Inflammation-induced skeletal muscle atrophy in critically ill patients: identification of molecular mechanisms and preventive therapies

Critically ill patients who have to be treated in intensive care units often develop muscular weakness due to neuromuscular organ failure. By investigating the molecular mechanisms of this muscular weakness, the team of Prof. Carmen Birchmeier (MDC), PD Dr. Steffen Weber-Carstens (Charité) and PD Dr. Jens Fielitz (Charité) aims at developing new treatment options in order to shorten the time of intensive care treatment and to improve recovery and physical functioning of patients.

Coordination

Prof. Carmen Birchmeier
Max Delbrück Center for Molecular Medicine

Priv. Doz. Dr. Med. Jens Fielitz
Priv. Doz. Dr. Med. Steffen Weber-Carstens

Charité - Universitätsmedizin Berlin

Three questions for the project team

Carmen Birchmeier
Carmen Birchmeier

What is the central idea of your project?

We are working on Clear Cell Renal Cell Carcinoma (ccRCC). Kidney cell carcinomas of this cell type are by far the most frequently occurring ones. Tumor stem cells control the growth of tumors and play a crucial role in metastasis as well as in how the tumors respond to drug therapy approaches. We have observed that the tumor stem cell carcinomas respond differently among individual patients to drugs already employed and those under development. Whereas the tumor stem cells of some patients show a very good response to a treatment, those of other patients do not, or do so only weakly. Our project aims to develop novel therapy strategies that specifically target cancer stem cells in Clear Cell Renal Cell Carcinoma and to identify molecular markers that can predict therapeutic responses. For this purpose, we analyze the genome, the transcription (all genes transcribed, i.e. rewritten as RNA by DNA, in a cell at a given point), and the epigenetic signature of the tumor cells, which shows us which regulators influence the development of the cell and its succeeding generations. Ultimately, these results are to be used in the development of new therapies. We are also using the results to derive new, non-invasive markers from the molecular signature of tumor stem cells circulating in the blood of patients with metastasizing kidney carcinomas.

How does your project benefit from BIH?

Jonas Busch und Klaus Jung of the Department of Urology are providing clinical expertise on the kidney cell carcinoma and its treatment, especially on therapy involving tyrosine-kinase inhibitors. Tyrosine kinases are a group of enzymes that play a role in signal transmission between proteins and make an important contribution to cellular signal transmission as part of receptor systems. The research groups of Walter Birchmeier with Annika Fendler and Wei Chen of MDC have several years of experience in research on tumor stem cells and in the development and application of next-generation sequencing. The combination of this expertise enables us to integrate data from the genomic profiles of circulating cancer stem cells and from the molecular characterization of therapy responses to establish novel biomarkers that can be used in treatment decisions and disease monitoring.

How will kidney cancer patients one day benefit from your results?

As yet, metastasized kidney cell carcinomas only show a restricted response for a limited period to the therapies that are currently applied. Moreover, opting for a therapy is based solely on clinical parameters (such as the size of the tumor or the number of metastases). And at the moment, imaging techniques remain the option to measure tumor recurrence after tumor extirpation or therapy surveillance, and few molecular markers have been proposed for that purpos We want to use our research results to develop more effective therapies for metastasized kidney cell carcinomas. In parallel, we seek to identify molecular markers that enable individualized therapy decisions and therapy surveillance. The long-term goal is to employ novel treatment methods that have proved successful in preclinical studies in compassionate use or in early clinical trials.