Pancreatic cancer is one of the deadliest kinds of cancer in the western world. It is insidious and aggressive and can only rarely be defeated. Despite the enormous progress in medical research, it is still not known how pancreatic carcinomas develop or how to effectively fight them. Scientists from Ulm have now demonstrated on a mouse model how certain cancer cells can be driven to death in a preclinical study.
The cancer researchers from Ulm have chosen a mutation-specific combined therapy approach, which targets a type of carcinoma with a mutation in an important DNA repair game (ATM). The researchers have succeeded in turning off the cellular repair mechanisms by combining three substances. This approach resulted in the death of cancer cells and inhibition of tumour growth. The study was published in the renowned British journal “GUT”, and an extension of the therapeutical approach was published in “Cells”
Pancreatic cancer is not always the same. Today, we know that different genetic mutations are associated with this type of cancer. “We think it makes a lot of sense to group the pancreatic cancer patients according to their mutations, in order to better treat their illnesses”, says the director of the study, Professor Alexander Kleger from the Ulm University Medical Centre. As a Heisenberg professor for molecular oncology, he heads a team of pancreatic researchers. Prof Kleger is a senior physician and head of pancreatology in the Department of Internal Medicine I.
A fifth of patients with pancreatic cancer exhibit mutations in DNA repair genes. The most commonly affected gene is the ATM gene. This gene codes for the enzyme ATM serine/threonine kinase, which plays a key role in repairing DNA double-strand breaks. A mutation in this gene means that the enzyme cannot be produced, resulting in malfunctions in the double-strand repair. Alternative repair mechanisms are then used to repair the DNA damage, but these mechanisms are much more likely to contain errors. This poses a certain reproduction risk for the cells, as the cellular quality control eliminates faulty “copy templates” during the cell division process and kills damaged cells.
Cancer cells with mutations more likely to react to DNA-damaging medications
Researchers are making use of this interesting fact in order to selectively kill tumour cells that exhibit ATM mutations, while keeping the side effects as low as possible: “Cancer cells with mutations in DNA repair genes react more sensitively to DNA-damaging medications than healthy cells do. This makes it easier to focus the specificity of cell death on the cancer cells”, explain Dr Lukas Perkhofer, senior physician, and Dr Johann Gout, postdoc researcher. These two scientists from the Department of Internal Medicine I co-authored the study.
In order to block not only the repair of DNA double strands, but also alternative means of repair, the research team combined three different groups of drugs. These include PARP-, ATR- and DNA-PK inhibitors, all of which inhibit genetic damage regulation, but in different ways. If massive genetic damage is not repaired, the cell initiates controlled cell death by “suicide”, or apoptosis, stopping the growth of the tumour. In combing these three components, the hope is to have fewer side effects and reduce resistance as much as possible. “The simultaneous inhibiting of the kinase ATM with specific drugs allows a potential expansion of the therapy to non-ATM-mutated tumours. However, the toxicity of such potential therapies must be taken into account”, points out Kleger, the head of the study.
Mutation-specific combination approach opens up new perspectives for cancer treatment
In the course of this preclinical study, scientists from Ulm, Munich and Mainz were able to demonstrate this effect on the cell culture of a mouse model as well. Both murine and human pancreatic carcinoma cells were used for the study. The results were validated using human organoids, ie three-dimensional cell cultures. “The study has shown that our mutation-specific combination approach is very promising. But it’s still a long road to clinical cancer treatment”, the researchers agree. This direction at least opens up new perspectives for more specific and gentler forms of treatment. “The Department of Internal Medicine I is augmenting its profile in translational cancer research with this significant study”, relates Professor Thomas Seufferlein happily. The medical director of the Department of Internal Medicine I is president of the German Cancer Society. Financial supporters of this research project include: German Cancer Aid, the German Research Foundation and the Baden-Württemberg Foundation.
Media contact: Andrea Weber-Tuckermann