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作者：Jerry
Introduction: Heterogeneous molecular subtypes of gliomas respond differently to chemotherapy and have different prognosis. Gliomas with isocitrate dehydrogenase 1 (IDH1) mutations have a better prognosis and a more pronounced response to temozolomide (TMZ). Compared with gliomas without IDH1 mutations, IDH1-mutated gliomas increase levels of D-2-hydroxybutyrate (D-2HG) and may have a twofold effect on tumor progression. Although there are a few studies exploring the anti-glioma effect of D-2HG in combination with TMZ, there are still limited studies.
On July 9, Wang Bin's research team from Fudan University published a paper titled "IDH1-mutant metabolite D-2-hydroxyglutarate inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/ PI3K/AKT", in this study, clinical data from more than 2500 glioma patients confirmed that patients with IDH1 mutations had an enhanced response to TMZ chemotherapy and their prognosis was significantly better than that of IDH1 wild-type patients. In subsequent cell experiments, the researchers found that the metabolite D-2HG produced by the IDH1 mutation inhibited the expression of the integrin subunit β4 (ITGB4) and reduced the phosphorylation levels of PI3K and AKT, ultimately inhibiting cell proliferation and promoting apoptosis, thereby improving glioma prognosis. In addition, the investigators also demonstrated the synergistic effects of D-2HG and TMZ in antiglioma treatment, including inhibiting glioma cell proliferation and promoting apoptosis. Finally, by integrating the data of CGGA and TCGA databases, it was verified that patients with low ITGB4 expression and low ITGB4 expression in IDH1-mutant gliomas had a better prognosis. These findings suggest that ITGB4 may be a promising target for the treatment of glioma, with D-2HG inhibiting glioma cell proliferation and making it sensitive to TMZ by downregulating ITGB4/PI3K/AKT. These findings have promoted theoretical innovation and research progress in glioma treatment.
https://www.nature.com/articles/s41420-024-02088-y
Background
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Glioma is a highly fatal central nervous system tumor with an extremely poor prognosis, with a recurrence rate of up to 90%, of which 80% occur within 2 cm of the primary tumor. At present, the main clinical treatment for glioma is surgical intervention, supplemented by adjuvant radiotherapy and chemotherapy. Despite the emergence of innovative therapies such as targeted therapy, immunotherapy, and electric field therapy, their efficacy remains limited. The latest classification of the World Health Organization divides adult gliomas into two broad categories: IDH1 wild-type and IDH1-mutant. Patients with IDH1-mutant gliomas generally respond better to temozolomide (TMZ) chemotherapy and have a significantly better prognosis than patients with IDH1 wild-type tumors.
While current evidence suggests that IDH1 mutations catalyze the conversion of α-ketoglutarate (α-KG) to D-2-hydroxybutyric acid (D-2HG), this is associated with a unique pattern of cancer metabolism and signaling pathways, leading to malignant transformation, progression, and drug resistance. However, clinical studies have shown that patients with IDH1 mutations have a significantly better clinical prognosis than those with wild-type glioma (median overall survival: 3.8 years vs. 1.1 years). In addition, higher levels of D-2HG (above 1.489 mmol) were associated with prolonged median overall survival (OS) in patients with brain tumors (not detected vs. 2.2 years). In addition, D-2HG has been shown to exert anticancer effects on leukemia by modulating the FTO/m6A/MYC/CEBPA pathway and the FTO/m6A/PFKP/LDHB axis. An experimental study showed that IDH1 mutations and D-2HG can induce oxidative stress, autophagy, and apoptosis in glioma cells. Based on these observations, the investigators speculated that D-2HG itself may have anti-glioma properties and may enhance the anti-tumor effects of TMZ through synergistic mechanisms.
D-2HG works synergistically with TMZ to inhibit the proliferation and migration of glioma cells
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After 48 hours of treatment with U251 cells at 500 μM D-2HG, 500 μM TMZ, and 500 μM D-2HG + 500 μM TMZ, the number of cells decreased compared to the control group, with the most significant reduction in the combination treatment group. In addition, cell proliferation EdU staining showed that the combined effect of D-2HG and TMZ significantly inhibited cell proliferation more than D-2HG or TMZ alone. The quantitative results of EdU staining are shown in Figure S3B. In addition, the researchers observed that D-2HG increased G1 phase cells and decreased G2 phase cells. In contrast, TMZ and TMZ+D-2HG reduced G1 phase cells and increased S phase and G2 phase cells. Notably, the combined effect of D-2HG and TMZ significantly increased S-phase cells, compared to treatment with D-2HG or TMZ alone. In addition, scratch experiments showed that the control group exhibited the highest migration capacity, with mobility rates of 48% and 72% at 24 and 48 hours, respectively. D-2HG potently inhibits cell migration, with migration rates of 20% and 35% at 24 and 48 hours, respectively. In contrast, the migration rates after TMZ treatment were 35% and 52% at 24 and 48 hours, respectively. When D-2HG and TMZ were combined, cell migration was significantly inhibited, reaching 11% at 24 h and 17% at 48 h. Studies have shown that the combination of D-2HG with TMZ is more effective in inhibiting the proliferation and migration of glioma cells than either drug alone, suggesting that combination therapy is more effective against glioma.
D-2HG can enhance the antiproliferative effect of TMZ
Summary of the study
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In summary, this study is based on the clinical data of more than 2500 glioma patients, which confirmed that the prognosis of patients with IDH1 mutant glioma is better than that of IDH1 wild-type patients, and they have higher sensitivity to TMZ. For the first time, cell experiments revealed that D-2HG, a byproduct produced by IDH1 mutations, can effectively inhibit the ITGB4/PI3K/AKT pathway, resulting in a potent anti-glioma effect, and provide new insights into its mechanism of action, including its synergistic effect with TMZ. In addition, this study provides a plausible molecular explanation for the improvement of the prognosis of IDH1-mutant glioma and its enhanced response to TMZ. In addition, the findings of this study suggest that ITGB4 is a promising therapeutic target for glioma, laying the foundation for the development of D-2HG as a potential anti-glioma therapeutic agent. Currently, investigators are using glioma xenograft models for further in vivo antiglioma efficacy assessments.
Resources:
https://www.nature.com/articles/s41420-024-02088-y
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