Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors through
Mariangela Morelli1, Francesca Lessi1, Sara Franceschi1
1Fondazione Pisana per la Scienza, San Giuliano Terme, 56017 Pisa, Italy.
Abstract:
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.
Insights
Regorafenib (REGO) shows higher efficacy than temozolomide (TMZ) in recurrent glioblastoma. This study utilized 3D organoids to identify molecular biomarkers predicting patient response to REGO, advancing precision medicine for brain tumors.
Area of Science:
- Neuro-oncology
- Precision Medicine
- Cancer Genomics
Background:
- Glioblastoma exhibits limited response to standard therapies like temozolomide (TMZ).
- Recurrent glioblastoma presents significant treatment challenges.
- Regorafenib (REGO) has shown promise in improving survival in recurrent glioblastoma.
Purpose of the Study:
- To develop a 3D ex vivo precision medicine approach for assessing recurrent glioblastoma sensitivity to REGO.
- To investigate molecular mechanisms underlying tumor response or resistance to REGO and TMZ.
- To identify potential biomarkers for predicting drug response in glioblastoma.
Main Methods:
- Generation of three-dimensional glioblastoma organoids (GB-EXPs) from patient tumors.
- Treatment of GB-EXPs with temozolomide (TMZ) and Regorafenib (REGO).
- Evaluation of drug response using NAD(P)H FLIM, whole-exome sequencing, and whole-transcriptome analysis.
Main Results:
- 77% of recurrent glioblastoma tumors responded to REGO, compared to 35% responding to TMZ.
- Distinct mutational profiles and gene expression patterns were identified in REGO responders versus non-responders.
- Signaling pathways including Rho GTPase and NOTCH were implicated in drug response.
Conclusions:
- Recurrent glioblastoma demonstrates higher sensitivity to REGO than TMZ.
- The 3D ex vivo organoid model facilitates exploration of treatment-induced molecular changes.
- This approach can uncover biomarkers for predicting glioblastoma drug response, supporting precision medicine.
