protein

Scientists find cancer drug could help type 2 diabetics as new protein link is found

by Barbara Hewitt on September 17, 2013

A molecular pathway, or a series of interactions among proteins, has been identified in the development of diabetes in two scientific studies.

Scientists have found that a drug already approved for the treatment of cancer has beneficial effects and could be used to regulate this pathway. Studies carried out by researchers at the Stanford University School of Medicine have led scientists to believe that the drug also has the potential be helpful for people with type 2 diabetes.

diabetesproteinlink

Proteins could be targeted for the development of new diabetes therapies.

They identified a previously unexpected link between a low oxygen condition called hypoxia and the ability of cells in the liver to respond to insulin. The drug aflibercept, marketed as Eylea or Zaltrap, is used to treat metastatic colorectal cancer and a form of macular degeneration. Aflibercept is a member of a family of proteins that inhibit the vascular endothelial growth factor, or VEGF, pathway. It works by blocking the growth of the blood vessels into tumours and starving them of oxygen.

The researchers identified a series of protein interactions that link VEGF inhibitors and blood glucose levels. ‘We were surprised to find that this drug currently used in patients for cancer treatment had beneficial effects on diabetes in laboratory mice and could, potentially, in humans,’  said Dr Calvin Kuo, professor of medicine at Stanford School of Medicine.

The Giaccia Lab at the Stanford School of Medicine identified a protein called PHD3 that could be a particularly attractive target. ‘Proteins involved in this pathway could also be targeted for the development of new diabetes therapies,’ said Amato Giaccia, professor and director of radiation oncology.

Together, the studies explain an observation made several years ago by Kuo and his team that VEGF inhibitors, such as aflibercept, could lower blood glucose levels in mice. There have been intriguing hints that these inhibitors could function in a similar way in humans, but human studies have not been formally conducted.

‘Anecdotally, there have been reports that diabetic patients who have been prescribed VEGF inhibitors to treat their cancer are better able to control their diabetes,’ Kuo said.

‘Much work remains to translate these studies to human patients, but it will be interesting to explore VEGF inhibitors or drugs that can stabilize HIF-2alpha, such as prolyl hydroxylase inhibitors, for diabetes treatment, possibly in combination with pre-existing therapies to minimize toxicities,’ Kuo explained.

Researchers also found that blocking the expression of a protein called PHD3 specifically taps into the pathway identified by the Kuo group, stabilizing the HIF-2alpha protein and prolonging its effect on IRS2 expression. Laboratory mice missing Phd3 are more sensitive to insulin and exhibit improved glucose tolerance.

The specificity of the effect of PHD3 on HIF-2alpha is important. Because it doesn’t appear to regulate other proteins in the HIF family in the liver, it’s possible a diabetes treatment could be designed that would avoid unwanted or dangerous side effects that could occur by blocking the production of a more broadly acting protein.

‘Targeting the PHD3/HIF-2 pathway represents a new therapeutic approach for the treatment of diabetes with little toxicity. These studies indicate that PHD specific inhibitors, especially PHD3, should be more widely developed for clinical development,’ said Giaccia.

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