Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment

Abstract

Glioblastoma (GBM) is the most common aggressive primary brain tumor in adults, with a short survival time even after aggressive therapy. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Previous work produced such biomarkers in preclinical GBM using semi-supervised source extraction and single-slice Magnetic Resonance Spectroscopic Imaging (MRSI). Nevertheless, GBMs are heterogeneous and single-slice studies could prevent obtaining relevant information. The purpose of this work was to evaluate whether a multi-slice MRSI approach, acquiring consecutive grids across the tumor, is feasible for preclinical models and may produce additional insight into therapy response. Nosological images were analyzed pixel-by-pixel and a relative responding volume, the <i>Tumor Responding Index</i> (<i>TRI</i>), was defined to quantify response. Heterogeneous response levels were observed and treated animals were ascribed to three arbitrary predefined groups: high response (HR, <i>n</i> = 2), <i>TRI</i> = 68.2 ± 2.8%, intermediate response (IR, <i>n</i> = 6), <i>TRI</i> = 41.1 ± 4.2% and low response (LR, <i>n</i> = 2), <i>TRI</i> = 13.4 ± 14.3%, producing therapy response categorization which had not been fully registered in single-slice studies. Results agreed with the multi-slice approach being feasible and producing an inverse correlation between <i>TRI</i> and Ki67 immunostaining. Additionally, ca. 7-day oscillations of <i>TRI</i> were observed, suggesting that host immune system activation in response to treatment could contribute to the responding patterns detected.