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Restoration of tumor suppressor function by induction of translational read-through of premature termination codons - a strategy for improved cancer therapy (TRANSREAD)
Start date: Sep 1, 2016, End date: Aug 31, 2021 PROJECT  FINISHED 

Tumor suppressor genes such as TP53, RB1, PTEN and APC are frequently inactivated in sporadic and inherited human tumors. A significant fraction of the mutations in these genes are nonsense mutations that lead to premature termination of translation and expression of truncated unstable and non-functional proteins. We will identify and characterize novel molecules that can induce translational read-through of premature termination codons in nonsense mutant TP53 and expression of full length p53 protein. Hits will be tested for their effect on nonsense mutant RB1, PTEN and APC. We will also elucidate the molecular mechanism of action of the identified compounds by CETSA and other techniques. Moreover, we will test hit compounds on primary tumor cells from patients ex vivo, and generate mouse knock-in tumor models with nonsense mutant tumor suppressor genes for further characterization of hits. We will take the most promising hits through preclinical development towards clinical trials. Our aim is to develop novel and efficient targeted therapy for tumors with nonsense mutations in the TP53, RB1, PTEN and/or APC tumor suppressor genes.

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