Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors Through Longitudinal In Vitro Sampling

Mariangela Morelli
* ORCID logo ,
Francesca Lessi
ORCID logo ,
Sara Franceschi
ORCID logo ,
Gianmarco Ferri
,
Manuel Giacomarra
,
Michele Menicagli
,
Carlo Gambacciani
,
Francesco Pieri
,
Francesco Pasqualetti
,
Nicola Montemurro
ORCID logo ,
Paolo Aretini
ORCID logo ,
Orazio Santo Santonocito
,
Anna Luisa Di Stefano
,
Chiara Maria Mazzanti
ORCID logo
Version 1 : Received: 7 February 2024 / Approved: 8 February 2024 / Online: 8 February 2024 (14:13:16 CET)

A peer-reviewed article of this Preprint also exists.

Morelli, M.; Lessi, F.; Franceschi, S.; Ferri, G.; Giacomarra, M.; Menicagli, M.; Gambacciani, C.; Pieri, F.; Pasqualetti, F.; Montemurro, N.; Aretini, P.; Santonocito, O.S.; Di Stefano, A.L.; Mazzanti, C.M. Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors through Longitudinal In Vitro Sampling. Cells 2024, 13, 487. Morelli, M.; Lessi, F.; Franceschi, S.; Ferri, G.; Giacomarra, M.; Menicagli, M.; Gambacciani, C.; Pieri, F.; Pasqualetti, F.; Montemurro, N.; Aretini, P.; Santonocito, O.S.; Di Stefano, A.L.; Mazzanti, C.M. Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors through Longitudinal In Vitro Sampling. Cells 2024, 13, 487.

Abstract

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like te-mozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glio-blastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. 3D glioblastoma organoids (GB-EXPs) obtained from 18 patients’ resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NR). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n=9) and 77% (n=20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp be-ing REGO-NR. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO com-pared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal ex-ploration of the molecular changes induced by treatment, unveiling promising biomarkers in-dicative of drug response.

Keywords

Glioblastoma; NADP(H) FLIM; Regorafenib; drug response; organoids

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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