Studying a new therapeutic approach for HER2+ breast cancer
Despite the considerable progress made in the development of new therapies, breast cancer remains the most common cause of cancer-related death in women in Germany. New treatment options are therefore needed, thus prompting scientists to continuously investigate alternative approaches. Researchers at the Leibniz Research Centre for Working Environment and Human Factors (IfADo) have already shown that the enzyme EDI3 is associated with changes in the metabolism of cancer cells. The team now focuses on the potential of EDI3 as a therapeutic target in a specific breast cancer subgroup. This new project will be funded by the „Deutsche Krebshilfe“.
Tumor cells alter their metabolism to feed their need to continuously grow, divide, and survive. Enzymes control the reactions which regulate the cell’s metabolic pathways. Therefore, an in-depth knowledge of the enzymes responsible for these metabolic processes is a central starting point in the search for targeted cancer therapies. Researchers at IfADo identified such an enzyme a few years ago called EDI3. They could show that higher EDI3 expression in the primary tumor of endometrial and ovarian cancer patients is significantly associated with worse survival and metastasis.
Focus on EDI3 and choline metabolites in HER2-positive breast cancer
EDI3 is a key enzyme in vital metabolic pathways, such as choline and lipid metabolism, both of which are altered in various types of cancer. In breast cancer, for example, it is known that products of the choline metabolism are elevated, especially in aggressive tumors. However, the role of EDI3 in this cancer type is still not characterised. An IfADo team led by Dr. Rosemarie Marchan and Dr. Karolina Edlund is now investigating whether EDI3 is a relevant therapeutic target in the treatment of HER2-positive (HER2+) breast cancer patients.
Breast tumors differ from one another, for instance with regard to which molecules are found on the surface of the cells. HER2+ is one breast cancer subtype, accounting for 25% of breast cancer patients. Within this subtype, tumor cells express higher than normal levels of the HER2 receptor on the surface. The consequence of this overexpression is that the cell receives too many proliferation signals and the tumor grows uncontrollably. Drugs are available that specifically target HER2, and most patients respond quite successfully. However, some develop resistance, which warrants alternative treatment approaches.
Analysing effects of EDI3 inhibition
In preliminary experiments, the IfADo team could show that the level of EDI3 is particularly high in a subset of HER2+ breast cancer patients whose tumors do not express the estrogen receptor. In the laboratory, silencing EDI3 in these specific breast cancer cells decreased their survival. „We will investigate whether a targeted inhibition of EDI3 improves the anti-tumourigenic effect of the known HER2+ breast cancer drugs. In addition, we will examine the effects of EDI3 inhibition on tumor cells that are resistant to known therapy“, explains project leader Dr. Rosemarie Marchan.
In addition to studying EDI3 as a possible therapeutic target in HER2+ breast cancer, there are many more open questions regarding EDI3 in this subtype of breast cancer. It is unclear, for example, which signaling pathway downstream of HER2 causes the high EDI3 expression. The role of other enzymes and metabolites in the choline metabolic pathway should also be clarified. The researchers will therefore analyse these aspects in experiments using a combination of molecular biology techniques, protein and metabolic network analysis in tumor tissue from breast cancer patients, breast cancer cell lines and mouse tumor models.
About the project:
The project is entitled „A role for the glycerophosphodiesterase EDI3 and choline metabolism as a treatment target in HER2+ breast cancer „. The project will be funded by the Deutsche Krebshilfe with more than 230,000 Euros for the next three years. The work will be done in collaboration with the University Medical Center of the Johannes Gutenberg University in Mainz, that provides human breast cancer samples, and with the Lead Discovery Center, Dortmund, that will perform pharmacokinetic measurements and analyses in plasma from mice after inhibitor exposure.
The abbreviation EDI3 stands for endometrial carcinoma differential 3. Alternative names include GPCPD1, GDE5 and GDPD6. The glycerophosphodiesterase cleaves glycerophosphocholine to choline and glycerol-3-phosphate. Both substances are central intermediates for various central metabolic pathways, e.g. choline, fat and sugar metabolism. In 2012, researchers at IfADo, together with an international team of scientists characterised EDI3 for the first time, showing that it is relevant in metastasis in endometrial and ovarian cancer and is a key enzyme in choline and fat metabolism that influences cell migration.
Dr. Rosemarie Marchan
Head of IfADo research group “Cellular Toxicology“
Dr. Karolina Edlund
PostDoc in IfADo research group “Systems Toxicology“