Introduction

Metabolic alterations are common to all cancer types and represent promising targets for cancer therapy. However, therapeutic strategies aimed at tackling one metabolic pathway alone, are often ineffective. Thanks to their metabolic plasticity, cancer cells escape such therapies by adapting their metabolism and switching among the metabolic pathways depending on the specific stimuli. Recent studies coordinated by Prof. Minucci (IEO) and Prof. Foiani (IFOM) have led to the identification of a new molecular mechanism responsible for tumor metabolic plasticity, and to the in vivo validation of a new therapeutic strategy against cancer escaping metabolic inhibitors.

Technical features

The molecular mechanism identified by the groups of Prof. Minucci and Prof. Foiani is mediated by a particular form of the phosphatase 2A (PP2A), located at the crosstalk between the oxidative phosphorylation and the glycolysis pathways. In vivo studies in mouse models have demonstrated that the combined modulation of the oxidative phosphorylation (via metformin administration)  and the glycolysis (via hypoglicemia diet or PP2A activators) effectively counteracts tumor growth, through the activation of the PP2A-mediated molecular mechanism. Taking advantage of a drug already in the market and widely used for treating type 2 diabetes, the metformin, scientists have designed and validated two new efficacious combination cancer therapies. This is a still unexplored approach to affect tumor metabolism, and it offers a new molecular solution to a therapeutic area with a high unmet medical need, that is the design of effective metabolic therapies to fight cancer.

Possible Applications

• Treatment of cancer escaping metabolic inhibitors.

Advantages

• Reduced development costs and times through repurposing metformin;
• Combination of metformin and hypoglicemia diet currently under clinical validation;
• Ongoing studies for the identification of a new chemical entity acting as PP2A activator.