Notes from the Lab: Leveraging a Dietary Approach to Improve Glioblastoma Survival

The Gabriele Bartoli Brain Tumor Laboratory

We are a multidisciplinary group of researchers and clinicians — led by Jeffrey N. Bruce, MD and Peter D. Canoll, MD, PhD — dedicated to the care of patients with brain tumors, primarily glioblastoma, the most common and aggressive malignant primary brain tumor. Our lab studies the cellular and molecular mechanisms of gliomagenesis, immune responses to brain tumors, and the development of therapies for brain tumor patients.

The Research

“Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism,” published in Nature Communications.

The cancer problem we are solving

Currently, the median length of survival after a glioblastoma diagnosis is only 16 months, which is devastating for patients and their loved ones. Brain tumors in general are hard to treat. Surgeons must be careful not to damage healthy brain tissue when removing the tumor and cannot remove a large margin. In addition, the blood-brain barrier — a semi-permeable membrane that keeps unwanted substances out of the brain — prevents many drugs from reaching the tumor.

Another issue that affects glioblastoma along with other types of cancer is the treatment of quiescent, or slowly proliferating, cancer cells. Both chemotherapy and radiotherapy generally target actively proliferating cells. Surviving quiescent cells may re-proliferate at a later point, leading to progression and relapse.

A bit of background

Several years ago, we began a collaboration with the Stockwell Lab, which discovered a new type of iron-dependent cell death called ferroptosis in 2012. Our joint experiments demonstrated that ferroptosis-inducing drugs are particularly effective at killing quiescent cancer cells.

Ferroptosis starts with the failure of glutathione-dependent antioxidant defenses, leading to unchecked lipid peroxidation, and eventual cell death. Therefore, we wondered whether dietary restriction of cysteine and methionine — both essential components of glutathione — would render tumor cells more sensitive to ferroptosis.

Also, our lab has recently tested an implantable pump system in five patients with recurrent glioblastoma, finding that it effectively bypasses the blood-brain barrier to deliver drugs to tumor cells. The results of the phase 1 trial, published in November of last year, suggest that this new approach may offer a safe way to treat patients with brain cancer.

In this current study, we combined these three approaches — a ferroptosis-inducing drug, dietary restriction, and the implantable pump — in a mouse model of glioblastoma to see whether it might be a feasible approach for humans.

What this new research uncovers

We found that treating mice with a methionine-restricted, cysteine-depleted diet was safe and decreased glutathione levels in vivo. The intervention improved therapeutic response to RSL3, a ferroptosis-inducing drug, as well as survival in a mouse model of glioma. The diet appears to alter the lipid composition of tumors to create a pro-ferroptotic environment.

Compared to controls, co-treatment with a methionine-restricted, cysteine-depleted diet and local delivery of RSL3 through an implantable pump led to robust survival improvement. These results support using dietary restriction as a non-invasive method for improving the efficacy of ferroptotic treatments and survival of glioma patients.

Next steps

This dietary strategy is the first of its kind that opens up a whole new approach to cancer treatment. We plan to investigate this treatment combination in clinical trials to determine the effects of cysteine and methionine deprivation on the brain tumor microenvironment and assess whether it would be therapeutically actionable.