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.; Lacle, M. M.; Kops, G. J. P. L.; Rinkes, I. H. M. Borel; Kranenburg, O.

doi:https://doi.org/10.1002/bjs.11206

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy

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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.; Lacle, M. M.; Kops, G. J. P. L.; Rinkes, I. H. M. Borel; Kranenburg, O.

(2019) British Journal of Surgery, volume 106, issue 10, pp. 1404 - 1414

(Article)

Abstract

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 ... read more 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.

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Keywords: Surgery

DOI: https://doi.org/10.1002/bjs.11206

ISSN: 0007-1323

Publisher: John Wiley and Sons Ltd

Note: Funding Information: The authors thank O. Imhof for the HIPEC perfusion reports, J. Laoukili and E. K???kk?se for help with organoid transfection, L. Wijler and J. Laoukili for setting up high-throughput drug screening in the authors' laboratory, and C. Huysentruyt for the microscopic image of p02-1. This work was supported by the Dutch Cancer Society (UU2014?6617 to I.U.), and the Marie Curie Network Ploidynet which is funded by the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement number 607722 (to A.C.F.B.). The sponsors had no influence on the study design, or collection, analysis and interpretation of data. Disclosure: The authors declare no conflict of interest. Funding Information: The authors thank O. Imhof for the HIPEC perfusion reports, J. Laoukili and E. Küçükköse for help with organoid transfection, L. Wijler and J. Laouk-ili for setting up high-throughput drug screening in the authors’ laboratory, and C. Huysentruyt for the microscopic image of p02-1. This work was supported by the Dutch Cancer Society (UU2014–6617 to I.U.), and the Marie Curie Network Ploidynet which is funded by the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement number 607722 (to A.C.F.B.). The sponsors had no influence on the study design, or collection, analysis and interpretation of data. Disclosure: The authors declare no conflict of interest. Publisher Copyright: © 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.

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