New methods in cancer treatment by Hungarian researchers

English2019. szept 14.Anna Szabó

György Markó-Varga, a senior clinical research professor at Lund University in Sweden, was a key protagonist in a recent clinical program held at Semmelweis University in Budapest. The outcome from the trial was that 50 percent of end-stage cancer patients were successfully treated. Together with his research team, György Markó-Varga identified new proteins that can aid in preventing the spread of malignant melanoma.

Few people really understand the importance of proteomics; the analysis of the proteins that are encoded by genes. How did you get involved in this area of cancer research and treatment?

For nearly twenty years, I worked at AstraZeneca; where I became a global leader in proteomics. Proteomics focuses on the qualitative and quantitative characterisation of the protein content in Diseased patient cells and it is here that the link between disease and drugs needs be demonstrated. In 2009, when the FDA approved a breakthrough drug in the United States, I became a professor at Tokyo Medical Hospital in Japan.

In 2010, I began working at Lund University Hospital in Southern Sweden and was tasked with the construction of the Swedish Biobank that has a capacity of 100 million samples. The biobank stores specimens from ten hospitals in the region and cost 11 million euros to establish. From 2011 to 2015, I was also the President of the European Proteomic Association (EuPA) and later became the Secretary General of the Human Proteomic Organisation (HUPO). In 2016, I was awarded a professorship at Yonsei University in South Korea. Today, however, I devote myself entirely to research and hospital work, and I directly interact with cancer patients.

Hungary is participating in an international pilot program that has raised awareness on cancer patients that regress at a very high rate of almost 50 percent. What exactly is this treatment and how can people gain access?

For over half a decade now we have been aiming at understanding the tumour biology processes of malignant melanoma and identifying potential targets for new drugs. Often the disease is only identified in the final stage when there is very few treatment options available. Thus, we have been focusing on therapeutic approaches that are based on a totally different concept.

As an adjuvant to cancer treatment, so-called hyperthermia is now used together with, or after, conventional treatment. The inventor of vitamin C, Albert Szent-Györgyi, was already researching this subject after he was awarded the Nobel Prize. In recent decades, this process has evolved considerably.

New machines and equipment have been developed to use and apply this type of therapy. Particularly in the Far East (including South Korea, Japan, China), Southern Europe (Italy, Spain and Greece), German-speaking countries (Germany, Austria, Switzerland and the Netherlands), and in Canada.

For three years, the Semmelweis University in Budapest has been leading the clinical trial program; and, to date, 140 patients have been treated. A year ago, I joined the program; simply because the treatment is effective in almost 50 percent of cases where previously, all hope had been lost.

These numbers indicate that almost half of the patients responded favourably to therapy. Tumours began to regress and shrink as a result of the treatment, and in many cases completely disappeared. There are now patients that are once again living a full and healthy life.

It is important to realise that the 240 patients that we treated in the program all had end-stage cancer with a maximum life expectancy of 6 months. In addition, traditional treatment had been abandoned by the doctors treating the patients.

This new approach has already been introduced in many countries and is covered by health insurance. In South Africa, for example, the results of some very successful treatments have recently been released and the data exceeded all expectations.

Who can apply for the treatment and what types of cancer should it be used for?

This procedure works primarily on so-called solid (circumscribed) tumours but is also applicable to haematological disorders. In particular, the method is most commonly used to treat pancreatic, lung and breast cancer. Nevertheless, we are currently investigating a cure for brain tumours; traditionally a difficult cancer to treat.

In a pilot program in Hungary, the tumours are treated by radio frequency radiation. Eligible candidates are final stage cancer patients where the tumour has metastasised throughout the body, no other therapy has been successful in eradicating the tumour, and doctors predict a survival of three to six months.

Patients from around the world have come to Semmelweis University for treatment. Here, physicians such as Dr. A. Marcell Szász are responsible for coordinating this complex clinical research module. Dr Szász has gained considerable experience at Lund University, and as such, we are in negotiations with Swedish patients, are also recruited American patients.

How long is this treatment (thermotherapy or hyperthermia) and how painful is it?

The treatment lasts six to eight weeks and usually requires one hour three times a week. It is a painless procedure, and the patients only feel a little bit of warmth. It is important to note too, that treatment for cancer patients is completely free.

When can you say that the treatment is effective?

Firstly, the spread of cancer must be stopped. To achieve this, an understanding of how cancer cells function is essential. The cells of our body are constantly dying and self-renewing. New cells are generated through cell division, however, errors can and do occur in this copy process. There are often defective cells, however, problems only arise if these ‘bad’ cells find a compatible surface to bind to at  some location within the human body.

Perhaps as a consequence of a weakened immune system, a cancer cell will find a fragile point in the body. Here, the cell will begin to uncontrollably divide; thereby leading to damage. The high energy consumption of tumour cells is well known; therefore, the metabolism of aberrant cells is altered compared to normal cells (Warburg effect) and certain proteins are needed for subsequent development. Therefore, thorough clinical and histopathological analyses performed in our laboratory is necessary, and this is independent of treatment.

In simple terms, we measure the types of proteins that are present in tumour tissue, in what quantity these are present, and how changes occur in such proteins as the disease progresses. In essence, we play the role of biological detectives. Such a part is only effective when combined with the unsurpassed  medical background of the scientists and doctors at the Semmelweis University.

