White Paper: Mimetics of Class 2 Tumor Suppressor Proteins as Novel Drug Candidates for Personalized Cancer Therapy

Simple Summary A concept is presented for a new therapeutic approach, still in its early stages, which focuses on the phenotypic mimicry (mimesis) of proteins encoded by highly disease-relevant class 2 tumor suppressor genes that are silenced by DNA promoter methylation. Proteins derived from tumor suppressor genes are usually considered control systems of cells against oncogenic properties. Thus they represent the brakes in the car-of-life. Restoring this brake function in tumors by administering mimetic drugs may have a significant therapeutic effect. The proposed approach could thus open up a new, hitherto unexploited area of research for the development of anticancer drugs for difficult-to-treat cancers. The aim of our proposed concept is to find new target structures for combating cancers with unmet medical needs. This, unfortunately, still applies to the majority of the clinically most relevant tumor entities such as, for example, liver cancer, pancreatic cancer, and many others. Current target structures almost all belong to the class of oncogenic proteins caused by tumor-specific genetic alterations, such as activating mutations, gene fusions, or gene amplifications, often referred to as cancer driver alterations or just drivers. However, restoring the lost function of tumor suppressor genes (TSGs) could also be a valid approach to treating cancer. TSG-derived proteins are usually considered as control systems of cells against oncogenic properties; thus, they represent the brakes in the car-of-life. Restoring these tumor-defective brakes by gene therapy has not been successful so far, with a few exceptions. It can be assumed that most TSGs are not being inactivated by genetic alteration (class 1 TSGs) but rather by epigenetic silencing (class 2 TSGs or short C2TSGs). Reactivation of C2TSGs in cancer therapy is being addressed by the use of DNA demethylating agents and histone deacetylase inhibitors which act on the whole cancer cell genome. These epigenetic therapies have neither been particularly successful, probably because they are shotgun approaches that, although acting on C2TSGs, may also reactivate epigenetically silenced oncogenic sequences in the genome. Thus, new strategies are needed to exploit the therapeutic potential of C2TSGs, which have also been named DNA methylation cancer driver genes or DNAme drivers recently. Here we present a concept for a new translational and therapeutic approach that focuses on the phenotypic imitation (mimesis) of proteins encoded by highly disease-relevant C2TSGs/DNAme drivers. Molecular knowledge on C2TSGs is used in two complementary approaches having the translational concept of defining mimetic drugs in common: First, a concept is presented how truncated and/or genetically engineered C2TSG proteins, consisting solely of domains with defined tumor suppressive function can be developed as biologicals. Second, a method is described for identifying small molecules that can mimic the effect of the C2TSG protein lost in the cancer cell. Both approaches should open up a new, previously untapped discovery space for anticancer drugs.

Automated summary

A concept is presented for a new therapeutic approach that focuses on mimicking proteins encoded by tumor suppressor genes to restore the lost function in tumors. This approach may have a significant therapeutic effect on difficult-to-treat cancers.