Integration of MRI and MRS approaches to monitor molecular imaging and metabolomic effects of trabectedin on a preclinical ovarian cancer model

Abstract

Although several drugs are available to treat recurrences of human epithelial ovarian cancer (EOC), clinical responses often remain short lived and lead to only marginal improvements in patients' survival. One of the new drugs proposed for recurrent platinum-resistant EOC patients is trabectedin (Trab), a marine-derived antitumor agent initially isolated from the tunicate Ecteinascidia turbinata and currently produced synthetically. Predictive biomarkers of therapy response to this drug and the potential use of non-invasive functional MRI and MRS approaches for an early assessment of Trab efficacy have not yet been evaluated, although they might be relevant for improving the clinical management of EOC patients. In the present work we combined functional and spectroscopic magnetic resonance technologies, such as in vivo diffusion-weighted MRI and 1 H MRS, with ex vivo high resolution MRS (HR-MRS) metabolomic analyses, with the aim of identifying new pharmacodynamic markers of Trab effectiveness on well characterized, highly aggressive human SKOV3.ip (a HER2-enriched cell variant derived from SKOV3 cells) EOC xenografts. In vivo treatment with Trab (three consecutive weekly 0.2 mg/kg i.v. injections) resulted in the following: (1) a significant reduction of in vivo tumor growth, along with the formation in cancer lesions of diffuse hyper-intense areas detected by T 2 -weighted MRI and attributed to necrosis, in agreement with histopathology findings; (2) significant increases in the apparent diffusion coefficient mean and median values versus saline-treated control tumors; and (3) a significant reduction in the cholinecontaining metabolites' signal detected by quantitative in vivo MRS. Multivariate and quantitative HR-MRS analyses on ex vivo tissue samples revealed Trab-induced alterations in phospholipid and glucose metabolism identified as a decrease in phosphocholine and an increase in lactate. Collectively, these data identify Trab-

Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

“…After phase separation by centrifugation at 20,000 g at 4 C for 30 min, the polar water-methanol phase containing water soluble cellular metabolites was evaporated using a rotary evaporator and then lyophilized, while the organic phase (lipid phase) was evaporated under nitrogen gas. Both phases of cell extracts were stored at À20 C. High-resolution 1 H NMR analyses were performed at 25 C at 400 MHz (9.4 T Bruker AVANCE spectrometer, Karlsruhe, Germany) on aqueous and organic cell extracts using acquisition pulses, water presaturation, data processing and peak area deconvolution as previously described (Canese et al, 2019;Iorio et al, 2010). Quantification of individual metabolites was obtained from peak areas applying the correction factors determined by experiments at the equilibrium of magnetization (90o pulses, 30.00 s interpulse delay).…”

Peptide-Based Soft Hydrogels Modified with Gadolinium Complexes as MRI Contrast Agents

“…Magnetic resonance imaging (MRI) is a diagnostic imaging technique currently used in clinic routine for a wide range of pathological conditions [1][2][3]. This technique is able to provide very well resolved images of the body, which are generated by signals related to the relaxation of water hydrogen nuclei excited by magnetic fields.…”

Impact of Cold Ischemia on the Stability of 1H-MRS-Detected Metabolic Profiles of Ovarian Cancer Specimens

“…For both types of experiments ( 1 H-MRS and HR-MAS 1 H-MRS), spectral assignments were based on literature data, and comparative analyses were carried out on spectra obtained from tissue extracts. , …”