Brägelmann, Johannes - CAP 18

A major factor limiting the survival of cancer patients is the lack of durable treatment response and the emergence of therapy resistant disease. The causal genetic and epigenetic mechanisms driving tumor evolution and therapy resistance are still largely unknown. However, we consider a detailed knowledge of these processes vital in order to improve existing and design novel treatment strategies. Accordingly, our group explores the molecular determinants of tumor development and therapy response by combining forward genetic screens and data-driven molecular biology with a special focus on lung and head and neck cancer.  

Cell-autonomous adaptation mechanisms to therapeutic stress
Despite tremendous advances in precision cancer medicine, chemotherapy remains a backbone of oncologic treatment for most lung and head and neck cancer (HNC) patients. The intended effect of chemotherapy is to elicit tumor cell death. However, it has been recognized that treatment may induce a state of persistent, but reversible, cell cycle arrest termed therapy induced senescence (TIS) in a subset of tumor cells. These persisting tumor cells are characterized by alteration of fundamental properties including metabolism and stemness. More importantly, they may eventually regain proliferative capacity and form a drug resistant tumor. Additionally, TIS is associated with sensitivity to senolytic drugs and with the expression of a senescence associated secretory phenotype (SASP) including cytokines that may impact the tumor microenvironment. Currently knowledge is limited regarding how lung and HNC cells manage to survive therapeutic stress, whether TIS is involved and which molecular mechanisms drive persistence and resistance. We therefore leverage tools established in previous studies including pharmacogenomic screening and longitudinal RNA-sequencing to characterize the dynamic adaptation processes of lung and HNC cells under therapy. We complement these efforts with forward genetics approaches using CRISPR-activation screening to specifically identify causal factors driving the persistence/resistance phenotype.

Reshaping tumor-immune interactions with targeted inhibitors
A relevant step forward in the treatment of lung and HNC has been the introduction of immune checkpoint blockade. Nevertheless, disease recurrence following ICB is frequent and response rates remain disappointing. Recent reports propose that small molecule inhibitors targeting cell cycle regulation, epigenetic enzymes and DNA damage response (DDR) may directly and indirectly activate cell intrinsic interferon pathways in several tumor types. Similarly, we observed induction of a tumor cell-autonomous inflammatory response using kinase inhibitors in kinase-driven tumor models. This process was paralleled by a change in the tumor-immune environment and increased sensitivity to an immunotherapy in vitro and in vivo. Combining targeted agents with ICB may thus help to relieving immunosuppressive effects exerted by tumor cells and increase ICB response. We therefore systematically investigate the effects of CDK and the DDR inhibitors in pre-clinical lung and HNC models with the goal of tailoring effective treatment strategies in conjunction with ICB.

Perspectives

Despite tremendous advances in tumor biology and clinical oncology the majority of advanced lung and HNC patients cannot be treated with precision medicine approaches yet. Moreover, primary or acquired lack of therapy response limits patient survival. We aim to address this clinical need by investigating the processes and molecular changes underlying tumor development and therapy resistance evolution. A unifying theme of our research is the systematic analysis of large-scale ‘omics’ and molecular biology data sets coupled with iterative experimental validation. In particular, in the current project we will employ functional genomics screens, computational biology, and experimental model systems in order to define novel therapeutic targets and molecular markers of response. Our ultimate goal in addressing these translationally relevant questions is to contribute the ongoing improvement of cancer care.