Biweekly Raltitrexed Plus Oxaliplatin or Irinotecan to Treat Advanced CRC
Ontology highlight
ABSTRACT:
DISEASE(S): Advanced Colorectal Cancer
PROVIDER: 2669558 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Desmoplastic small round cell tumor (DSRCT) is a rare and incurable malignancy characterized by the oncogenic EWSR1-WT1 transcription factor. This study exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological and molecular characteristics of the paired clinical tumor, to comparatively assess the activity of cytotoxic and targeted anticancer agents. Anti-tumor effect was moderate for single-agent doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI): 55-66%] while trabectedin had a higher effect (max TVI: 82%). Single-agent vinorelbine, irinotecan and eribulin achieved a nearly complete tumor growth inhibition (max TVI: 96-98%), although tumors started to re-growth after the end of treatment. Combination of irinotecan with either eribulin or trabectedin resulted in complete responses which were maintained until the end of the experiment for irinotecan plus trabectedin. Irinotecan-based combinations almost completely abrogated the expression of proteins involved in the G2/M checkpoint preventing cell entrance in mitosis and induced apoptotic and necroptotic cell death. This study emphasizes the importance of patient-derived pre-clinical models to explore new treatments in DSRCT and fosters clinical investigation in the activity of irinotecan plus trabectedin.
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Project description:Desmoplastic small round cell tumor (DSRCT) is a rare and incurable malignancy characterized by the oncogenic EWSR1-WT1 transcription factor. This study exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological and molecular characteristics of the paired clinical tumor, to comparatively assess the activity of cytotoxic and targeted anticancer agents. Anti-tumor effect was moderate for single-agent doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI): 55-66%] while trabectedin had a higher effect (max TVI: 82%). Single-agent vinorelbine, irinotecan and eribulin achieved a nearly complete tumor growth inhibition (max TVI: 96-98%), although tumors started to re-growth after the end of treatment. Combination of irinotecan with either eribulin or trabectedin resulted in complete responses which were maintained until the end of the experiment for irinotecan plus trabectedin. Irinotecan-based combinations almost completely abrogated the expression of proteins involved in the G2/M checkpoint preventing cell entrance in mitosis and induced apoptotic and necroptotic cell death. This study emphasizes the importance of patient-derived pre-clinical models to explore new treatments in DSRCT and fosters clinical investigation in the activity of irinotecan plus trabectedin.
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Project description:Irinotecan, an analogue of camptothecin, is frequently used in combination with various anticancer drugs or as a single agent in treatment of colorectal cancer. But drug resistance of tumor is still a major obstacle to overcome for the success of cancer treatment. In this study, We established chronic irinotecan resistant cell line for new marker to increase the sensitivity to irinotecan and investigated gene expression profiles of the irinotecan-resistant colorectal cancer cell line.
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Project description:We report ChIP-seq for H3K36me3 that were performed as supplementary experiments to the U-DNA-Seq study (GSE126822). H3K36me3 ChIP-seq was conducted in raltitrexed (RTX) treated or non-treated (NT) HCT116 cells expressing the UNG inhibitor (UGI). We found that the applied RTX treatment did not result in major differences in the genome-wide distribution of the H3K36me3 histone marker. For wider context of the study, see the related publication.
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Project description:Irinotecan, an analogue of camptothecin, is frequently used in combination with various anticancer drugs or as a single agent in treatment of colorectal cancer. But drug resistance of tumor is still a major obstacle to overcome for the success of cancer treatment. In this study, We established chronic irinotecan resistant cell line for new marker to increase the sensitivity to irinotecan and investigated gene expression profiles of the irinotecan-resistant colorectal cancer cell line. To create stable CRC cell line chronically resistant to Irinotecan, LoVo cell was exposed to an initial Irinotecan concentration of 0.1 M-NM-<mol/L in RPMI 1640 supplemented with 10% FBS. When the growth of the cultured cells reaches at 80% confluency, cells were passaged twice at same drug concentration to ensure adaptation and then concentration of Irinotecan was sequentially increased in the same manner to 8 M-NM-<mol/L and then we investigated the gene expressions between parental colorectal cancer cell line, LoVo and Irinotecan resistant LoVo cell lines
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