Patient-Derived Organoid Serves as a Platform for Personalized Chemotherapy in Advanced Colorectal Cancer Patients

Khamushavalli Geevimaan; Jing-You Guo; Chia-Ning Shen; Jeng-Kai Jiang; Cathy S J Fann; Ming-Jing Hwang; Jr-Wen Shui; Hsiu-Ting Lin; Mei-Jung Wang; Hsuan-Cheng Shih; Anna Fen-Yau Li; Shih-Ching Chang; Shung-Haur Yang; Jeou-Yuan Chen

doi:10.3389/fonc.2022.883437

Patient-Derived Organoid Serves as a Platform for Personalized Chemotherapy in Advanced Colorectal Cancer Patients

Front Oncol. 2022 Jun 1:12:883437. doi: 10.3389/fonc.2022.883437. eCollection 2022.

Authors

Khamushavalli Geevimaan^{1

2}, Jing-You Guo¹, Chia-Ning Shen², Jeng-Kai Jiang^{3

4}, Cathy S J Fann¹, Ming-Jing Hwang¹, Jr-Wen Shui¹, Hsiu-Ting Lin¹, Mei-Jung Wang¹, Hsuan-Cheng Shih¹, Anna Fen-Yau Li⁵, Shih-Ching Chang^{3

4}, Shung-Haur Yang^{3

4

6}, Jeou-Yuan Chen¹

Affiliations

¹ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
² Genomic Research Center, Academia Sinica, Taipei, Taiwan.
³ Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
⁴ Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
⁵ Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Department of Surgery, National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan.

Abstract

Background: Addition of oxaliplatin to adjuvant 5-FU has significantly improved the disease-free survival and served as the first line adjuvant chemotherapy in advanced colorectal cancer (CRC) patients. However, a fraction of patients remains refractory to oxaliplatin-based treatment. It is urgent to establish a preclinical platform to predict the responsiveness toward oxaliplatin in CRC patients as well as to improve the efficacy in the resistant patients.

Methods: A living biobank of organoid lines were established from advanced CRC patients. Oxaliplatin sensitivity was assessed in patient-derived tumor organoids (PDOs) in vitro and in PDO-xenografted tumors in mice. Based on in vitro oxaliplatin IC₅₀ values, PDOs were classified into either oxaliplatin-resistant (OR) or oxaliplatin-sensitive (OS) PDOs. The outcomes of patients undergone oxaliplatin-based treatment was followed. RNA-sequencing and bioinformatics tools were performed for molecular profiling of OR and OS PDOs. Oxaliplatin response signatures were submitted to Connectivity Map algorithm to identify perturbagens that may antagonize oxaliplatin resistance.

Results: Oxaliplatin sensitivity in PDOs was shown to correlate to oxaliplatin-mediated inhibition on PDO xenograft tumors in mice, and parallelled clinical outcomes of CRC patients who received FOLFOX treatment. Molecular profiling of transcriptomes revealed oxaliplatin-resistant and -sensitive PDOs as two separate entities, each being characterized with distinct hallmarks and gene sets. Using Leave-One-Out Cross Validation algorithm and Logistic Regression model, 18 gene signatures were identified as predictive biomarkers for oxaliplatin response. Candidate drugs identified by oxaliplatin response signature-based strategies, including inhibitors targeting c-ABL and Notch pathway, DNA/RNA synthesis inhibitors, and HDAC inhibitors, were demonstrated to potently and effectively increase oxaliplatin sensitivity in the resistant PDOs.

Conclusions: PDOs are useful in informing decision-making on oxaliplatin-based chemotherapy and in designing personalized chemotherapy in CRC patients.

Keywords: colorectal cancer; connectivity map; oxaliplatin sensitivity assessment; patient-derived organoids (PDOs); personalized chemotherapy.