Can targeting TSP-1 with gabapentin enhance survival in glioblastoma? A 20-year retrospective cohort study.

2048

Background: Molecularly-defined cellular subpopulations of glioblastoma secrete high levels of the synaptogenic protein thrombospondin-1 (TSP-1) which promotes functional integration of tumor into neural circuity. A greater extent of glioma-neuronal crosstalk portends worse survival for patients. In preclinical studies, gabapentin was shown to inhibit TSP-1, in turn disrupting neuronal synaptogenesis and neuronal activity-dependent glioblastoma proliferation; however, clinical survival data is lacking. We aim to determine whether treatment with gabapentin is associated with improved survival and reduced serum TSP-1 in a retrospective cohort of patients with IDH-wildtype glioblastoma. Methods: Newly-diagnosed, IDH-wildtype glioblastoma patients who received care at the UCSF Brain Tumor Center between 1997-2017 were included in this study. Kaplan-Meier curves and multivariate Cox proportional-hazards models, controlled for age, MGMT promoter methylation status, preoperative tumor volume, and extent of resection, were used for survival analyses. Differences in serum TSP-1 measured by ELISA for gabapentin treated patients and matched non-gabapentin treated controls were assessed using unpaired two-tailed student’s t-test. Control samples were matched 2:1 by age, tumor volume, and extent of resection. After 2005, patients were treated with chemoradiation with concurrent and adjuvant temodar. Results: Among 379 adult patients with glioblastoma, 36 (9.5%) were treated with gabapentin. The median daily dose of gabapentin was 600 mg (IQR: 300-900 mg). There were no significant differences between gabapentin treated and non-gabapentin treated patients by age (0.06), sex (p=0.14), or race (p=0.52). Median overall survival for gabapentin treated and non-gabapentin treated patients was 20.8 months (IQR: 11.7 - 32.1) and 14.7 months (IQR: 8.9-23.5), respectively (p= 0.02). On Kaplan-Meier survival analysis, overall survival was longer for gabapentin treated patients compared with non-gabapentin treated patients (p=0.005). In the multivariate Cox proportional-hazards model, gabapentin use was associated with decreased hazard of death (HR 0.67, p=0.030). Mean serum TSP-1 in gabapentin-treated patients was significantly lower than in the matched control group (10181 ng/ml vs 17015 ng/ml, p=0.017). Conclusions: Gabapentin use is associated with a survival benefit for patients with glioblastoma, possibly mediated through a reduction in TSP-1. This promising result lays the foundation for future prospective studies to further evaluate TSP-1 as a circulating prognostic biomarker as well as to explore the therapeutic benefits of gabapentin as a life-prolonging treatment for patients with newly diagnosed glioblastoma.