Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma

Objective:O6 methylguanine-DNA methyltransferase(MGMT)promoter methylation is a biomarker widely used to predict the sensitivity of IDH-wildtype glioblastoma to temozolomide therapy.Given that the IDH status has critical effects on the survival and epigenetic features of glioblastoma,we aimed to assess the role of MGMT promoter methylation in IDH-mutant glioblastoma.Methods:This study included 187 IDH-mutant glioblastomas and used 173 IDH-wildtype glioblastomas for comparison.KaplanMeier curves and multivariate Cox regression were used to study the predictive effects.Results:Compared with IDH-wildtype glioblastomas,IDH-mutant glioblastomas showed significantly higher(P<0.0001)MGMT promoter methylation.We demonstrated that MGMT promoter methylation status,as determined by a high cutoff value(≥30%)in pyrosequencing,could be used to significantly stratify the survival of 50 IDH-mutant glioblastomas receiving temozolomide therapy(cohort A);this result was validated in another cohort of 25 IDH-mutant glioblastomas(cohort B).The median progression-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases,and 18.37 and 41.61 months for methylated cases,and in cohort B were 6.97 and 9.10 months for unmethylated cases,and 23.40 and 26.40 months for methylated cases.In addition,we confirmed that the MGMT promoter methylation was significantly(P=0.0001)correlated with longer OS in IDH-mutant patients with GBM,independently of age,gender distribution,tumor type(primary or recurrent/secondary),and the extent of resection.Conclusions:MGMT promoter methylation has predictive value in IDH-mutant glioblastoma,but its cutoff value should be higher than that for IDH-wildtype glioblastoma.

Evolution-driven crosstalk between glioblastoma and the tumor microenvironment

Glioblastoma(GBM)is a malignant adult brain tumor for which 90%of patients experience recurrence within a year after surgery1.Evolution confers treatment resistance capabilities on tumors2.The diversification of malignant and non-malignant(i.e.,stromal and immune cell)compartments in the tumor microenvironment(TME)during tumor evolution3-7 eventually results in the formation of a complex interaction network that promotes tumor progression.

削弱自己的贸易壁垒

美国总统奥巴马2009年在上海演讲时提到大幅增长的中美贸易额，到2008年已经上升到4000亿美元，贸易增长对中美关系有重要意义。

Role of the tumor microenvironment in shaping IDH-wildtype glioma plasticity,and potential therapeutic strategies

Diffuse glioma is the most common primary malignant brain tumor in adults.Currently,the prognosis of glioma remains dismal,and almost all patients with glioma experience recurrence even after comprehensive treatment including maximal surgical resection,radiotherapy,and/or chemotherapy1.Gliomas can be stratified according to their IDH mutation status.As we have previously reported2,3,the genetic characteristics,pathogenesis,and chemotherapy response are distinct between IDH-mutant and IDH-wildtype tumors.For instance,IDH-wildtype tumors are associated with poor prognosis and frequently have genomic alterations,including a gain of chromosome 7 and loss of chromosome 10.IDHmutant tumors often show findings including CpG island hypermethylation and MET alterations.

Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors.Although instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance mechanisms.Furthermore,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less understood.However,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance.In this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented processes.This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen masking.Such type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell type.However,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol metabolism.Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities.Together,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

PTPRZ1-METFUsion GENe(ZM-FUGEN)trial:study protocol for a multicentric,randomized,open-label phase II/III trial

Background PTPRZ1-MET fusion was reported to associate with glioma progression from low-grade to high-grade glioma,which was a target by a MET inhibitor vebreltinib.However,little is known about the further efficacy of vebreltinib among more glioma patients.This trial aims to evaluate the safety and efficacy of vebreltinib enteric-coated capsules in the treatment of sGBM/IDH mutant glioblastoma patients with the ZM fusion gene.Methods This multicentric,randomized,open-label,controlled trial plans to include 19 neurosurgical centers and recruit 84 sGBM or IDH mutant glioblastoma patients with the ZM fusion gene.This trial enrolls sGBM or IDH mutant glioblastoma patients with the inclusion criteria and without the exclusion criteria.It was registered with chinadrugtrials.org.cn(CTR20181664).The primary efficacy endpoint is overall survival(OS).The secondary endpoints are progression-free survival(PFS)and objective response rate(ORR).Discussion If proven effective,this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors.Trial registration It was registered with chinadrugtrials.org.cn(CTR20181664).

Long-term adjuvant administration of temozolomide impacts serum ions concentration in high-grade glioma

Background:Adjuvant temozolomide(TMZ)chemotherapy with standard regimen remarkably improves survival in patients with high-grade glioma(HGG).However,the influence of long-term TMZ chemotherapy on serum ions concentration is unclear.Methods:One hundred and thirty-eight patients with HGG were included.Their blood samples were collected for blood biochemistry and routine test.The alteration in serum ions concentration,total protein,albumin,globin,and blood cells counts were used to identify the impact of long-term TMZ chemotherapy.Results:Through the comparation of quantitative value of diverse parameters among different chemotherapy cycles,we identified that serum potassium concentration had a downward trend after TMZ administration(1st vs.6th,p<0.001;1st vs.12th,p<0.001).Additionally,the correlation analysis showed that platelets was negatively correlated with chemotherapy cycles(r=−0.649,p=0.023).The hematological adverse events mainly centered on grade 1 to 2.Conclusion:Long-term administration of TMZ may lead to serum ions disturbance.Besides the myelosuppression,we should pay attention to the alteration in serum ions concentration,and give patients proper symptomatic treatment when necessary.

Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma

Background Metabolism reprogramming plays a vital role in glioblastoma(GBM)progression and recurrence by producing enough energy for highly proliferating tumor cells.In addition,metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms.Epidermal growth factor receptor(EGFR)amplification and EGFR-vIII mutation are often detected in GBM cells,contributing to the malignant behavior.This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.Methods Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis.A metabolism-associated RTK-fatty acid-gene signature was constructed and verified.MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism.Energy metabolism in GBM with activated EGFR pathway was monitored.The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide(TMZ)was analyzed by an intracranial tumor model in vivo.Results GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels,supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples.Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production.Mechanistically,the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3(ACSS3),acyl-CoA synthetase long-chain family member 3(ACSL3),and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2(ELOVL2)in an NF-κB-dependent manner.Moreover,inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes,thereby affecting the signal transduction of the EGFR/AKT pathway.Therefore,targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.Conclusions Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

A novel gene signature based on five immune checkpoint genes predicts the survival of glioma

Background:Glioma is the most common and fatal type of nerve neoplasm in the central nervous system.Several biomarkers have been considered for prognosis prediction,which is not accurate enough.We aimed to carry out a gene signature related to the expression of immune checkpoints which was enough for its performance in prediction.Methods:Gene expression of immune checkpoints in TGGA database was filtrated.The 5 selected genes underwent verification by COX and Lasso-COX regression.Next,the selected genes were included to build a novel signature for further analysis.Results:Patients were sub-grouped into high and low risk according to the novel signature.Immune response,clinicopathologic characters,and survival showed significant differences between those 2 groups.Terms including“naive,”“effector,”and“IL-4”were screened out by GSEA.The results showed strong relevance between the signature and immune response.Conclusions:We constructed a gene signature with 5 immune checkpoints.The signature predicted survival effectively.The novel signature performed more functional than previous biomarkers.

Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.