Peter ten Dijke Group
Our research is focussed on understanding the molecular mechanisms that control normal and tumour cell behaviour, and how we can use these insights to manipulate signalling pathways for the development of new anti-cancer drugs. In particular our studies are concentrated on elucidating the mechanisms by which the multifunctional cytokine transforming growth factor-b (TGF-b) switches from a tumor suppressor at early stages into a tumor promoter at late stages of cancer progression.
Targeting of the TGF-b-induced aggressive mesenchymal cancer cell phenotype can blunt metastasis and overcome therapy resistance. Interference with TGF-b-induced activation of cancer associated fibroblasts and TGF-b-mediated immune evasion may allow for better immune cell mediated cancer cell killing. To do this while leaving the function of TGF-b to maintain tissue homeostasis intact, poses a challenge that we want to tackle. Indeed, current TGF-b agonists fail to progress beyond phase 2 clinical trials because of toxic side effects.
By using an integrated combination of biological, genetic and chemical approaches we continue to identify and validate novel targets of the pro-tumorigenic TGF-b responses. Some of the corresponding inhibitory agents for these undesired responses are awaiting further optimization towards drug candidates. Moreover, we are exploring ways to harness endogenous E3 ubiquitin ligases or the proteasome/lysosomal machinery to mediate the specific degradation of signaling components in a cell type dependent manner.