Interestingly, the number of cases of malignant diseases is quite high in Hungary. Therefore, in general terms there is an unprecedented level of knowledge and experience in the treatment of cancer within the local healthcare system.

And what is the next step?

Cancer treatment is changing. In the past, we always approached tumours with the intent of full eradication. Consequently, treatment was often quite brutal. The purpose of radiation therapy, chemotherapy or antibody therapy was to completely destroy the cancer cells. These approaches, however, take a huge toll on the human body. Data is now accumulating that indicates that these measures may no longer be necessary.

We now consider that tumours, once under control,  may actually be able to reside in the body long term without any negative effects. Rather than destroying cancer cells, the focus is now shifting towards co-existence. In this way, cancer can be considered as a chronic illness. The ultimate outcome from this scenario is that these stabilised conditions does not result in any symptoms or pain for the patients.

Due to the elimination of severe side effects, is low-dose chemotherapy a possibility?

I come from the pharmaceutical industry, so I know the importance of the dose received by the patient. Too little active ingredient will have no effect, too much will cause toxicological problems. It is essential to find that delicate balance where there are no strong side effects, but the drug is still effective. Practically, personalised treatment is needed; and this applies not only to cancer but to all diseases. Low-dose chemotherapy may be an option in the future, but this needs to be carefully studied before being applied clinically.

What is important is that we accept the notion that tumour cells do not necessarily have to be completely destroyed. Cancer can be modulated as a chronic disease.

It is now understood that chemotherapy not only has a direct anti-tumour cellular effect, but also induces changes in the tumour that can be recognised and attacked by the immune system.

How can you maintain the program? You receive support from the Kamprad Foundation, bearing the name of the founder of Ikea; and from the Barbra Streisand Foundation.

The development was part of an application for a consortium that was sponsored by the National Office for Research, Development and Innovation (NKFIH). ; a hallmark of the Semmelweis University and Oncotherm Kft.

And indeed, the money received from these foundations is being used to analyse plasma samples from patients that are an integral component of the pilot program at Semmelweis University in Budapest, in addition to a sponsorship from The European Cancer Moonshot Center in Lund, Sweden. At present, there is still no hyperthermia treatment in Szeged. Nevertheless,  we are also cooperating on tests for melanoma both there and in Budapest. We have already constructed laboratories; one based on the knowledge gained from the Swedish Biobank where we built a patient-specimen storage infrastructure. This is related to the hyperthermia treatments, and data shows that the results are outstanding and internationally recognised. That is why I brought robotic machines for blood samples and a protein sequencer to the new Semmelweis laboratory. At the same time, introducing expertise on the Southern Sweden Biobanking and Protein expression analysis and Deep Sequencing.

Currently the treatment is free, and the program will last for approximately 11 months. During this period, we will be able to treat about another hundred patients.

In the future, however, we must establish an international foundation to receive further support through donations. There are global organisations and charitable individuals that can be shown the benefits of the program, ideally be impressed and enamoured by the results, and subsequently provide additional financing. I must emphasise that my colleagues and I are not receiving monetary benefits for this work. Our time is voluntarily and is completely based on non-profit. Our rewards are obtained from maintaining sustainability, creating the right environment and professional evidence, and most importantly, benefiting patients and families.

According to recent research, tumour cells are now seen in three dimensions. Within this concept, is it possible to determine which tumour is malignant and which is benign?

That's our goal. The cell is the smallest biological entity, and the proteins in the cells are the ‘workers’. Genes determine our overall properties, and the human gene map that was discovered in the 2000’s provides the code for all the protein molecules that constitute the human form. We should not forget, however, that proteins represent more than 15 percent of our body. Although a very complex task, we study the proteins that constitute the major building blocks, and is the functional engine in  all cells. With the establishment of the ‘European Cancer Moonshot Center in Lund and collaboration with 50 researchers from 15 countries, we can currently identify and measure 180,000 individual protein sequences in a single tumour from a patient.

When do you think cancer will be completely cured? Can artificial intelligence or 3D technology accelerate the process?

The phenomenon of cancer cell proliferation was discovered by the Greeks about three thousand years ago. Recently, impressive results have been achieved in treating breast and prostate cancer. Therapies have become so effective such that about 70-90 percent of cases are cured.

We have only reached this point with a lot of money and a lot of research. At the same time, however, the occurrence of the most aggressive form of skin cancer, melanoma, has recently increased. In addition, metastases can rapidly develop throughout the body. This is now one of the greatest challenges in medicine, so I do not believe it is realistic to specify a deadline.

When still President of the U.S.A., Barack Obama announced that research should be accelerated, made more effective, and that a cure for cancer should be found by 2025. But money alone is not sufficient to find that ultimate cure.

Cancer can only be combated through a joint international effort. Different laboratories play an important role in this battle by analysing patient data at a scientific level and using the information learnt through treatment. We have now reached a point where we have sufficient data to compare this information with histology and to pursue gene-protein combinations to determine the optimal drug application. At present, we still do not really know why a given treatment works for one patient and not for another.

In conclusion, we require increased personalised treatment that ideally is based on further development of new technology.

What do you consider the most exciting progress in your current scientific research?

We have discovered ten new proteins that have never been previously identified in the human body. Our research team has diagnosed these proteins in more than a hundred Hungarian and Swedish cancer patients. We believe these play a key role in malignant melanoma, and that by targeting these proteins we can limit the growth of tumours and the spread of metastases. As a researcher I consider it a great achievement, and this is the primary focus for most of my current work.