Kliniken & Institute … Institute Pathologisches Institut… Angewandte… Forschung Wissenschaftliches…

Research concept

Our research  aims are the identification of key alterations responsible for cancer formation and the development of novel clinical applications targeting these alterations. Our vision is to develop novel diagnostic tools, drugs and vaccines  to better diagnose, treat and prevent cancer. Our research thereby focuses on two distinct tumor entities that share unique molecular features of neoplastic transformation.

Overview of research activities at ATB

Each cancer emerges from one single cell in our body. This cell needs to acquire many new biological features as for example continuous growth, the ability to invade underlying tissues and to spread via the blood stream and lymphatic vessels (Hanahan and Weinberg, 2011). A further prominent feature of  cancer cells is the ability to evade the attack of the immune system that potentially can recognize emerging cancer cells by the expression of “cancer related antigens” (Mittal et al., 2014). The biological features of cancer cells are caused by profound changes of their genomes.  This implies that transformation of normal cells is accompanied by a dramatically increased flexibility of their genomes that results in a tremendous amount of mutant offspring cells. From these highly heterogeneous offspring cells only the ones with the best adopted biological features are further selected. As the inital steps require the tremendously enhanced genomic flexibility, all offspring cells retain the ability to continuously modify their genomic information. This state is referred to as genomic instability. Basic mechanisms to acquire the state of genomic instability are

  1. chromosomal instability (CIN) that afffects structure, replication and even distribution of chromosomes during cell divisions, and
  2. microsatellite instability (MSI-high), a mechanisms that allows cells to acquire a very high number of mutations in their genomes by loosing essential proofreading and repair functions responsible for maintaining genetic fidelity. MSI-H specifically is caused by inactivation of the DNA mismatch repair system (MMR).

A prominent example of CIN cancers is induced by oncogenic human papilloma viruses (HR-HPVs) that can  induce “chromosomal instability”  by inactivating critical host cell tumor suppressor pathways. We are particularly interested to explore how the responsible viral oncogenes (E6 and E7) become activated in infected cells. This research allowed us to identify p16INK4a as the clinically most useful biomarkers for HPV- transformed cells in clinical samples. p16INK4a also shares distinct features that makes it particularly interesting as vaccine target for HPV-transformed cells, an approach that we have just evaluated in a first clinical trial. Studying the basic mechanisms of HPV-induced cancer formation further allowed us to  detect epigenetic mechanisms that control the expression and activity of the viral oncogenes that are potentially “drugable”.  Currently we are developing topical treatments to block the expression of the viral oncogenes with the intent to stop progression of localized precursor lesions into invasive cancers.

Loss of DNA mismatch repair functions triggers MSI-H. The MSI-H phenotype occurs in 15% of colorectal cancers, but also in a substantial proportion of other common tumors, such as other gastrointestinal tumors or endometrial cancers. MSI-H results in the generation of frame shift mutations in tumor cells. The expression of mutation-induced frameshift peptides (FSPs) renders MSI-H cancer cells particularly immunogenic. Our research aims to understand the basic immune biology of these cancers and to develop a vaccine against MSI-H cancers that is based on immunogenic FSPs. Such an approach is of exceptional clinical significance, particularly for patients who carry a genetic predisposition for hereditary colon cancer (HNPCC or Lynch syndrome) and therefore have a very high risk to develop multiple MSI-H cancers during their life.