Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.

Factors associated with survival and recurrence for patients undergoing surgery of cerebellar metastases.

OBJECTIVE: Patients with cerebellar and non-cerebellar metastases are often included in the same study population, even though posterior fossa lesions typically have different presenting symptoms, clinical outcomes, and complications. This is because the outcomes for patients with cerebellar metastases are unclear. METHODS: Adult patients who underwent surgery for an intracranial metastasis (single or multiple) between 2007 and 2011 were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify an association between cerebellar location with survival and recurrence. RESULTS: Of the 708 patients who underwent intracranial metastatic surgery, 140 (19.8%) had surgery for cerebellar metastasis. A cerebellar location was associated with poorer survival [RR (95% CI); 1.231 (1.016-1.523), P  =  0.04] and increased spinal recurrence [RR (95% CI); 2.895 (1.491-5.409), P  =  0.002], but not local (P  =  0.61) or distal recurrence (P  =  0.88). The factors independently associated with prolonged survival for patients with cerebellar metastases were: decreasing number of intracranial metastases (P  =  0.0002), decreasing tumor size (P  =  0.002), and radiation (P  =  0.0006). The factors associated with prolonged local progression free survival were: decreasing tumor size (P  =  0.0009), non small cell lung cancer (NSCLC) (P  =  0.006), non-bladder cancer (P  =  0.0005), and post-operative radiation therapy (P  =  0.02). The factors independently associated with prolonged distal progression free survival were: age > 40 years (P  =  0.02), surgical resection (P  =  0.01), and whole brain radiation (WBRT) therapy (P  =  0.02). DISCUSSION: Patients with cerebellar metastases have more distinct clinical presentations and outcomes than patients with non-cerebellar lesions. The findings of this study may help risk stratify and guide treatment regimens aimed at maximizing outcomes for patients with cerebellar metastases.