Our new paper shows that a precision diet that promotes ferroptosis can be used to treat brain cancers
I’m excited to share a paper that just came out in Nature Communcations on our longstanding collaboration between my lab, and the labs of Peter Canoll, Jeff Bruce and other groups on diet and ferroptosis:
Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces…
Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties…
A custom diet for promoting ferroptosis in brain cancers
For many years, I have suspected that diets should be modified based on individual’s health, taking account specific disease states and therapeutic regimens.
Several years ago, Peter, Jeff, our colleagues, and I began to test whether removing two dietary amino acids would promote ferroptosis.
We knew that the amino acids cysteine and methionine are needed to make the antioxidant peptide glutathione in many cancers, so we suspected that removing these amino acids from the diet would promote ferroptosis in some cancers.
Ferroptosis is a form of cell death discovered in my lab in 2012 (and independently discovered in Marcus Conrad’s work). Here is our original paper:
Cells can be triggered to die by ferroptosis when the amount of glutathione falls below a critical threshold, because they use glutathione, along with an enzyme called GPX4 to remove damage to membranes that would otherwise promote ferroptosis.
We tested this idea in mouse and human glioma (brain cancer) cell lines — by removing cysteine and methionine from the medium in which the cells grow in the lab. Indeed, removing these two amino acids dramatically promoted ferroptosis in these cell culture conditions by depleting glutathione.
The CMD diet promotes ferroptosis
We then designed a mouse chow diet that was depleted in cysteine and methionine. We tested if this diet was well tolerated in mice, and it was — the mice could stay on this diet without any issues.
Next, we examined the effect of this diet in a mouse model of glioma — a type of brain cancer. We found that mice that develop these brain cancers actually survive longer if they are on the diet lacking cysteine and methionine. That was striking, because the mice didn’t receive any therapy other than the special diet.
Next, we tested if mice on this cysteine-and-methionine-depleted diet (which we called CMD) were also more sensitive to ferroptosis-inducing therapies. We delivered a ferroptosis-inducing compound called RSL3 into the brains of these mice that were either on a normal diet or the CMD diet. Indeed mice on the CMD diet lived longer than mice on the regular diet, when both received RSL3.
The journal PNAS did a nice writeup of our story that explains it in simple terms:
A new approach that combines diet and pharmacology
This is an exciting beginning. These results show that we can design precision-tailored diets to promote cancer therapies that act through ferroptosis. We know of a number of existing and experimental cancer therapies that trigger ferroptosis, so this paper opens up a new field of pairing the CMD diet with such therapies — radiation, sorafenib, and immunotherapy, for example.
More broadly, I am envisioning a future in which cancer patients not only receive drug therapy, but also a tailored diet specific to their cancer’s genetic and metabolic makeup. This could substantially change the way we treat cancer by harnessing metabolism in service of our therapies.