With the help of the Einstein Foundation, one of the most renowned RAS researchers from the USA was successfully brought to Charité as a Fellow. Professor Channing J. Der, from the University of North Carolina (UNC) at Chapel Hill, was the first to clone RAS genes during his time as a young postdoctoral researcher at the Dana-Farber Cancer Institute in Boston. Since then, he has been studying the molecular biology of the RAS gene family at UNC and has become the most-cited author in this field.
RAS family cancer genes, originally named after sarcoma-inducing cancer viruses, play a crucial role as drivers of malignancy in numerous human tumors, particularly in pancreatic and colon cancers. While drugs are now available that either block RAS proteins directly or inhibit the RAS-dependent cellular signaling system, tumor cells frequently and rapidly develop treatment resistance. Understanding these resistance mechanisms is key to developing new therapeutic approaches for advanced tumors.
As a guest laboratory for the Fellow, the working group led by Professor Christine Sers at the Institute of Pathology is available. This group is one of the few in Germany that has systematically studied RAS proteins and their effects in tumors for many years. While Professor Der focuses primarily on pancreatic carcinoma, which has a 95% prevalence of KRAS mutations, the guest laboratory primarily works on colon tumors, around half of which carry similar mutations. The Fellow's work and that of the guest laboratory complement each other ideally, driven by the shared goal of translating basic research findings into clinical applications.
The collaboration incorporates cutting-edge experimental designs and methods, such as the use of CRISPR/Cas technology to identify vulnerabilities in therapy-resistant tumor cells and organoids derived from tumor patients. Over three years of funding from the foundation, the cooperation partners have produced several publications.
Two studies describe the molecular basis for targeted combination therapies for pancreatic cancer. One well-known drug, palbociclib, compensates for the frequent loss of a key protein in tumor cells that normally suppresses malignancy. However, during treatment, tumor cells activate a RAS-dependent growth-promoting signaling pathway. The study demonstrates that simultaneously inhibiting this signaling pathway alongside palbociclib enhances the therapeutic effect. This combination therapy is currently being tested in a clinical trial.
The second study describes the principle of "vertical inhibition" as a new type of signaling pathway blockade. It was previously known that a single drug can cause undesired reactivation of other molecules in the same pathway due to feedback mechanisms, leading to resistance. This effect is neutralized when a second drug targeting another point in the signaling chain is applied simultaneously. The great advantage of this combination therapy is that it allows for lower drug concentrations, thereby reducing or even avoiding severe side effects.
The third study highlights a relatively unexplored gene that acts as a cancer driver in colon cancer. A detailed understanding of this gene and its protein product is essential for the future development of effective therapeutic inhibitors.
Furthermore, earlier groundbreaking work by BIH Einstein Visiting Fellow Professor Channing Der forms the foundation for the combination therapy currently recommended by the molecular tumor board at Charité's oncology center for pancreatic cancer patients with no other treatment options.