Antiangiogenic therapy with bevacizumab in recurrent malignant gliomas: analysis of the response and core pathway aberrations.
BACKGROUND
Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown promising activity in recurrent malignant gliomas. We reported the treatment response for the combination of bevacizumab and chemotherapy in a series of six patients with recurrent malignant glioma and investigated the molecular alterations in cancer pathways using the surgical biopsies from these patients.


METHODS
Standard therapy with primary resection followed by adjuvant chemoradiotherapy had failed in all patients. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks. Concomitantly, four patients received temozolomide (50 mgxm(-2)xd(-1)), one patient irinotecan (125 mg/m(2) every 2 weeks) and one patient topotecan (1.2 mgxm(-2)xd(-1)). Response to therapy was mainly determined by magnetic resonance imaging. The expression of Ras, phosphorylated mitogen activated protein kinase (p-MAPK), phosphorylated AKT (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) were semiquantitatively assessed by immunohistochemistry using surgical biopsies before the initial treatment.


RESULTS
Five of the six patients had a radiographic response. Three were complete response, and two were partial response. Only one patient had progressive disease. The 6-month progession-free survival (PFS) was 33% and the median PFS was 15 weeks, with a range of 6 to more than 60 weeks. Of the three core pathways analyzed in this study, the Ras/MAPK and phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathways were more likely to be associated with the treatment response to bevacizumab. In two younger patients (ages < 50) with complete response, simultaneous overexpression of p-MAPK, p-AKT and p-mTOR might be the crucial feature.


CONCLUSIONS
Bevacizumab in combination with chemotherapeutic agents may be an effective strategy for patients with recurrent malignant glioma. Activated MAPK and AKT might be possible biomarkers for selecting suitable patients for this targeted therapy.
Zhang
Wei
W
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
Qiu
Xiao-guang
XG
Chen
Bao-shi
BS
Li
Shou-wei
SW
Cui
Yun
Y
Ren
Huan
H
Jiang
Tao
T
D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D000068258:Bevacizumab; D000077146:Irinotecan; D002166:Camptothecin