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Axitinib Monotherapy With Early Dynamic Contrast Enhanced Ultrasound Monitoring in Chemorefractory Third Line Metastatic Colorectal Cancer

ABSTRACT: This is a study of Axitinib versus placebo as monotherapy for people with colorectal cancer who have liver metastases and who have relapsed within 6 months of their last chemotherapy regime. The research will also look at the potential of CEHPI (Contrast Enhanced Hepatic Perfusion Index) reduction, a technique developed for this research to measure the changes in how the blood vessels pump blood into the different liver metastases (tumours) and therefore to assess and predict response to treatment.

DISEASE(S): Rectum,Colorectal Cancer,Colorectal Neoplasms,Third Line Colorectal Liver Metastases

PROVIDER: 2336681 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Purpose: To identify how axitinib stabilized the rabbit's engineered cartilage through the niche Methods: Rabbit's engineered cartilage was encapsulated in the PCL/collagen nanofibrous membrane containing no axitinib (0%-Axitinib group) or 3% axitinib (3%-Axitinib group) and implanted into nude mice. After 12 weeks of implantation, samples from the 0%-Axitinib group and 3%-Axitinib group were harvested, with the murine tissues entangled. Transcriptional profiles were generated by deep sequencing, in triplicate, using an Illumina HiSeqTM2000 machine, and filtered using Fastp software. The trimmed reads were mapped to the mouse genome (mm10, genome.UCSC.edu) using the STAR software to identify the transcriptional information in the niche of engineered cartilage. Then, the DESeq2 “counts” function of the R package was used to normalize gene expression levels based on the number of total reads of each sample. Differentially expressed genes between the 0%-Axitinib group and 3%-Axitinib group were identified as meeting the criteria of fold change ≥ 1.5 and P-value＜0.05. Lastly, we used Metascape (http://metascape.org) for gene ontology analysis. Results: Using an optimized data analysis workflow, we mapped about 20 to 30 million sequence reads per sample to the mouse genome (build mm10) and identified 20318 transcripts in the 0%-Axitinib and 3%-Axitinib groups. 837 genes were differentially expressed by more than 1.5-fold, p-value <0.05, with 313 genes downregulated and 524 genes upregulated in the 3%-Axitinib group. Gene ontology (GO) analysis revealed that the genes downregulated in the 3%-Axitinib group were mainly enriched in endothelial development, angiogenesis, and immune response. Genes upregulated in the 3%-Axitinib group were mainly enriched in response to hypoxia, Hif-1 signaling pathway, cartilage differentiation and development, and muscle structure development. Altered expression of 15 genes was further illustrated by heatmap, demonstrating the inhibited angiogenesis and improved chondrogenesis. Especially, Timp1, as a response to hypoxia, was remarkably upregulated, which also in turn inhibited the activity of matrix metalloproteinases (MMPs) and played an important role in preventing ossification. Conclusion: In this study, we proposed the first detailed transcriptional analysis of the effects of the sustainable and localized release of axitinib on the subcutaneous niche of engineered cartilage. The sustainable and localized release of axitinib created a relatively avascular, hypoxia, and low immune response niche in the 3%-Axitinib group. In this niche, Timp1 was remarkably upregulated, which inhibited the activity of MMPs and prevented endochondral ossification.

Dataset Information

Axitinib Monotherapy With Early Dynamic Contrast Enhanced Ultrasound Monitoring in Chemorefractory Third Line Metastatic Colorectal Cancer

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