Elias Arnér

Dietary intake of the element selenium has long been discussed in connection with cancer, but the results regarding the effects of selenium on cancer have been ambiguous and the connections between selenium intake and cancer development are very complex. Selenium plays a major role for humans through the so-called selenium proteins, i.e. protein substances containing the unusual amino acid selenocysteine. In a very general way, it seems that selenium intake and thus the functions of selenium proteins can protect against the onset of cancer (so-called carcinogenesis), while once a cancer has arisen and a cancerous tumor grows, the cancer cells themselves need selenium proteins. We know that two of the selenium proteins we study, TXNRD1 and GPX4, are particularly important for the survival of cancer cells, while normal cells can survive via alternative enzyme pathways. We want to study this relationship further in the project described here. Among other things, we wish to develop new small molecules that can specifically inhibit TXNRD1 or GPX4 and which we then want to study as possible new drugs for cancer therapy. We also study basic mechanisms for how selenium proteins affect the functions of different cells, and thus how and why selenium is a vital trace element for humans. Overall, our research aims to develop new forms of cancer treatment, with few or no side effects, which should be able to complement existing therapy and thus give a higher chance of a good prognosis when treating several different forms of cancer where selenium proteins play an important role in tumor growth. Through our research, we also map previously unknown fundamental mechanisms for how the trace element selenium regulates both healthy and diseased cells to their functions via so-called redox biology, i.e. processes involving reduction and oxidation.

The element selenium has long been discussed in relation to the development of cancer, but the relationships that exist between the degree of intake of selenium and the risk of cancer are quite complex. In simple terms, it can be said that the selenium protects against the onset of cancer, while if cancer nevertheless developed, selenium can exacerbate a tumor disease. The selenium works in the cells, e.g. via so-called selenoproteins. Recent research has shown that certain selenium proteins, especially TXNRD1 and GPX4, appear to play a particularly important role in maintaining the growth of a variety of cancers. Possibly, these selenium proteins can thus be promising targets for cancer drugs. This research project describes how new cancer drugs can be developed, which are proposed based on inhibition of selenium proteins TXNRD1 and GPX4. The research group is a world leader in techniques for producing selenium proteins, which is required to be able to find molecules that can inhibit them and thus form the basis for the development of new drugs. Recent results from the group with TXNRD1 show that the strategy described can be very successful and the hope is that inhibitors of GPX4 will function equally well. The research also needs to enable clinical trials with the most promising molecules, which is both demanding and costly. The overall objective of the research project is to be able to develop new methods of treatment for cancer therapy, based on drugs that inhibit the specific selenium proteins described in the project. It is hoped that this therapy will be effective as a complement to other therapy, while the side effects are expected to be very mild. Preliminary results are promising and although the challenges are great, we hope for continued development and good results in the project in the next few years.

Selenium is a vital tracer that is sold in health food stores as a protective substance against dangerous forms of oxygen, so-called oxygen radicals. However, the way the harness gives its protective effect is very complicated. This happens, e.g. through its function in so-called selenoproteins. These selenium proteins (man has 25) have different functions and some can protect against the onset of cancer while others can help the cancer cells to grow and thus constitute cellular targets in drug treatment of cancer. Our research aims to understand in detail how selenium proteins work in cancer cells and how this knowledge can be used for better cancer treatment. We study molecular mechanisms how one of the most important selenium proteins works (thioredoxin reductase) with studies at both atomic level and in cells and in model organisms. In addition, we examine how redox signaling, i.e. signals in the cells due to the oxidation or reduction of particularly important cellular substances affect cell growth and cell function and how this can be linked to the function of selenium proteins. Finally, we have produced new inhibitors of thioredoxin reductase which we have found to show good effect in cancer treatment in mouse models. Our hope is to develop these findings against new principles for cancer treatment. The goal of our research is to generate new knowledge about how selenium proteins and so-called Redox signaling controls the development and growth of cancer cells. We try to develop inhibitors of these processes, which in this way must be able to kill cancer cells without killing normal cells and thus be able to be used for the development of new drugs for cancer treatment. The imaging methods we develop based on selenium protines aim at new, more sensitive diagnostics for cancer and follow-up on how well different forms of treatment work. All in all, our research aims to reduce ill health in cancer through knowledge of the function of selenium proteins and medical use.

