A ketogenic (high-fat, adequate-protein, low-carbohydrate) diet can, in combination with pharmaceutical approaches, improve the effectiveness of the anti-cancer drugs known as PI3K inhibitors, a study in mice published online in Nature this week suggests.
Although further research is needed to determine whether these results can be translated to the clinic, the study indicates that strategies combining dietary modifications with targeted therapy could potentially be explored to improve responses.
Several inhibitors have been developed to target mutations in PI3K, which are known to drive cancer. PI3K regulates glucose metabolism and inhibitors can thus lead to hyperglycaemia (high blood sugar) and increased insulin levels.
This effect is usually transient, but can be prolonged in patients with any degree of insulin resistance.
In these cases, therapy is discontinued because insulin is a stimulator of PI3K signalling in tumours and can affect cancer progression.
Lewis Cantley and colleagues show, in several mouse models, that glucose‒insulin feedback can reactivate PI3K signalling in tumours during therapy, potentially compromising the anti-tumour effects of the inhibitors.
They demonstrate that this insulin feedback can be prevented using dietary or pharmaceutical approaches, increasing the efficacy of the inhibitors.
In particular, mice placed on a ketogenic diet — which depletes glycogen stores in the liver, limiting glucose release after PI3K inhibition — experienced lower insulin levels after treatment with PI3K inhibitors, resulting in tumour shrinkage in various mouse tumour models.
Ketogenic diet alone was shown to have variable effects in different tumour models in mice, suggesting that these dietary changes alone were insufficient to cause the therapeutic responses that were observed across the mouse models.
In mouse models of acute myeloid leukaemia, for example, a ketogenic diet alone accelerated disease progression, suggesting that this diet may be detrimental for some patients with cancer when used in isolation.