Targeting phospholipid metabolism for glioblastoma therapy

See the article by Yi et al. in this issue pp. 387–399.

Glioblastoma (GBM) is the most commonly diagnosed and malignant primary brain tumor in adults. Despite standard treatment strategies consisting of aggressive surgical resection followed by chemotherapy and ionizing radiation or other therapeutic regimens, tumor recurrence is inevitable and prognosis in patients with GBM remains poor. Therefore, there is an urgent unmet need to identify new targets for developing effective therapeutic approaches for GBM treatments. Cancer cells rewire their metabolism to sustain both their cell growth and to adapt to harsh microenvironments. Metabolic reprogramming confers metabolic dependencies, which can be exploited for therapeutic targeting of cancer.¹ For example, lipid metabolism especially phospholipid metabolism, is significantly altered in various types of cancers, including GBM.² However, the roles and mechanisms of phospholipid remodeling in tumor cells are poorly understood.

In this issue of Neuro-Oncology, Yi et al.³ built on their previous work showing that increased expression of PTRF (polymerase 1 and transcript release factor), also known as Cavin-1, a critical factor in caveola formation, is correlated with a worse prognosis in patients with glioma.⁴ They also revealed that PTRF-remodeled phospholipid metabolism, lead to an increase in tumor cell proliferation and immune suppression in GBM. The authors demonstrated a relationship between PTRF and lipid metabolism in GBM by using nontargeted metabolomics profiling and a subsequent lipidomics analysis. To provide mechanistic insight on the role of PTRF in lipid metabolism remodeling, the authors examined the expression of several enzymes related to multiple lipid metabolic pathways and detected a significant increase in the cytoplasmic phospholipase A₂ (cPLA2) protein in GBM cells with PTRF overexpression. Furthermore, the authors showed that PTRF promoted protein stability of cPLA2, resulting in an increase of cPLA2 activity. This, in turn, increased the cells’ capacity of endocytosis and energy metabolism, boosting GBM cell proliferation and immune suppression, thus suggesting cPLA2 as an attractive therapeutic target. Indeed, a cPLA2 inhibitor, arachidonyl trifluoromethyl ketone (AACOCF₃) that inhibits PTRF-mediated phospholipid reprogramming repressed endocytosis, ATP production, and GBM cell proliferation. The authors corroborated these findings in an intracranial GBM PDX model and a mouse GBM GL261 intracranial xenograft model that overexpressed PTRF. The authors further showed that monotherapy or a combination therapy of the cPLA2 inhibitor AACOCF₃ and metformin, a drug that inhibits ATP synthesis, reduced tumor xenograft growth, and enhanced CD8⁺ tumor infiltration in GL261 brain GBM xenografts. Despite the promising preclinical data in the present study, neither AACOCF₃ nor metformin are known to effectively cross the blood-brain barrier (BBB). To establish that a combined AACOCF₃/metformin treatment strategy is clinically applicable for GBM treatment, more studies are warranted to validate that AACOCF₃ and metformin are capable of penetrating the BBB to achieve a functionally relevant therapeutic dose at the tumor site. In addition, it will be critical to determine the effects of AACOCF₃ and metformin on normal neural stem cells and astrocytes to rule out the undesirable toxicity to normal cells.

The findings of Yi et al. partially dovetail with other recent reports on PTRF and lipid metabolism.³ In melanoma,⁵ Paulitschke et al. found that downstream targets of CRISPR/Cas-derived PTRF knockouts are involved in diverse functions such as endosomal trafficking (eg, EDH2, PRKCDBP), endocytosis (eg, IGF2R, TFRC), and immune regulatory processes (eg, PRKCDBP, HLA-DRA2). The role of PTRF in lipid metabolism is further supported by evidence from the PTRF knockout mice, which display a variety of pathophysiological changes, including abnormalities of glucose and lipid metabolism, lung morphology and function, and nitric oxide expression.^6,7 Murakami et al. also reported that patients with a homozygous mutation (insertion mutation) in the PTRF gene were found to have congenital generalized lipodystrophy with muscular dystrophy.⁸

Metabolic remolding is one of the vital hallmarks of cancer, and rapidly proliferating cells depend on the uptake of nutrients, which are then directed into multiple metabolic pathways to produce energy. Lipid membrane remodeling is an important metabolic pathway to support energetic demands.⁹ Phospholipase activity is linked to lipid remodeling, such as cPLA2, and is activated in various types of human cancers, including GBM.¹⁰ The expression of cPLA2 in GBM cells is associated with cell growth and tumor response to chemotherapy.¹⁰ Therefore, inhibition of cPLA2 is an attractive target for cancer therapy. The findings of Yi et al.³ demonstrated that inhibition of cPLA2 by the inhibitor AACOCF₃ represses endocytosis, ATP production, and GBM cell proliferation. It is interesting to note that the stability and activity of cPLA2 are controlled by PTRF, whose expression is controlled by the EGFR/PI3K/AKT pathway through epigenetic regulation.⁴ Since EGFR amplification/mutation is a frequent event in GBM, it will be interesting to determine the relationship of genomic aberrations in EGFR and cPLA2 dependency. Given that monotherapies against EGFR have been disappointing and have failed to halt disease progression in patients with GBM, a rationale for combinatorial therapies to overcome the resistance to anti-EGFR therapies could be explored. As such, dual targeting of EGFR and cPLA2, which act as partners in crime for promoting tumor proliferation, represents a conceptual advancement for combinatorial therapy in GBM.

Although this study suggests multiple therapeutic targets for developing new strategies in GBM treatments, outstanding mechanistic questions still remain. For example, how does PTRF regulate caveola structure and function to stabilize cPLA2? Identification of the mediators of this pathway could provide other targets with known inhibitors that are able to cross the BBB. Lastly, it would be of great interest to investigate the underlying mechanisms of immune modulation by either AACOCF₃, metformin, or in combination within the tumor microenvironment.

Taken together, cancer metabolism is emerging as a potential target to limit GBM aggressiveness. Further understanding of the links between upstream genetic mutations and PTRF/cPLA2-mediated lipid remodeling should provide new synergistic targeting strategies for improving efficacy in treating malignant GBM.

Conflict of interest statement. None declared.