Selenium is a vital tracer that is sold in health food stores as a protective substance against dangerous forms of oxygen, so-called oxygen radicals. However, the way the harness gives its protective effect is very complicated. This happens, e.g. through its function in so-called selenoproteins. These selenium proteins (man has 25) have different functions and some can protect against the onset of cancer while others can help the cancer cells to grow and thus constitute cellular targets in drug treatment of cancer. Our research aims to understand in detail how selenium proteins work in cancer cells and how this knowledge can be used for better cancer treatment. We study molecular mechanisms how one of the most important selenium proteins works (thioredoxin reductase) with studies at both atomic level and in cells and in model organisms. In addition, we examine how redox signaling, i.e. signals in the cells due to the oxidation or reduction of particularly important cellular substances affect cell growth and cell function and how this can be linked to the function of selenium proteins. Finally, we have produced new inhibitors of thioredoxin reductase which we have found to show good effect in cancer treatment in mouse models. Our hope is to develop these findings against new principles for cancer treatment. The goal of our research is to generate new knowledge about how selenium proteins and so-called Redox signaling controls the development and growth of cancer cells. We try to develop inhibitors of these processes, which in this way must be able to kill cancer cells without killing normal cells and thus be able to be used for the development of new drugs for cancer treatment. The imaging methods we develop based on selenium protines aim at new, more sensitive diagnostics for cancer and follow-up on how well different forms of treatment work. All in all, our research aims to reduce ill health in cancer through knowledge of the function of selenium proteins and medical use.

"Everyone is an expert in different parts of cancer biology, the combination of a common hypothesis and tumor model allows us to approach the problem from different but complementary directions," explains Elias Arnér, professor of biochemistry with a focus on selenium biochemistry. The project, which is supported by the Knut and Alice Wallenberg Foundation, is based on redox biology. Redox, the reduction or oxidation of molecules in the cells, are vital chemical reactions. Upon reduction, electrons are absorbed and, upon oxidation, electrons are emitted. Processes that, among other things, allow us to breathe and which give us and all living energy. But some percent of the oxygen we breathe forms reactive oxygen radicals, ROS, in the cells. These can easily react with the structures and functions of the cells, which in turn can disrupt a balance that is important to prevent disease.  - It has become increasingly clear over the years that redox processes play a major role in the functioning of cells, both in normal, healthy, cells and cancer cells. Different redox processes are important for how cancer develops, but also for how effective different cancer therapies can be. Oxidative stress Radiation and cytostatics often appear to increase oxidation in cancer cells and this is something that is good for a good treatment effect if the researchers' hypothesis is correct. - We believe that an even more effective treatment would be possible with the help of increased levels of free oxygen radicals in the cancer cells, through increased oxidation, while at the same time reducing the levels of these in immune cells. By increasing the oxidation in cancer cells, many of them would die from so-called oxidative stress, while a reduced oxidative stress in the immune system can strengthen its ability to fight the cancer cells. The trick is to gas and brake at the same time. - Oxidative stress depends on many factors, how the cell grows, its metabolism, how it is treated and how high the sugar levels are. Two birds with one stone By inhibiting the enzyme NOX2, which is found only in immune cells and not in cancer cells, the reduction in the immune cell could be increased, which could theoretically provide better protection against cancer. Another way would be to stimulate the transcription factor Nrf2, which also increases the reduction and could make the immune cells function better. - The cancer cells already have a maximum Nrf2 activity, a reduction activity at the top, and thus counteract their own already high levels of oxygen radicals. But there is another way and this is where Elias Arnér's expertise on the harness comes in. Selenium proteins that, among other things, TrxR protect the cells against free oxygen radicals and prevent them from being exposed to oxidative stress. - It is possible to inhibit the enzyme TrxR, or functions of GSH (glutathione) in the cancer cells. If you succeed in inhibiting TrxR you could hit two flies in one blow. It would increase the oxidation in cancer cells and kill them, while we believe that the reduction in normal cells would increase through stimulated activity of Nrf2, thus providing overall protection against cancer. Carefully optimistic The aim of the project is to improve existing cancer treatments and medicines, but also to develop platforms for new drugs. A decisive factor in the work is the specific mouse models and the knowledge about these, and about the redox biology in cancer, that the participating research groups have. - With the help of genetic technology we can remove important enzymes in the redox process and see what happens. We can manipulate both the cancer cells and the host's specific genes. We can also give the mice tumors and then treat them to see which method and combination of modulation of the redox processes is the most effective. The tumor forms that the researchers are working on as a model system are lung cancer and skin cancer. - But we think the principles are pretty general for most cancers. One advantage is that we, through Rolf Kiessling and his group, also have tissue from patients with skin cancer that we can use to see if conclusions and results from the mouse models are also correct in humans. Despite the massive research that is ongoing, cancer diseases continue to be the second most common cause of death after cardiovascular disease in Sweden, among others. But Elias Arnér is cautiously optimistic. - I think we are somewhat on track in this project. In general, we always get a better understanding of how cancer develops and develops, which provides better and better treatment options. Development is constantly advancing and it would be strange if medical developments would stop today. Text Carina Dahlberg Pictures Magnus Bergström Published: 2016

