Colorectal Cancer Treated With Adjuvant Regorafenib Versus Placebo After Curative Treatment of Liver Metastases in a Randomized, Double-blind, Placebo-Controlled Phase-III STudy
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ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Neoplasm Metastasis,Colorectal Neoplasms
PROVIDER: 2151352 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description: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.
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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.
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Project description:Background: Hepatocellular carcinoma (HCC) is a major therapeutic challenge, with limited long-term benefits from treatments such as regorafenib due to their efficacy and adverse effects. Proteoglycan-4 (PRG4) has previously shown promise in enhancing anti-proliferative effects of multi-kinase inhibitors in simple in vitro two-dimensional (2D) HCC models. Objective: We evaluated the adjuvant effect of PRG4 in enhancing regorafenib’s anti-tumor efficacy in preclinical more complex in vitro three-dimensional (3D) HCC tumoroids, and in vivo HCC models. Design: HLC19 and HLF HCC cell lines were engineered to stably overexpress PRG4. Anti-proliferative effects of PRG4, either alone or in combination with regorafenib, were evaluated in 2D monolayers, 3D Matrigel embedded spheroids and orthotopic xenograft mouse models established via HCC cells intrahepatic injection. RNA sequencing was done to assess the transcriptomic profiles of PRG4 overexpressing spheroids. Results: PRG4 expression partially inhibited HCC tumor growth in vivo, but enhanced regorafenib treatment leading to a near-complete tumor regression. PRG4 expression significantly impaired cell growth in both 2D and 3D HCC models in vitro. In an angiogenesis in vitro model, PRG4 hindered endothelial tubulogenesis both alone and in combination with regorafenib. By transcriptomic analysis of matrigel-embedded HCC cell spheroids exposed to PRG4 and/or regorafenib, PDGF pathway emerged as a target of PRG4 + regorafenib, corroborating the role of PRG4 in impairing angiogenesis. G0/G1 phase of cell cycle resulted more delayed in spheroids exposed to PRG4 and regorafenib than those treated with regorafenib only, compared to untreated cells. Conclusions: PRG4 enhances the anti-tumor activity of regorafenib across various HCC models. These findings support PRG4 as a promising adjuvant candidate to improve clinical outcomes in HCC.
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