Else Kröner Forschungskolleg Cologne

During the last two decades, cancer therapy has witnessed dramatic developments as we have begun to treat our patients based on deep molecular understanding of their individual disease. Particularly the advent of modern technologies, such as (single cell) genome sequencing and novel approaches in high-performance computational biology, have truly revolutionized cancer research throughout the past decades. Through extensive sequencing studies, the cancer research community was able to carve out essential driver genes for the majority of cancer entities. Many of these, particularly the kinase oncogenes, have subsequently been targeted by small molecule compounds. Prime examples are the use of specific tyrosine kinase inhibitors for BRAF-mutant, EGFR-mutant-, EML4-ALK-rearranged- or ROS1-rearranged tumors, as well as BCR-ABL-fused leukemia. However, numerous unresolved issues remain and require the attention of the scientific community. These include tumor heterogeneity, which we are only beginning to understand mechanistically and grasp in its complexity, clonal evolution and the development of resistance, as well as difficult to drug oncogenes, such as MYC.

In addition to these cancer genome-focused developments, cancer immunology has recently moved into the focus of the cancer research community. This is fueled by the impressive results of novel agents targeting immune checkpoints, such as the PD1/PD-L1 axis, as well as genetically modified T cell, which harbor chimeric antigen receptors (CAR-T cells) and bispecific T cell engagers (BiTEs). Intriguingly, it is becoming evident that cancer cell autonomous genomic aberrations, which clearly drive tumorigenesis, and cancer immunology are intimately linked to each other. For instance, oncogenic NFkB signaling, which can be driven by recurrent MYD88 or CARD11 mutations, drives supra-physiological PD-L1 surface expression and hence promotes immune escape. Similarly, CD274 (encoding PD-L1) is frequently rearranged or focally amplified in a variety of human malignancies. This illustrates that a comprehensive understanding of cancer involves not only a thorough understanding of the cancer genome, which we have worked on in the first funding period, but also includes a deep understanding of the various tumor-host interactions. The training and education of early career oncologists and physician scientists needs to be tailored to these scientific and technical developments. Unfortunately, the curricula in medical school and during residency training do not systematically provide this type of specialized training.

In the second funding period, we have refined our training measures and aim to continue the education of our fellows and to further promote their independent scientific careers. Thus, we have assembled a consortium of clinical opinion leaders and internationally competitive cancer researchers to create a structured training program for physician scientists that aim for a career in translational oncology. Our proposal is a cross-faculty joint effort of the members of the comprehensive cancer center of the University Hospital Cologne (CIO) and also involves non-university research centers (MPIs for Metabolism Research and Aging). The central scientific goal for the second funding period is to map and catalogue potentially actionable interactions between molecularly characterized individual cancer cells and their TME, with a particular focus on understanding anti-cancer immune responses.