Cargando…
Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy
BACKGROUND: Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival,...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771632/ https://www.ncbi.nlm.nih.gov/pubmed/31197820 http://dx.doi.org/10.1002/bjs.11206 |
_version_ | 1783455731172769792 |
---|---|
author | Ubink, I. Bolhaqueiro, A. C. F. Elias, S. G. Raats, D. A. E. Constantinides, A. Peters, N. A. Wassenaar, E. C. E. de Hingh, I. H. J. T Rovers, K. P. van Grevenstein, W. M. U. Laclé, M. M. Kops, G. J. P. L. Borel Rinkes, I. H. M. Kranenburg, O. |
author_facet | Ubink, I. Bolhaqueiro, A. C. F. Elias, S. G. Raats, D. A. E. Constantinides, A. Peters, N. A. Wassenaar, E. C. E. de Hingh, I. H. J. T Rovers, K. P. van Grevenstein, W. M. U. Laclé, M. M. Kops, G. J. P. L. Borel Rinkes, I. H. M. Kranenburg, O. |
author_sort | Ubink, I. |
collection | PubMed |
description | BACKGROUND: Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. METHODS: Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. RESULTS: MMC was more effective in eliminating peritoneal metastasis‐derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis‐derived organoids to MMC, as the IC50 decreased 2·6–12·4‐fold to well below concentrations commonly attained in clinical practice. Live‐cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC‐induced cell cycle arrest, but caused increased replication stress and accelerated cell death. CONCLUSION: Peritoneal metastasis‐derived organoids can be used to evaluate existing HIPEC regimens on an individual‐patient level and for development of more effective treatment strategies. SURGICAL RELEVANCE: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient‐derived organoids can accurately predict clinical therapeutic response in vitro. A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient‐derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery–HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC. Peritoneal metastasis‐derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent‐tailored HIPEC regimens. |
format | Online Article Text |
id | pubmed-6771632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-67716322019-10-03 Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy Ubink, I. Bolhaqueiro, A. C. F. Elias, S. G. Raats, D. A. E. Constantinides, A. Peters, N. A. Wassenaar, E. C. E. de Hingh, I. H. J. T Rovers, K. P. van Grevenstein, W. M. U. Laclé, M. M. Kops, G. J. P. L. Borel Rinkes, I. H. M. Kranenburg, O. Br J Surg Original Article BACKGROUND: Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. METHODS: Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. RESULTS: MMC was more effective in eliminating peritoneal metastasis‐derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis‐derived organoids to MMC, as the IC50 decreased 2·6–12·4‐fold to well below concentrations commonly attained in clinical practice. Live‐cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC‐induced cell cycle arrest, but caused increased replication stress and accelerated cell death. CONCLUSION: Peritoneal metastasis‐derived organoids can be used to evaluate existing HIPEC regimens on an individual‐patient level and for development of more effective treatment strategies. SURGICAL RELEVANCE: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient‐derived organoids can accurately predict clinical therapeutic response in vitro. A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient‐derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery–HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC. Peritoneal metastasis‐derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent‐tailored HIPEC regimens. John Wiley & Sons, Ltd 2019-06-14 2019-09 /pmc/articles/PMC6771632/ /pubmed/31197820 http://dx.doi.org/10.1002/bjs.11206 Text en © 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Article Ubink, I. Bolhaqueiro, A. C. F. Elias, S. G. Raats, D. A. E. Constantinides, A. Peters, N. A. Wassenaar, E. C. E. de Hingh, I. H. J. T Rovers, K. P. van Grevenstein, W. M. U. Laclé, M. M. Kops, G. J. P. L. Borel Rinkes, I. H. M. Kranenburg, O. Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
title | Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
title_full | Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
title_fullStr | Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
title_full_unstemmed | Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
title_short | Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
title_sort | organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771632/ https://www.ncbi.nlm.nih.gov/pubmed/31197820 http://dx.doi.org/10.1002/bjs.11206 |
work_keys_str_mv | AT ubinki organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT bolhaqueiroacf organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT eliassg organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT raatsdae organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT constantinidesa organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT petersna organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT wassenaarece organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT dehinghihjt organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT roverskp organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT vangrevensteinwmu organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT laclemm organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT kopsgjpl organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT borelrinkesihm organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy AT kranenburgo organoidsfromcolorectalperitonealmetastasesasaplatformforimprovinghyperthermicintraperitonealchemotherapy |