apatinib and Glioma

Malignant glioma is the most common primary malignant brain tumor that displays high vascularity, making vascular endothelial growth factor receptors become promising targets. This study was conducted to evaluate the efficacy and safety of apatinib, a new potent oral small-molecule tyrosine kinase inhibitor targeted vascular endothelial growth factor receptor 2, combined with irinotecan, in patients with recurrent malignant glioma.. Ten patients with recurrent malignant glioma who were experiencing relapse after treatment of temozolomide were enrolled in this study. They received oral apatinib (500 mg qd) in conjunction with irinotecan (340 mg/m or 125 mg/m depending on use of enzyme-inducing antiepileptic drugs) for 6 cycles. After that the patients continued to take apatinib as maintenance. Dosage adjustment occurred in only 3 (30.0%) patients.. Among the 10 patients, 9 were available for the efficacy evaluation. There were 5 with partial response, 2 with stable disease and 2 with progressive disease. The objective response rate and the disease control rate (DCR) were 55% (5/9) and 78% (7/9), respectively. The median progress free survival time was 8.3 months. As for safety analysis, the most 3 common adverse events were gastrointestinal reaction (31.8%), hypertension (22.7%), and myelosuppression (18.0%).. Apatinib combined with irinotecan seems to be a promising therapeutic option for recurrent malignant glioma patients. Perspective clinical studies with adequate sample size are required to validate our results.. NCT02848794 /Ahead-BG306.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Glioma; Humans; Irinotecan; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Pilot Projects; Pyridines; Treatment Outcome

Glioma is a common tumor that originated from the brain, and molecular targeted therapy is one of the important treatment modalities of glioma. Apatinib is a small-molecule tyrosine kinase inhibitor, which is widely used for the treatment of glioma. However, the underlying molecular mechanism has remained elusive. Recently, emerging evidence has proved the remarkable anticancer effects of ferroptosis. In this study, a new ferroptosis-related mechanism of apatinib inhibiting proliferation of glioma cells was investigated, which facilitated further study on inhibitory effects of apatinib on cancer cells.. Human glioma U251 and U87 cell lines and normal astrocytes were treated with apatinib. Ferroptosis, cell cycle, apoptosis, and proliferation were determined. A nude mouse xenograft model was constructed, and tumor growth rate was detected. Tumor tissues were collected to estimate ferroptosis levels and to identify the relevant pathways after treatment with apatinib.. Treatment with apatinib could induce loss of cell viability of glioma cells, but not of normal astrocytes, through eliciting ferroptosis in vitro and in vivo. It was also revealed that apatinib triggered ferroptosis of glioma cells via inhibiting the activation of nuclear factor erythroid 2-related factor 2/vascular endothelial growth factor receptor 2 (Nrf2/VEFGR2) pathway. The overexpression of Nrf2 rescued the therapeutic effects of apatinib.. Our study proved that treatment with apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Ferroptosis; Glioma; Humans; Kelch-Like ECH-Associated Protein 1; Mice; NF-E2-Related Factor 2; Pyridines; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

We determined the antitumor mechanism of apatinib in glioma using a patient-derived orthotopic xenograft (PDOX) glioma mouse model and glioblastoma (GBM) cell lines. The PDOX mouse model was established using tumor tissues from two glioma patients via single-cell injections. Sixteen mice were successfully modeled and randomly divided into two equal groups (n = 8/group): apatinib and normal control. Survival analysis and in vivo imaging was performed to determine the effect of apatinib on glioma proliferation in vivo. Candidate genes in GBM cells that may be affected by apatinib treatment were screened using RNA-sequencing coupled with quantitative mass spectrometry, data mining of The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases, and immunohistochemistry analysis of clinical high-grade glioma pathology samples. Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and co-immunoprecipitation (co-IP) were performed to assess gene expression and the apatinib-mediated effect on glioma cell malignancy. Apatinib inhibited the proliferation and malignancy of glioma cells in vivo and in vitro. Thrombospondin 1 (THBS1) was identified as a potential target of apatinib that lead to inhibited glioma cell proliferation. Apatinib-mediated THBS1 downregulation in glioma cells was confirmed by qPCR and western blotting. Co-IP and mass spectrometry analysis revealed that THBS1 could interact with myosin heavy chain 9 (MYH9) in glioma cells. Simultaneous THBS1 overexpression and MYH9 knockdown suppressed glioma cell invasion and migration. These data suggest that apatinib targets THBS1 in glioma cells, potentially via MYH9, to inhibit glioma cell malignancy and may provide novel targets for glioma therapy.

Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Glioma; Humans; Inhibitory Concentration 50; Mice, Nude; Models, Biological; Myosin Heavy Chains; Neoplasm Invasiveness; Protein Binding; Pyridines; RNA, Messenger; Signal Transduction; Thrombospondin 1; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Recurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma.. From the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%).. Apatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Brain Neoplasms; Drug Therapy, Combination; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Pyridines; Quality of Life; Survival Rate; Temozolomide; Treatment Outcome

Despite the approval of antiangiogenic therapy for high grade glioma (HGG) patients, survival benefits are still limited. New treatment plans have always been developed to improve the survival.. A 26-year-old woman was admitted to our hospital for distending pain of head and eye.. Resonance imaging (MRI) revealed a large spherical heterogeneously enhancing, mixed cystic and solid mass in the right frontal region, and the midline shifted.. The patient received apatinib therapy for positive vascular endothelial growth factor.. A partial response was observed after 4 weeks and remains sustained until now.. It suggests that apatinib might be a feasible option for the treatment in advanced HGG patients or patients with poor physical condition.

Topics: Adult; Antineoplastic Agents; Brain Neoplasms; Female; Frontal Lobe; Glioma; Humans; Magnetic Resonance Imaging; Neoplasm Grading; Neoplasm Recurrence, Local; Pyridines; Vascular Endothelial Growth Factor A