Translational Research (English)
Adrenocortical carcinoma (ACC) is a rare endocrine malignany. The treatment of ACC is challenging, in particular in advanced stages. Women are more frequently affected than men and early signs may be related to excessive adrenocortical hormone secretion. Adrenal overproduction of cortisol may lead to Cushing’s syndrome. In cases without clinical hormone production, tumor-related mass effect may cause discomfort or even pain.
Drugs currently recommended by guidelines for advanced ACC are mitotane and chemotherapy. Mitotane shows relative tissue-specific toxicity to the adrenal cortex and has been used for more than sixty years. Mitotane is particularly effective in inhibiting tumoral steroid hormone production. Chemotherapeutic agents inhibit cell division or cause cell death by damaging genetic material and inhibiting repair mechanisms.
Cell death mechanisms and immune modulation in adrenocortical carcinoma
Recently, immunotherapy has been shown to be effective in different types of tumors. In many types of malignancies, certain surface signals prevent the immune system from killing tumor cells. Inhibition of these inhibitory signals then allows therapeutic reactivation of the immune system with so-called immune checkpoint inhibitors. In adrenocortical carcinoma, immunotherapy has raised great hopes as well. Yet, clinical trials demonstrated objective response in only a small proportion of patients.
Our project has two aims: First, to exploit cell death mechanisms active in ACC therapeutically and impede their survival. Second, we aim to understand immunodulation induced by these cell death processes with the perspective to facilitate tumor recognition by the immune system.
The cell death mechanism we focus on is termed ferroptosis, a cell death mechanism that is particularly pronounced in adrenocortical cells. We have shown in adrenocortical cells that ferroptosis occurs as "collateral damage" of steroid hormone production (Weigand et al., Cell Death Dis 2020). ACC cells appear to efficiently protect themselves against this damage. We are working to understand how exactly this is accomplished and how to therapeutically influence these protective mechanisms. We know from preliminary experiments that ferroptosis can be both pro-inflammatory and anti-inflammatory and we investigate both aspects.
To achieve these aims we continuously collaborate with different research groups within the Collaborative Research Center "The adrenal - central relay in health and disease" (www.adrenal-research.de).
New therapies for endocrine tumors
Most of the currently available tumor therapies are administered without effective prediction of tumor response. We are pursuing different approaches to identify tailored therapies for specific subgroups of patients with adrenocortical carcinoma and other endocrine tumors. To this end, we are collaborating, amongst others, with groups in the German Consortium for Translational Cancer Medicine (https://dktk.dkfz.de) for personalized therapy approaches.
Additionally, we are conducting research to better understand the mechanisms of action of currently used cancer drugs such as mitotane. To this end, we use mass spectrometry, cell biological and biophysical methods in our laboratory and in close collaboration with national and international partners.