Objective This study aimed to reveal the potential function of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and emphasized its importance in brain low-grade glioma (LGG). Methods We firstly explored the differential expression of MTHFD2 mRNA in LGG and normal tissues, followed by correlation analysis of MTHFD2 mRNA expression with patient’s clinical characteristics. MTHFD2 protein expression in LGG and subcellular location were also evaluated. Then, survival analysis was performed to reveal the influence of MTHFD2 expression on the overall survival of patients, and Cox regression analysis was applied to predict the prognostic factor for overall survival of LGG. Finally, we performed functional analysis to reveal potential MTHFD2-associated pathways involved in LGG. Results We found that MTHFD2 was highly expressed in LGG patients (P<0.05), and MTHFD2 expression was related to patient’s age and IDH mutation status (all P<0.05). MTHFD2 protein was mainly localized to the mitochondria. Survival analysis showed that high expression of MTHFD2 desirably improved the prognosis of LGG patients (P<0.001), especially for those patients with age ≥45 years (P<0.05). But independent prognostic role of MTHFD2 in LGG was not observed. Pathway enrichment analysis indicated that MTHFD2 high expression significantly and positively participated in the pathway of one carbon pool by folate (all P<0.05). Conclusion High expression of MTHFD2 was observed in LGG, which was favorable for the overall survival of LGG patients. Our results assumed that MTHFD2 high expression might play a pivotal role in LGG through positively regulating pathway of one carbon pool by folate.
Background Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was found to be up-regulated in various cancers and has been identified as a potential target for cancer treatment, but the potential function of MTHFD2 in low-grade gliomas (LGG) has not been well-examined. This study initially revealed the potential function of MTHD2 and emphasized its importance in LGG. Methods We first explored the expression of MTHFD2 in LGG patients using Oncomine and UALCAN database. Survival analysis on LGG patients was then conducted based on age, gender, radiation therapy, histologic grade, tumor type and MTHFD2 expression. Cox regression analysis was also applied to predict the prognostic factor for overall survival (OS) of LGG. Finally, we performed enrichment analysis to reveal the potential MTHFD2-associated pathways involved in LGG. Results We found that MTHFD2 is highly expressed in LGG patients, and MTHFD2 expression is related with age, sub-types and TP53-mutation status (all P<0.05). Age, radiation therapy, histologic grade and tumor type were implicated in the survival of LGG patients (all P<0.05). High expression of MTHFD2 desirably improved the prognosis of LGG patients (P<0.001), especially for those patients with characteristics of age≥45 years old (P<0.001), receiving radiation therapy treatment (P=0.001), sub-type of astrocytoma and oligodendroglioma (all P<0.05), and histologic grade 3 (P<0.05). MTHFD2 was determined as an independent prognostic factor with age and grade for OS of LGG patients (all P<0.01). Pathway enrichment analysis indicated that MTHFD2 mainly participates in mTOR signaling pathway, apelin pathway and folate-mediated one-carbon metabolism.Conclusions The expression of MTHFD2 is associated with key clinical phenotype. High expression of MTHFD2 is favorable for the overall survival of LGG patients. MTHFD2 may serve as a novel prognostic biomarker and potential therapeutic target for LGG treatment.
study with AN0025 was conducted to assess safety, MTD and RP2D. AN0025 was well tolerated in 30 patients with advanced cancer at 125, 250, 500, 750 mg QD with no DLTs. The MTD was not reached. 23% of patients achieved stable disease, 5 were clinically stable for 18 weeks. 10 patients received AN0025 treatment longer than their most recent prior therapy, including 2 immunotherapy patients (Hong DS, et al. J Immunother Cancer 2020).Trial design: AN0025 and Pembrolizumab have unique mechanisms of action and safety profiles. Combination therapy may safely provide synergistic antitumor outcomes and improve retreatment with pembrolizumab. AN0025S0103 is an open-label, multicenter, phase I study to evaluate safety of AN0025 with pembrolizumab in patients with locally advanced/metastatic tumors, including Bladder, NSCLC, TNBC, Cervical, and MSS CRC. Patients have received no more than 3 prior lines of systemic therapy and have either 1) progressed on treatment with an anti-PD-1/PD-L1 and failed or are deemed inappropriate for additional standard treatments, or 2) have not received prior anti-PD-1/PD-L1 therapy and failed SOC treatment. Study includes a DLT observation phase (Ia), followed by an expansion phase (Ib), to assess AEs and safety. Pembrolizumab given 200 mg Q3W for each dose level of AN0025 (500, 250, and 125 mg QD), for a maximum of 35 cycles. In phase 1a, 12-24 patients will be enrolled, sample size determined by DLTs. In Expansion Cohorts, 10-12 patients will be enrolled in each tumor type. With 12 patients per cohort, the probability of observing 1 responder is 72% when the true underlying response rate in the cohort is as low as 10%. Secondary Endpoints include ORR, DOR, PFS OS overall and by PD-L1 abstracts Annals of OncologyVolume 32 -Issue S5 -2021 S863Trial design: In this single-arm, prospective, phase II study, 30 patients with inoperable solid tumors are enrolled. Eligible patients have measurable tumor lesions, ECOG performance score of 0-2, aged 18-75 years and the expected overall survival 3 months. Each patient receives Camrelizumab (200 mg, iv, for 2-4 times) accompanied by vascular intervention (for 2-4 times). Treatments are repeated every 28 days last for 4 cycles, followed by maintenance with Camrelizumab (200 mg, iv, q3w) and Apatinib (250 mg, QD). The treatment regimens will continue until the disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoints are safety and progress-free survival assessed by investigator according to RECIST v1.1, while the secondary endpoints contain objective response rate, disease control rate and overall survival.
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