Systems medicine of BRAF-driven malignancies

In their TRG project, Dr. Markus Landthaler (MDC) and Prof. Nils Blüthgen (Charité) investigate why different cancer types that carry the same genetic alteration, e.g. a mutation in the BRAF gene, respond differently to similar drug therapy approaches. The research team focuses on the examination of the post-transcriptional regulatory mechanisms in tumor cells to obtain a better understanding of the regulatory networks involved in oncogenesis and cancer progression. In the long term, insights from this study will help to develop novel cancer therapies.

Coordination

Dr. Markus Landthaler
Max Delbrück Center for Molecular Medicine 

Prof. Nils Blüthgen
Charité – Universitätsmedizin Berlin

Three questions for the project team

Markus Landthaler (left) and Nils Blüthgen
Markus Landthaler (left) and Nils Blüthgen

What is the central idea of your project?

Over the last few years, genomic research has developed rapidly. This has enabled the analysis of recurrent mutations in the genomes of tumors, resulting in novel targeted therapies. Some mutations occur at high frequencies across multiple tumour entities. One example of such mutations is a mutation in the BRAF gene that occurs among 40 per cent of the melanoma patients but also in colorectal cancer. This inhibitor shows high response in patients with malignant melanoma that carry this BRAF mutation. In contrast, 10 per cent of the patients with colorectal cancer that carry the same mutation show no response. We will investigate the posttranscriptional networks that relay BRAF signals in order to understand the mechanisms responsible for intrinsic resistance to BRAF inhibitors. Moreover, we want to identify novel biomarkers of the BRAF associated networks for therapy stratification of BRAF tumors.

How does your project benefit from BIH?

At MDC, in Markus Landthaler’s research group, we developed novel methods to investigate the regulation of RNAs. Here, these methods, which have so far been used mainly in basic research, are to be applied to a clinically relevant issue. This has been made possible by working together with Charité research groups in tumor biology (Christine Sers/Reinhold Schäfer), pathology (Hendrik Bläker) and mathematical and bioinformatics analysis (Nils Blüthgen).

How will patients with malign tumors one day benefit from your results?

Of course there is still a long way to go. The regulatory mechanisms that we have examined in posttranscriptional regulation with which the oncogenic mutation turns the cell into a tumor cell can be accurately manipulated by small RNA molecules. If we can specifically influence these mechanisms, this could lead to the development of novel therapies to cure cancer diseases by blocking molecular interactions that are essential for tumors. Also, a precise understanding of the networks involved in oncogenesis and oncoprogression can unveil targetable vulnerabilities and new therapeutic opportunities.

Subprojects

  1. Reconstructing the BRAF-driven gene regulatory networks
  2. Testing BRAF-driven networks in patient-derived primary cultures