Investigating treatment resistance in cancer

Melanoma and liver cancer are becoming more widespread in Europe and the US. Whilst both diseases progress very differently, they are among the types of cancer which are most likely to be fatal in the Western world. Three groups of researchers from the Institute of Biochemistry at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) led by Prof. Dr. Anja Bosserhoff, Dr. Peter Dietrich and Prof. Dr. Claus Hellerbrand have jointly discovered a mechanism used to steer the growth of the cancer cells in both types of cancer, a discovery which is highly significant for future treatment strategies. The researchers' work has now been recognised with a prestigious award from the Deutsche Leberstiftung (German Liver Foundation) for a groundbreaking publication in the field of liver research.

At first glance, there are not many similarities between two such different types of cancer as black skin cancer (malignant melanoma) and liver cancer (hepatocellular carcinoma). The main risk factors for melanoma are too much exposure to the sun, sunburn and genetic predisposition. Liver cancer, on the other hand, very often occurs in a liver which has been damaged by alcohol or obesity or as a result of chronic viral hepatitis. However, what both types of cancer have in common is an uncontrolled growth of malignant cells. These end up destroying vital tissues and organs within the body, leading eventually – often over many years, sometimes within a very short period of time – to the death of the patient.

Similar approaches to treatment

Similar chemotherapy treatments are used to treat both types of cancer. 'Although these tumours are found in very different locations, the drugs used to treat them focus on the same signal pathway, inhibiting the growth and splitting of cancer cells,' explains Dr. Peter Dietrich. 'These treatments are very effective in the first few weeks, but unfortunately after a few months the cancer cells nearly always become resistant to them.' Groups of researchers at the Institute of Biochemistry at FAU have now discovered a mechanism which steers the growth of the cancer cells and their resistance to chemotherapy in both types of cancer.

New approaches opening up new treatment options

The scientists at FAU took a new approach, with experts on two very different types of cancer, melanoma and liver cancer, carrying out joint research. They cooperated in an attempt to discover more general mechanisms which cause cancer and resistance to treatment. Their research was successful: the teams of researchers led by Prof. Dr. Anja Bosserhoff, Dr. Peter Dietrich and Prof. Dr. Claus Hellerbrand discovered that both skin cancer and liver cancer cells produce more of a certain protein – KRAS – and increase production even more during treatment, making them dependent on this protein.

'While these may at first glance appear to be such different types of cancer, they are both able to create more of this protein due to the lack of an extremely small RNA molecule, referred to as a microRNA,' explains Prof. Dr. Anja Bosserhoff. 'Levels of the KRAS protein, which is responsible for increased growth and resistance, are usually kept at a low level by this microRNA, which acts as a stop sign and integrated safety switch in healthy cells. We noticed much lower levels than normal of this microRNA in both types of cancer, and even a complete absence in some cases. As a result, the cancer gene KRAS is released, which can in turn lead to an unchecked growth of the cancer and resistance to treatment.'

Patent applied for

This mechanism can be used to treat cancer effectively in future. Based on their new findings, the researchers want to inhibit tumour growth and prevent resistance to treatment. 'Several approaches were successful in our studies,' emphasises Dr. Peter Dietrich. 'The lost microRNA can be returned to the cancer cells using genetic engineering, allowing the uninhibited KRAS protein to be regulated again. Another option is to switch off KRAS directly in the cells, which could also lead to a breakthrough in treatment resistance. Finally, new substances were used successfully to inhibit KRAS. These substances, used alone or in combination with previous drugs, could form the basis for new, effective treatments.' Prof. Dr. Claus Hellerbrand is also convinced by the concept. 'The approach has a lot of potential and we working on developing it. FAU has now filed an application to have this discovery patented as a treatment option for skin and liver cancer.'

Prize from Deutsche Leberstiftung

The researchers at FAU have since published their findings in several articles in renowned journals. One of their articles was published in Gut, one of the leading journals in the field of liver research, and has now been awarded the 'Preis der deutschen Leberstiftung 2018' (German Liver Foundation Award 2018). This is one of the most prestigious awards in the field of liver research in German-speaking countries and is awarded annually for a groundbreaking publication.

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