A methylome-based score to predict response to regorafenib in recurrent glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE283494 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM. Methods.Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS). Results. At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months). Conclusions. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
2020-12-31 | GSE154042 | GEO
Project description:Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM. Methods.Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS). Results. At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months). Conclusions. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
2020-12-31 | GSE154041 | GEO
Project description:Registered systemic treatment options for glioblastoma patients are limited, particularly for progressive glioblastoma, including bevacizumab in the US and some other countries as well as lomustine. The phase II REGOMA trial suggested an improvement of overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE, however. Of note, regorafenib has been administered as monotherapy in progressive glioblastoma or as an addition to standard of care in newly diagnosed glioblastoma. Rational combination therapies involving regorafenib, instead of entirely discontinuing any consideration of this compound, might be therefore a reasonable strategy. We addressed this research gap and used an innovative discovery and validation approach to identify functionally-instructed combination therapies. We applied a genome-wide CRISPR-Cas9-based functional genomics experimental approach including activation and knockout screens for the discovery of potential molecular targets modifying the therapeutic efficacy of regorafenib in experimental glioma. Selected functionally instructed molecular hits were then validated regarding synergistic interaction in vitro, ex vivo and in two orthotopic mouse models in vivo.This functional genomics approach led to the discovery of several molecular targets. Based on subsequent validation experiments including a customized compound library, we identified novel combination therapies. Particularly, the combination of regorafenib with Bcl-2/Bcl-xL inhibition was among the most promising strategies.
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2021-01-27 | GSE148948 | GEO
Project description:Low-dose regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR antibody) but produced higher T cell activation and M1 macrophage polarization, Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148947 | GEO
Project description:Developing effective model systems to evaluate new potential chemotherapeutic reagents is critical. Three-dimensional cell cultures, such as spheroids, aid in bridging the gap between commonly used monolayer cell cultures and significantly more complex and expensive animal models. Spheroid model systems contain pathophysiological and chemical gradients similar to an in vivo tumor, which ultimately form distinct cellular subpopulations. In the spatial SILAC model, labels are pulsed into the spheroid at discrete time windows during development. These media pulses result in labeled proteins in distinct regions of the spheroid, which allows for tracing of quantitative proteomic changes to be correlated to different cellular subregions. In this study, we use the Spatial SILAC model to evaluate the proteomic response of a colon carcinoma spheroid to the multikinase inhibitor Regorafenib. We determined regorafenib to be an effective kinase inhibitor which significantly altered whole spheroid proliferation and resulted in increased apoptosis when the signal was averaged for all cells in the culture. However, when regorafenib treatment is more closely examined among the cellular subpopulations, drastic differences are observed for how the drug impacted the proteome of the necrotic spheroid core and the proliferating outer regions. Whole spheroid and outer region analysis shows that regorafenib treatment inhibited critical pathways such as mTOR signaling, ERK/MAPK signaling, and colorectal cancer metastasis signaling. However, analysis of the core shows that regorafenib had an entirely different effect, including upregulation of MAPK1 and KRAS, possibly indicating drug resistance within these late apoptotic cells. Ultimately, these combinatory studies can be used to further understanding of drug metabolism is different cellular subpopulations and provide valuable information to ultimately improve the accuracy of therapeutic testing.
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Project description:We demonstrate that regorafenib treatment suppresses multiple canonical pathways and transcriptions factors We used microarrays to analyze the potential mechanism by which regorafenib regulates gene expression.
2022-04-28 | GSE149131 | GEO
Project description:Colorectal cancer (CRC) remains the third leading cause of cancer-related deaths worldwide, with its incidence continuing to rise. Regorafenib, a multi-kinase inhibitor approved as a palliative treatment, extends survival in patients with metastatic CRC (mCRC) who have failed standard therapies. However, the clinical benefit of regorafenib is limited to a subset of patients, is typically short-lived, and is often accompanied by significant toxicity. The mechanisms by which CRC cells develop resistance to regorafenib remain poorly understood.In this study, we investigated resistance mechanisms to regorafenib using a preclinical mouse colon organoid model. Transcriptomic analysis of Apc wild-type and Apc-deficient organoids treated with regorafenib revealed an upregulation of epithelial-to-mesenchymal transition (EMT), accompanied by alterations in the secretome and increased activation of phosphorylated Erk1/2. Notably, co-treatment with an autophagy inhibitor suppressed regorafenib-induced EMT and its associated secretory phenotype, resulting in reduced cell proliferation and enhanced apoptosis in mouse organoids. The effectiveness of this drug combination was further supported by cell viability assays in human CRC cell lines. In contrast, primary mouse colon fibroblasts displayed greater resistance to both single-agent and combination regorafenib treatments. In summary, our findings using a preclinical organoid model suggest that autophagy inhibition may offer a promising strategy to mitigate chemoresistance and reduce toxicity associated with regorafenib treatment in mCRC patients.
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2024-10-01 | GSE248154 | GEO
Project description:Regorafenib presented an antitumor activity in HNSCC mouse model and delayed the tumorigenesis of the 4NQO-indued oral mouse model. By tumor-infiltration lymphocytes isolation and RNA-seq analysis, the immunity-related function was activated by regorafenib. We approved that regorafenib can determine the macrophage polarization toward M1 inflammatory macrophages by suppressing the production of certain cytokines such as plasminogen activator inhibitor-1 (PAI-I) from tumor cells. Also, Regorafenib suppresses secretion of PAI-1 from ex vivo cultures of human HNSCC organoids.
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