Editors' ChoiceCancer

Patient-derived organoids: Are PDOs the new PDX?

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Science Translational Medicine  25 Jul 2018:
Vol. 10, Issue 451, eaau7377
DOI: 10.1126/scitranslmed.aau7377

Abstract

Patient-derived organoids in pancreatic cancer maintain genotypic, transcriptomic, and potentially phenotypic responses to chemotherapy of the primary tumor.

One of the difficulties in cancer biology is that the model systems we use for research do not accurately represent the complexity and heterogeneity of the primary tumor. The current state-of-the-art model is patient-derived xenografts, which require a long lead time to propagate, limiting their utility in clinical decisions. The possibilities for patient-derived organoids (PDO) in cancer biology are immense if the tumors grown ex vivo, as organoids, retain the architecture, genotype, and phenotype of the patient’s primary tumor in vivo. Tiriac and colleagues have developed a library of PDOs from pancreatic cancer that appear to retain the phenotypic responses to chemotherapy and could potentially be used to identify patients that are sensitive to specific treatment regimens.

With limited response to chemotherapy, pancreatic cancer is one of the most deadly forms of cancer and predictive biomarkers to direct treatment are urgently required. In this paper, the authors generated PDOs from over a hundred patient samples, and for the most part PDOs recapitulated the primary tumor at both the genomic and transcriptomic level. Interestingly, a proportion of the PDOs (22%) appeared to be due to the outgrowth of normal epithelial cells rather than transformed cells, highlighting a potential requirement for genomic analysis to confirm tumor PDOs. PDOs become a powerful research tool if the phenotypic responses to chemotherapy are comparable to the patient’s in vivo response, allowing for more efficient treatment decisions. Using therapeutic profiling, the authors showed that responses in PDOs matched the patient’s response to treatment in 8 of 9 patients with clinical follow-up data. Interestingly, there was evidence that PDOs from longitudinal samples from one patient correlated with development of resistance in the patient’s clinical disease course. They also showed that chemoresistant PDOs were sensitive to select targeted agents, potentially identifying alternative treatment options for chemorefractory patients.

This study is promising but preliminary and would need to be expanded with clinical follow-up data on a much larger sample of patients and assessed in other tumor types. The lack of an immune component and stromal cells in the PDOs may also limit utility. PDOs have the potential to offer an efficient way to assess complex biology within an appropriate timeframe to allow clinical direction of treatment for precision medicine.

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