Targeting glutamine addiction in meningioma

Meningioma, which arises from the arachnoid layer of the meninges, is the most common type of primary intracranial neoplasm.¹ Meningiomas are classified into WHO histological grades: grade 1 tumors (around 80% total) are considered slow-growing and benign, grade 2 tumors are atypical (around 18%) and the rest of the cases are anaplastic (grade 3).¹ Even though most of the tumors are considered benign, they may still impact brain structures, severely reduce the quality of life, and even be lethal. Standard of care for symptomatic meningiomas is maximum safe resection, followed by radiotherapy for atypical and anaplastic lesions.² Prognosis for patients with higher-grade meningiomas are poor, recurrence is common, and 5-year survival rates are low. Chemotherapies for meningiomas are not available and clinical trial results with a number of chemotherapy agents have been inconsistent and disappointing,³ which represent a major challenge for patient treatment and care.

In this issue of Neuro-Oncology, Ijare et al show the potential for glutaminase (GLS) inhibitors as therapeutic candidates for meningioma.⁴ Using ¹H NMR spectroscopy on surgically resected tumors, they found elevated levels of several nonessential amino acids, including alanine, lactate, glutamate, glutamine, and glycine, in grade II meningioma. In both grade I and II meningiomas, glutamine was shown by ¹³C/¹⁵N tracing to be actively utilized as a carbon and nitrogen source for biosynthesis of intermediates that are essential to tumor cell proliferation, such as alanine and proline. Glutamine metabolism, therefore, might play a key role in tumor growth in the hypoxic condition. Targeting glutamine metabolic pathways, as reported in this study by using the GLS1 inhibitor CB-839 (Telaglenastat), led to decreased meningioma cell proliferation.

This study is in line with other recent reports on targeting glutamine addiction and GLS dependence in cancers. While this is the first comprehensive study on the role of glutamine and its related metabolite in meningiomas, CB-839 has been being tested extensively in phase I/II clinical trials for triple-negative breast cancer, renal cell carcinoma, colorectal cancer, and others, as both a monotherapy and in combination with other standard chemotherapies.⁵ In breast cancer, Grinde et al reported that glutamine to proline conversion, shown to be prominent in meningiomas in this study, was a marker for tumors responsive to GLS inhibition.⁶ Rashmi et al found that CB-839 was a radiosensitizer for radioresistant cervical cancer cells in vitro and in vivo via thiol-mediated oxidative stress, with PI3K pathway mutations as a predictive biomarker.⁷ A similar observation was made in lung tumor cells and xenografts in which response to radiation was increased by up to 30% with GLS inhibition.⁸ Since radiotherapy is currently the only nonsurgical treatment for meningioma, this suggests a potential for the addition of GLS inhibitors to improve the standard of care for patients.

It should be noted that further preclinical and clinical studies are required to make the case for GLS inhibitors as targeted therapy in meningioma. This is complicated by the lack of low-grade in vivo models for the disease. Furthermore, the complexity, plasticity, and redundancy of metabolism mean that tumors may adapt and evade therapy. The anaplerotic role of glutamine can be substituted by other pathways and GLS inhibition can be rescued by exogenous metabolites, upregulation of alternative supply pathways for the TCA cycles or increased expression of liver-type GLS.⁵ Drug combination strategies may be necessary to maximize the efficacy of GLS inhibitors in meningioma.

In summary, glutamine metabolism is an emerging target for meningioma therapies, particularly for grade 1 tumors. An effective treatment strategy involving GLS inhibitors may help improve survival and quality of life for meningioma patients.