Abstract
Selecting the best treatment for individual patients with cancer has attracted attention for improving clinical outcomes. Recent progress in organoid culture may lead to the development of personalized medicine. Unlike molecular-targeting drugs, there are no predictive methods for patient response to standard chemotherapies for ovarian cancer. We prepared organoids using the cancer tissue-originated spheroid (CTOS) method from 61 patients with ovarian cancer with 100% success rate. Chemosensitivity assays for paclitaxel and carboplatin were performed with 84% success rate using the primary organoids from 50 patients who received the chemotherapy. A wide range of sensitivities was observed among organoids for both drugs. All four clinically resistant organoids were resistant to both drugs in 18 cases in which clinical response information was available. Five out of 18 cases (28%) were double-resistant, the response rate of which was compatible with the clinical remission rate. Carboplatin was significantly more sensitive in serous than in clear cell subtypes (P = 0.025). We generated two lines of organoids, screened 1135 drugs, and found several drugs with better combinatory effects with carboplatin than with paclitaxel. Some drugs, including afatinib, have shown an additive effect with carboplatin. The organoid sensitivity assay did not predict the clinical outcomes, both progression free and overall survival.
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The organoid lines and data are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) for providing the drug library.
Funding
This work was supported, in part, by a Grant-in-Aid from P-CREATE, a Japan Agency for Medical Research and Development, Japan, 19cm0106203h0004 (M.I., J.K., K.O.); a Grant-in-Aid from Takeda Science Foundation (M.I.)
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M.I. belong and J.K. belonged to the Department of Clinical Bio-resource Research and Development at Kyoto University, which is sponsored by KBBM, Inc. M.I. is an inventor of the patents related to CTOS method.
Ethics approval
This study was approved by the institutional ethics committees of the Osaka International Cancer Institute (1111112098, 1605137104), Osaka University (10182), and Kyoto University (R1575). Animal studies were approved by the Institutional Animal Study Committee of Osaka International Cancer Institute and Kyoto University and performed in compliance with the guidelines.
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Surgical specimens and ascites samples from patients with ovarian cancer were obtained from Osaka University and Osaka International Cancer Institute with the approved patients’ informed consent and permission.
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13577_2022_827_MOESM1_ESM.xlsx
Supplementary file 1: (XLSX 14 KB) Table S1 Clinical information and results of organoid preparation and xenograft formation in 61 patients in this study.
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Supplementary file 2: (XLSX 16 KB) Table S2 Information on the clinical response and prognosis of patients and summary of drug testing results.
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Supplementary file 4: (DOCX 413 KB) Figure S1 Morphological characteristics of the ovarian cancer organoids. Phase-contrast images of primary organoids from the indicated patient tumors. Histological subtypes are shown. Scale bar, 100 \(\upmu\)m. Figure S2 Chemosensitivity assay for paclitaxel and carboplatin using primary organoids. (A) Dose response analysis for paclitaxel and carboplatin. Actual values of the relative ATP values for most sensitive (blue lines) and resistant (red lines) cases to each drug are shown as indicated. SD bars are shown. (B) Scatter plot of the sensitivity assay-ranking with the clinical stage for 42 organoids with which the drug testing was performed. Stage I, blue; stage II, green; stage III orange; stage IV, red. Figure S3 Chemosensitivity assay of the organoid lines, OV114 and OV129. (A, B) The dose response sigmoid curves for paclitaxel (A) and carboplatin (B). The results of the two organoids were added to Figure 2B; OV114 organoids derived from xenografts of passage 2 (px2) and passage 3 (px3), and OV129 organoids derived from primary and xenografts of passage 5 (px5), shown with the indicated colors. Others from Figure 2B are shown with gray. (C) Scatter plot of the sensitivity ranking of Figure 2C adding the data in (A) and (B). These dots are indicated with the indicated colors, and others from Figure 2C are shown with gray. Figure S4 Validation of the hit drugs using the organoid lines. The dose-response curves for candidate drugs other than those shown in Figure 5. The red lines indicate the results for the candidate drugs alone. Blue lines indicate the results of the combination of the candidate drugs with 10 μM carboplatin. SD bars are shown. Figure S5 Effect of the hit drugs in OV101. The organoids of OV101 were prepared from xenograft tumors. (A) The dose response sigmoid curves for carboplatin are from three independent experiments. (B) The results of (A) are added to Figure 2B; each result of the OV101 organoids is shown in red. Others from Figure 2B are shown in gray. (C) In the dose-response curves of OV101 for candidate drugs, the red lines indicate the results for the candidate drugs alone. Blue lines indicate the results of the combination of the candidate drugs with 10 μM carboplatin. SD bars are shown. The experiments were performed 3 times as indicated.
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Ito, Y., Kondo, J., Masuda, M. et al. Ex vivo chemosensitivity assay using primary ovarian cancer organoids for predicting clinical response and screening effective drugs. Human Cell 36, 752–761 (2023). https://doi.org/10.1007/s13577-022-00827-w
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DOI: https://doi.org/10.1007/s13577-022-00827-w