Appendiceal Cancer Patient-Specific Tumor Organoid Model for Predicting Chemotherapy Efficacy Prior to Initiation of Treatment: A Feasibility Study

Abstract

Introduction

We have hypothesized that biofabrication of appendiceal tumor organoids allows for a more personalized clinical approach and facilitates research in a rare disease.

Methods

Appendiceal cancer specimens obtained during cytoreduction with hyperthermic intraperitoneal chemotherapy procedures (CRS/HIPEC) were dissociated and incorporated into an extracellular matrix-based hydrogel system as three-dimensional (3D), patient-specific tumor organoids. Cells were not sorted, preserving tumor heterogeneity, including stroma and immune cell components. Following establishment of organoid sets, chemotherapy drugs were screened in parallel. Live/dead staining and quantitative metabolism assays recorded which chemotherapies were most effective in killing cancer cells for a specific patient. Maintenance of cancer phenotypes were confirmed by using immunohistochemistry.

Results

Biospecimens from 12 patients were applied for organoid development between November 2016 and May 2018. Successful establishment rate of viable organoid sets was 75% (9/12). Average time from organoid development to chemotherapy testing was 7 days. These tumors included three high-grade appendiceal (HGA) and nine low-grade appendiceal (LGA) primaries obtained from sites of peritoneal metastasis. All tumor organoids were tested with chemotherapeutic agents exhibited responses that were either similar to the patient response or within the variability of the expected clinical response. More specifically, HGA tumor organoids derived from different patients demonstrated variable chemotherapy tumor-killing responses, whereas LGA organoids tested with the same regimens showed no response to chemotherapy. One LGA set of organoids was immune-enhanced with cells from a patient-matched lymph node to demonstrate feasibility of a symbiotic 3D reconstruction of a patient matched tumor and immune system component.

Conclusions

Development of 3D appendiceal tumor organoids is feasible even in low cellularity LGA tumors, allowing for individual patient tumors to remain viable for research and personalized drug screening.

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Acknowledgement

The authors thank Libby McWilliams (Procurement Manager), Kathleen Cummings (Protocol and Data Manager) and the Wake Forest Advanced Tumor Bank Shared Resource.

Funding

AS acknowledges funding through the Wake Forest Clinical and Translational Science Institute Open Pilot Program. AS and KV acknowledge funding through the Comprehensive Cancer Center at Wake Forest Baptist Medical Center’s Clinical Research Associate Director Pilot Funds.

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Corresponding authors

Correspondence to Konstantinos I. Votanopoulos MD, PhD or Aleksander Skardal PhD.

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The authors have no conflicts of interest to disclose.

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Votanopoulos, K.I., Mazzocchi, A., Sivakumar, H. et al. Appendiceal Cancer Patient-Specific Tumor Organoid Model for Predicting Chemotherapy Efficacy Prior to Initiation of Treatment: A Feasibility Study. Ann Surg Oncol 26, 139–147 (2019). https://doi.org/10.1245/s10434-018-7008-2

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Keywords

  • Tumor Organoids
  • Appendiceal Cancer
  • Individual Patient Tumors
  • Biospecimens
  • Organoid Development