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Cancer Metabolism

Cancer Metabolism
 
Unlike normal cells, cancer cells have an unusual metabolic profile, with greatly increased glucose uptake via GLUT 1 and a consequently enhanced rate of glycolysis even under aerobic conditions. This key observation was first reported by Otto Warburg in the 1920’s. This metabolic trait confers advantages to cancer cells by establishing a means of providing building blocks to support biomass synthesis for growth and proliferation while still supplying the cells with sufficient energy production even in the hypoxic environments often encountered in tumor tissue. In contrast non-transformed cells are able to utilise alternative carbon sources, e.g., glutamine, fatty acids and other oxidisable substrates, to feed the TCA cycle and meet their bioenergetic and biosynthetic needs. Cancer cells’ altered metabolism makes them significantly more sensitive than normal cells to inhibition of glucose uptake, and this phenomenon of ‘glucose addiction’ has been described as an Achilles’ Heel of cancer.

Extensive links have been identified between known oncogenes/tumor suppressor genes, such as p53, Myc and AKT, and increased expression of key glycolytic transporters and enzymes, including GLUT1, MCT1, HK2, PFKFB3, PKM2 and LDHA. These findings underline the relevance of the metabolic switch towards glycolysis to the initiation and progression of cancer. The aim of IOmet’s programs in this field is to discover novel small molecules that disrupt the activity of key transporters and enzymes required for tumor cell metabolism, leading to the selective killing of cancer cells.

cancer-metabolism

 

IOmet’s Novel GLUT1 Inhibitors
 
The glucose transporter, GLUT1, has been well-validated as a key drug target in cancer metabolism. It is overexpressed in most cancers, and higher expression is associated with more aggressive disease and reduced patient survival time. Glucose entry via GLUT1 is the first and rate-limiting step in cellular glucose utilisation. Preclinical evidence, both in vitro and in vivo, demonstrates that inhibition of GLUT1 function selectively kills cancer cells and reduces tumorogenicity. IOmet has identified multiple series of best-in-class, novel small molecules that potently inhibit glucose uptake via GLUT1, resulting in rapid cancer cell death.

cancer-metabolism