Evaluation of Eribulin Combined with Irinotecan for Treatment of Pediatric Cancer Xenografts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146687 | GEO | 2020/03/10
REPOSITORIES: GEO
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Project description:Evaluation of Eribulin Combined with Irinotecan for Treatment of Pediatric Cancer Xenografts
| PRJNA611620 | ENA
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.
2023-05-29 | GSE220172 | GEO
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.
2023-05-29 | GSE227897 | GEO
Project description:PurposeVincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models, and the combinations are effective in treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor.Experimental designVincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to event were used to assess antitumor activity. Pharmacodynamic studies and RNA sequencing (RNA-seq) were conducted 24 and 144 hours after single-agent or combination treatment. Effects on vascular development were studied in Matrigel plugs implanted in mice. The interaction between binary combinations was examined in vitro.ResultsEribulin combined with irinotecan was more effective than vincristine-irinotecan in 6 of 12 models. Pharmacodynamic markers induced by eribulin (phospho-histone H3) and irinotecan (γ-H2A.X) were abrogated in combination-treated tumors. The predominant RNA-seq signature in combination-treated tumors was activation of the TP53 pathway with increased nuclear TP53. Massive apoptosis was observed 24 hours only after treatment with the eribulin combination. In vitro, neither combination showed interaction using combination index analysis. Eribulin alone and the combination caused alterations in developing vasculature.ConclusionsThe eribulin combination is very active in these xenograft models, but not synergistic in vitro. The combination reduced pharmacodynamic markers indicative of single-agent mechanisms but in tumors, dramatically activated the TP53 pathway. Although a mechanism for in vivo synergy requires further study, it is possible that eribulin-induced inhibition of microtubule dynamics enhances irinotecan-induced nuclear accumulation of TP53, leading to rapid cell death.
| S-EPMC7299830 | biostudies-literature
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.
2014-07-18 | GSE59501 | GEO
Project description:Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, leading to inhibition of microtubule growth in the absence of effects on microtubule shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro. 27 breast cancer cell lines treated with eribulin and paclitaxel for 24 hours at concentration 10xIC50. Three technical replicates were included. for eribulin , paclitaxel and untreated cell lines.
2014-10-02 | E-GEOD-50811 | biostudies-arrayexpress
Project description:Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, leading to inhibition of microtubule growth in the absence of effects on microtubule shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro. 19 endometrial cancer cell lines treated with eribulin and paclitaxel for 24 hours at concentration 10xIC50. Three technical replicates were included. for eribulin , paclitaxel and untreated cell lines.
2014-10-02 | E-GEOD-50830 | biostudies-arrayexpress
Project description:Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics, leading to inhibition of microtubule growth in the absence of effects on microtubule shortening at microtubule plus ends, and formation of nonproductive tubulin aggregates. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro. 21 ovarian cancer cell lines treated with eribulin and paclitaxel for 24 hours at concentration 10xIC50. Three technical replicates were included for eribulin , paclitaxel and untreated cell lines.
2014-10-02 | E-GEOD-50831 | biostudies-arrayexpress
Project description:Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after cancer drug treatment. These cells are the living proof of response to a drug, and an interesting experimental subject for biomarker discovery. Here, we performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. First, we showed that eribulin induces a specific secretome in DTP cells as compared to other microtubule targeting agents. Then, we selected and functionally validated growth differentiation factor 15 (GDF15) as a protein significantly over-secreted upon eribulin treatment. Interestingly, GDF15 expression is low/absent in cells that are sensitive to eribulin, strongly upregulated during the response to the drug, and downregulated when stable resistance is ultimately established. Proteomic results were confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. Unexpectedly, despite its biomarker potential for eribulin response, we found that GDF15 is also paradoxically required for survival of DTP cells, although once full resistance to eribulin is established, GDF15 expression largely disappears. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function conditions. These results pointed to a potential benefit of simultaneous targeting of GDF15/GFRAL and eribulin, and indeed we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired eribulin resistance, and possibly other cytotoxic drugs. Overall, the combination of cytotoxic agents with targeted agents aimed specifically at DTP cells could be an effective therapeutic approach for metastatic breast cancer patients.
2023-01-09 | PXD034037 | Pride
Project description:In this experiment, 3 mice were implanted orthotopically with a patient-derived xenograft, SJRHB013759_X14. After tumor engraftment and visible nodule formation, all 3 mice underwent therapy. One mouse received vehicle control (saline), while two mice were treated with a combination of vincristine and irinotecan, to mimic salvage therapy for relapsed rhabdomyosarcoma. Sedated needle biopsies were performed before (time = 0), during therapy (time = 3, 7, and 14 days), and after recurrence.
2024-05-31 | GSE240308 | GEO