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

Abstract

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.

Impact of Altered Body Composition on Clinical and Oncological Outcomes in Intrahepatic Cholangiocarcinoma

“…Similarly, DKK3 was described to function as a negative regulator of insulin resistance and hepatic steatosis. Since tumor suppressor proteins lost in tumors cannot themselves be targeted, their function may be substituted with mimetic drugs [45]. This new concept involves the identification and validation of drug candidates that phenotypically mimic the lost tumor suppressor protein.…”

Secretion of Sphinganine by Drug-Induced Cancer Cells and Modified Mimetic Sphinganine (MMS) as c-Src Kinase Inhibitor

“…However, the molecular link between sphingolipid bases such as sphinganine and sphingosine with the modulation of the c-Src kinase is highly lacking and specifically in the context of colon cancer cells and apoptotic cell death. In recent, the small molecular inhibitors of c-Src kinase and other intracellular kinases are conceived as a new class of anticancer drugs to attenuate proliferation and induce cell death in cancer cells including colon cancer [34][35][36][37][38] Additionally, the mimetic class of anticancer drugs as inhibitors of intracellular signal transducers such as c-Src kinase appears to be a safe and feasible avenue in cancer therapies [39][40][41][42]. However, the extrapolation of understanding sphingolipid metabolites in the context of the development of inhibitors of c-Src kinase as a modified mimetic of sphinganine is highly scarce.…”

ITIH5 as a multifaceted player in pancreatic cancer suppression, impairing tyrosine kinase signaling, cell adhesion and migration

“…The characterization of ITIH5 as a C2TSG in pancreatic cancer has not yet been investigated, but its significance could emerge in the future. C2TSGs hold promise as potential targets for novel therapeutic approaches [ 24 ], especially given that promoter methylation in the context of general epigenetic changes plays a pivotal role in altered gene expression and defining the malignant phenotypes of pancreatic cancer [ 25 ].…”