DDIS-20. FASN INHIBITION AS A POTENTIAL TREATMENT TO PREVENT METABOLIC ADAPTATION IN GBM

Abstract

Response to antiangiogenic therapy (ie bevacizumab) in glioblastoma is mostly transient and without proven survival benefit. Acquired resistance to antiangiogenics is felt to be substantially driven by the hypoxic microenvironment. Tumor and matching sera from 12 patients having failed bevacizumab was performed by LCMS and NMR. Patient derived GBM neurosphere cultures were established using previously described methods and exposed to fatty acid synthase (FASN) inhibitor TVB-3166 at varying concentration in the presence of 20% or 2% oxygen. Evaluation of metabolic profiles from serum and tumor showed significant changes of number of fatty acids (including tricosanoic acid, carboceric acid, phosphatidylinositol 20:4, nonacosanoic acid, n-palmitoyl valine, ceramide 18:1/12:20), which was correlated with degree of hypoxic change. Continuous incubation in the presence of 200–800 nM TVB-3166 for 7–14 days leads to dose dependent inhibition of neurospheres formation and tumor cell death of patient derived GBM short term cultures. Given these findings, a pilot phase 2 study which evaluate the potential effectiveness and safety of TVB-2640 in combination with bevacizumab for patients with relapsed high-grade glioblastoma. This study will include an exploratory phase where patients will be randomized to either antiangiogenic therapy alone with bevacizumab, or the combination of bevacizumab and TVB-2640 for the first 28 days followed serum sampling and MRI. Fatty acid synthase inhibition is a potential strategy to overcome metabolic adaptation to antiangiogenics which will be explored in a recently initiated phase 2 study.