Ten years ago, Reuben Shaw discovered that a gene altered in lung cancer could improve the wellbeing of people with diabetes, as it regulated an enzyme used in therapies against the disease. Since then, Shaw has wondered if this may be a two-way street. If cancer-altered genes could improve diabetes wellness, could drugs originally designed to treat metabolic diseases also work against cancer?
There is growing evidence that cancer and metabolism are connected, though scientists are still working to identify what tumours might be most responsive and which drugs most useful. However, in a new study, published in the journal Cancer Cell, a team of scientists at the Salk Institute for Biological Studies, led by Shaw, discovered a derivative of the widely-used diabetes drug metformin, known as phenformin, increased the survival rates of mice with lung cancer and decreased the size of their tumours. This can improve the wellbeing of almost 30% of patients with non-small cell lung cancer (NSCLC) whose tumours lack LKB1 or STK11.
What happens is that when your ATP energy levels, which you need for almost everything, run low, the KB1 gene ignites a metabolic enzyme called AMPK. Shaw has already proven that when you cells lack a normal copy of the LKB1 gene, they fail to activate AMPK in response to your low energy levels, are unable to sense metabolic stress and can’t start the process to restore their ATP levels following a metabolic change.
Because of this, Shaw and his team turned to a class of drugs called biguanides, which lower cellular energy levels by attacking the power stations of the cell, called mitochondria. Phenformin inhibits mitochondria, so the team used it as a chemotherapy agent in genetically-engineered mice lacking LKB1 and with advanced stage lung tumours. There was a modest tumour reduction after just three weeks of treatment.
Though phenformin was taken off the market in 1978 due to a high risk of lactic acid build-up in patients with compromised kidney function, this is less of an issue for cancer patients, as would be the issue of kidney toxicity because the course of treatment is much shorter, a matter in weeks to months compared to years of treatment for diabetes patients.
According to David Shackelford, a postdoctoral researcher at Salk who spearheaded the study in Shaw’s lab and is now an assistant professor at UCLA’s David Geffen School of Medicine, ‘The good news is that our work provides a basis to initiate human studies. If we can organize enough clinicians who believe in investigating phenformin then phenformin as an anti-cancer agent could be a reality in the next several years.’
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