Selenium is a vital tracer that is sold in health food stores as a protective substance against dangerous forms of oxygen, so-called oxygen radicals. However, the way the harness gives its protective effect is very complicated. This happens, e.g. through its function in so-called selenoproteins. These selenium proteins (man has 25) have different functions and some can protect against the onset of cancer while others can help the cancer cells to grow and thus constitute cellular targets in drug treatment of cancer. Our research aims to understand in detail how selenium proteins work in cancer cells and how this knowledge can be used for better cancer treatment. We study molecular mechanisms how one of the most important selenium proteins works (thioredoxin reductase) with studies at both atomic level and in cells and in model organisms. In addition, we examine how redox signaling, i.e. signals in the cells due to the oxidation or reduction of particularly important cellular substances affect cell growth and cell function and how this can be linked to the function of selenium proteins. Finally, we have produced new inhibitors of thioredoxin reductase which we have found to show good effect in cancer treatment in mouse models. Our hope is to develop these findings against new principles for cancer treatment. The goal of our research is to generate new knowledge about how selenium proteins and so-called Redox signaling controls the development and growth of cancer cells. We try to develop inhibitors of these processes, which in this way must be able to kill cancer cells without killing normal cells and thus be able to be used for the development of new drugs for cancer treatment. The imaging methods we develop based on selenium protines aim at new, more sensitive diagnostics for cancer and follow-up on how well different forms of treatment work. All in all, our research aims to reduce ill health in cancer through knowledge of the function of selenium proteins and medical use.

Selenium is a vital tracer that is sold in health food stores as a protective substance against dangerous forms of oxygen, so-called oxygen radicals. However, the way the harness gives its protective effect is very complicated. This happens, e.g. through its function in so-called selenoproteins. These selenium proteins (man has 25) have different functions and some can protect against the onset of cancer while others can help the cancer cells to grow and thus constitute cellular targets in drug treatment of cancer. Our research aims to understand in detail how selenium proteins work in cancer cells and how this knowledge can be used for better cancer treatment. We study molecular mechanisms how one of the most important selenium proteins works (thioredoxin reductase), with studies at both atomic level and in cells and in model organisms. In addition, we examine how redox signaling, i.e. signals in the cells due to the oxidation or reduction of particularly important cellular substances affect cell growth and cell function and how this can be linked to the function of selenium proteins. Finally, we also produce synthetic selenium proteins that can be used to image tumors inside the body with so-called PET camera and also for determining how well a cancer responds to treatment. The goal of our research is to generate new knowledge about how selenium proteins and so-called Redox signaling controls the development and growth of cancer cells. We try to develop inhibitors of these processes, which in this way must be able to kill cancer cells without killing normal cells and thus be able to be used for the development of new drugs for cancer treatment. The imaging methods we develop based on selenium protines aim at new, more sensitive diagnostics for cancer and follow-up on how well different forms of treatment work. All in all, our research aims to reduce ill health in cancer through knowledge of the function of selenium proteins and medical use.