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

被引：2

作者：

Morelli, Mariangela ^{[1
]}

Lessi, Francesca ^{[1
]}

Franceschi, Sara ^{[1
]}

Ferri, Gianmarco ^{[1
]}

Giacomarra, Manuel ^{[1
]}

Menicagli, Michele ^{[1
]}

Gambacciani, Carlo ^{[2
]}

Pieri, Francesco ^{[2
]}

Pasqualetti, Francesco ^{[3
]}

Montemurro, Nicola ^{[4
]}

Aretini, Paolo ^{[1
]}

Santonocito, Orazio Santo ^{[2
]}

Di Stefano, Anna Luisa ^{[2
]}

Mazzanti, Chiara Maria ^{[1
]}

机构：

[1] Fdn Pisana Sci, I-56017 San Giuliano Terme, Pisa, Italy

[2] Neurosurg Dept Spedali Riuniti Livorno, I-57124 Livorno, Italy

[3] Azienda Osped Univ Pisana, Radiotherapy Dept, I-56126 Pisa, Italy

[4] Azienda Osped Univ Pisana, Dept Neurosurg, I-56126 Pisa, Italy

来源：

CELLS | 2024年 / 13卷 / 06期

关键词：

glioblastoma; NADP(H) FLIM; Regorafenib; drug response; organoids; ADJUVANT TEMOZOLOMIDE; POTASSIUM CHANNELS; PHASE-II; EXPRESSION; PROLIFERATION; RADIOTHERAPY; MULTICENTER; CONCOMITANT; INHIBITOR; GLIOMA;

D O I：

10.3390/cells13060487

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like temozolomide (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 glioblastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. Three-dimensional 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 (NRs). 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 being REGO-NRs. 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 compared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal exploration of the molecular changes induced by treatment, unveiling promising biomarkers indicative of drug response.

引用

页数：19

共 1 条

[1] INVESTIGATION OF REGORAFENIB TUMOR SENSITIVITY AND UNDERLYING TREATMENT INDUCED MOLECULAR MECHANISMS IN GLIOBLASTOMA RECURRENT TUMORS
Morelli, M.
Lessi, F.
Giacomarra, M.
Marranci, A.
Menicagli, M.
Santonocito, O. S.
Aretini, P.
Pasqualetti, F.
Di Stefano, A. L.
Franceschi, S.
Mazzanti, C. M.
NEURO-ONCOLOGY, 2023, 25

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