Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling.

Malignant gliomas are the most common primary brain tumors and are associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in approximately 30% of glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the binding affinity of the free peptide ( KD = 3.96 × 10-7 M), the binding affinity of the nanoinhibitor to MET increased 3 orders of magnitude to 1.32 × 10-10 M. This nanoinhibitor efficiently reduced the proliferation and invasion of human glioblastoma U87MG cells in vitro by blocking MET signaling with remarkably attenuated levels of phosphorylated MET ( pMET) and its downstream signaling proteins, such as pAKT and pERK1/2. Although no obvious therapeutic effect was observed after treatment with free cBMP peptide, in vivo T2-weighted magnetic resonance imaging (MRI) showed a significant delay in tumor growth after intravenous injection of the nanoinhibitor. The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials. Immunoblotting studies of tumor homogenate verified that the nanoinhibitor restrained glioma growth by blocking MET downstream signaling. pMET and its downstream proteins pAKT and pERK1/2, which are involved in the survival and invasion of cancer cells, decreased in the nanoinhibitor-treated group by 44.2%, 62.2%, and 32.3%, respectively, compared with those in the control group. In summary, we developed a peptide-functionalized MET nanoinhibitor that showed extremely high binding affinity to MET and effectively inhibited glioma growth by blocking MET downstream signaling. To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling with a novel nanoinhibitor. Compared to antibodies and chemical inhibitors in clinical trials, the nanoinhibitor blocks MET signaling and provides a new approach for the treatment of glioma with the advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance.

Can preoperative computed tomography predict tissue origin of primary maxillary cancer?

Based on the histopathologic origin, malignant maxillary neoplasms may share some clinical characteristics but have different biological behavior, treatments, and prognoses. The aim of the present study was to explore the association between CT characteristics and tissue origin of primary maxillary cancer (MC). A retrospective review of CT findings was performed in patients diagnosed with MC between January 1, 2005 and December 31, 2013. Univariate and multivariable logistic regression analyses were performed to determine the association between tissue of origin and CT characteristics, with adjustment for possible confounding factors. A total of 164 patients (70 male, 94 female, age: 46.8 ±â€Š18.3 years) were included. Patients were divided into epithelial (n = 88) and nonepithelial (n = 76), or odontogenic (n = 15) and nonodontogenic (n = 149) groups. After adjusting for age, sex, smoking status, alcohol use, tumor size, and stage in the multivariable logistic regression model, the lesions with cortical bowing were found more likely to be epithelial (odds ratio [OR] = 7.0, 95% confidence interval [CI], 1.4-36.1) than nonepithelial origin, while lesions with cervical lymphadenopathy were more associated with a nonodontogenic origin (OR = 12.6, 95% CI, 1.1-140.0) rather than odontogenic. Among epithelial cancers, lesions with cortical bowing were 14 times more likely to be salivary gland-type (OR = 13.8, 95% CI, 1.3-141.5). CT characteristics of cortical bowing and cervical lymphadenopathy might be suggestive of tissue origin in MC. Larger prospective studies are warranted to further examine the association.