UC Irvine

Abstract

INTRODUCTION

MRZ is a second-generation, irreversible proteasome inhibitor currently in clinical trials for GBM. MRZ has ability to cross the BBB in animal models. CNS side-effects (including hallucinations and cerebellar ataxia) are both common adverse events. Here we report on the regional fMRI-derived functional connectivity changes associated with hallucination severity (graded using CTCAE 4.03) after MRZ treatment, administered at day 1, 8, and 15 every 28 days.

METHODS

Longitudinal resting-state fMRI whole-brain volumes (TR 2500ms, TE 20ms, flip angle = 71°, slice thickness = 3mm, gap = 0 mm, FOV 19.2 cm, matrix = 64 x 64, 51 slices, 120 volumes) were acquired on six participants at baseline (day 0) and days 1 and 15 of the treatment cycle. Preprocessing included: linear detrending, band-pass filtering, EPI signal from the white matter and CSF masks1; hand-drawn tumor masks; rigid-body realignment parameters; and motion and artifact scrubbing2 as implemented in the CONN toolbox3. Linear models were used to assess the correlations of hallucination severity and longitudinal functional connectivity changes in regions from the Harvard-Oxford atlas.

RESULTS

After one day of treatment, we found hallucination severity was associated with decreased functional connectivity between the left lingual gyrus and both the left cerebellum (T(4)=-12.78, p<0.03 FDR) and left temporal cortex (T(4)=-9.56, p<0.04 FDR). After fifteen days, the association persisted but became more prominent between the bi-lateral temporal-occipital fusiform cortex and the bi-lateral cerebellum (left: T(4)=-20.20, p<0.005 FDR; right: T(4)=-17.75, p<0.008 FDR) along with decreased local efficiency in the left lateral occipital cortex (T(4)=-11.25, p<0.05 FDR). CONCLUSIONS: Our data suggest that MRZ induce changes in functional connectivity in selected brain areas, including the optic pathways and the cerebellum, confirming MRZ ability to cross the BBB in humans. Research to determine the relation between functional connectivity and response to MRZ are ongoing.