,000 dollars, or slightly more than SEK 20,000, for conducting genetic tests to determine who carries the genes. This has effectively slowed down the utilisation of this knowledge.

In Sweden, the patent issue does not really constitute a direct problem for the patients, as the company no longer maintains the patent here. This means that Swedish labs can perform genetic tests as they wish. However, there is an indirect effect due to the pharmaceutical companies operating in a global market. Furthermore, a treatment in the pharmaceutical companies' main market, the USA, which is associated with a very expensive test, may be hard to make financially viable.

Maya Stål Söndergaard underwent such a genetic test which revealed that her breast cancer was not of the hereditary type with defective BRCA genes. Something which she is grateful for.

"It is nice to know. I have two daughters and I don't want to pass anything on to them. It was also nice for my sisters to know" she says.

Maya Stål Söndergaard's treatment was fairly typical of the modern method of cancer treatment. The base is still the older treatments consisting of cytostatics and radiation, supplemented by one or several of the newer preparations to further enhance the effect. However, today's patients are still forced to endure all the severe side-effects of the old treatments, such as nausea and hair loss.

Finding a replacement for radiation and cytostatics

Thomas Helleday has now let go of the PARP inhibitor issue and has instead focused on new goals.

"In my lab, we work with trying to find treatments to replace radiation and cytostatics. We want to find a cure for cancer" he says.

And maybe they already have. Thomas Helleday says that he and his research team have identified some proteins that are specifically involved in repairing the DNA damage that naturally occurs in cancer cells, but that have no function in normal cells. So far they have achieved good results from animal experiments.

"When we treat these proteins with inhibitors, we see that they only kill cancer cells and not normal cells" says Thomas Helleday.

The function is basically similar to that of the PARP inhibitors, but there are significant differences, he continues.

"PARP are only used in certain cancer cells and most of the cancer cells survive without PARP. The proteins we are looking at now are more central and important for the cancer cells. The idea is for them to achieve a more widespread effect and that the cancer cells will not be able to develop resistance" he says.

There is, as yet, nothing published on the discovery and research is in what is known as the pre-clinical phase, involving animal experiments. There may be many unexpected turns along the way and there is still far to go before it can become an approved drug. However, Thomas Helleday is optimistic.

"My research team and I have complete faith in this method. And in a few years we can begin testing on patients" he says.

Positive goals

Maya Stål Söndergaard. Sitting in her newly renovated home, Maya Steel Söndergaard leafs through a notebook in which she wrote down facts and thoughts during the different cancer treatment phases.

"In order for me to create some positive goals, I wrote down things I wanted to do in the future. Among other things, build an extension onto the house and build a new kitchen. I can tick that one off" she says, looking around the house at the completed renovation.

In another list, she has written down things to do in order to enjoy life and make the most of every day. Sometimes she goes back to the list to remind herself of these thoughts, but it is easy to forget them when the day-to-day life takes over.

"Unfortunately, I don't do it as often as I should" continues Maya Stål Söndergaard.

Her relationship to cancer has also changed since that autumn day five years ago.

"I'm not bitter or angry. I was in the beginning when I felt that it was unfair. Now I can say that this whole story has given me a lot that I would not have been able to get otherwise. I notice it in my job, for example. I don't get wound up over little things. I am not my job in the same way as I was before and I am kinder to myself. It sounds a bit cliché, but my relationship with cancer is still quite positive. Just having got through this gives me strength" she says.

Disadvantages of traditional treatment

Currently, the main methods for combating cancer are the older ones: surgery, chemotherapy and radiation therapy. However, these have several limitations.

Radiation: effectively kills certain cancer cells but also affects the body's healthy cells, with side effects including hair loss and severe nausea.
Surgery: works primarily prior to the cancer spreading and it is difficult to know if all the cancer has been removed. It leaves scars and, in worst case scenarios, body parts may need to be removed.
Chemotherapy: can nowadays be increasingly concentrated on the actual tumour but still results in relatively severe side effects such as fatigue, skin problems and hair loss.

Text: Fredrik Hedlund. Published in the magazine "Medical Science" 2012.

Cancer and OncologyCell and Molecular Biology