Although many chemotherapy agents are effective at killing cancer cells, they are also toxic to normal cells. The discovery of new drugs that have better cancer cell-specific toxicity could reduce side-effects and improve quality of life for cancer patients.
A unique property of many cancer cells is their altered metabolism of glucose. Most normal cells oxidize glucose in the mitochondria to produce ATP and carbon dioxide (CO2), whereas cancer cells have higher rates of glycolysis and convert more glucose-derived carbon molecules to building blocks (nucleotides, proteins, and lipids) that are necessary for cell growth and proliferation. This type of metabolism also promotes metastasis and drug resistance. However, this unique characteristic of cancer cells exposes a potential weakness that can be exploited for cancer therapy.
One gap in knowledge is whether forcing cancer cells to oxidize glucose (like normal cells) is sufficient to result in cell death. We hypothesized that small molecule activators of glucose oxidation would selectively kill cancer cells and have low toxicity to non-cancerous cells.
To test this hypothesis, we developed a cell-based screening platform to identify new small molecules that increase glucose oxidation in cancer cells. From a screen of more than 5000 compounds, we identified a lead molecule named BAM10. BAM10 increases glucose oxidation and selectively kills cancer cells. In a preliminary study, BAM10 prevented the growth of an aggressive murine melanoma in vivo. Future studies will utilize proteomics and metabolomics approaches to identify the cellular target of BAM10, and pharmacokinetic/pharmacodynamic assessments will allow further testing of BAM10 in preclinical cancer models. The long-term goal of this study is to translate our basic science findings into a clinical treatment for cancer that has low toxicity to healthy tissues.