Sunitinib efficacy with minimal toxicity in patient-derived retinoblastoma organoids
Issued Date
2023-12-01
Resource Type
eISSN
17569966
Scopus ID
2-s2.0-85147157458
Journal Title
Journal of Experimental and Clinical Cancer Research
Volume
42
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Experimental and Clinical Cancer Research Vol.42 No.1 (2023)
Suggested Citation
Srimongkol A., Laosillapacharoen N., Saengwimol D., Chaitankar V., Rojanaporn D., Thanomchard T., Borwornpinyo S., Hongeng S., Kaewkhaw R. Sunitinib efficacy with minimal toxicity in patient-derived retinoblastoma organoids. Journal of Experimental and Clinical Cancer Research Vol.42 No.1 (2023). doi:10.1186/s13046-023-02608-1 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81367
Title
Sunitinib efficacy with minimal toxicity in patient-derived retinoblastoma organoids
Other Contributor(s)
Abstract
Background: Recurrence of retinoblastoma (RB) following chemoreduction is common and is often managed with local (intra-arterial/intravitreal) chemotherapy. However, some tumors are resistant to even local administration of maximum feasible drug dosages, or effective tumor control and globe preservation may be achieved at the cost of vision loss due to drug-induced retinal toxicity. The aim of this study was to identify drugs with improved antitumor activity and more favorable retinal toxicity profiles via screening of potentially repurposable FDA-approved drugs in patient-derived tumor organoids. Methods: Genomic profiling of five RB organoids and the corresponding parental tissues was performed. RB organoids were screened with 133 FDA-approved drugs, and candidate drugs were selected based on cytotoxicity and potency. RNA sequencing was conducted to generate a drug signature from RB organoids, and the effects of drugs on cell cycle progression and proliferative tumor cone restriction were examined. Drug toxicity was assessed with human embryonic stem cell-derived normal retinal organoids. The efficacy/toxicity profiles of candidate drugs were compared with those of drugs in clinical use. Results: RB organoids maintained the genomic features of the parental tumors. Sunitinib was identified as highly cytotoxic against both classical RB1-deficient and novel MYCN-amplified RB organoids and inhibited proliferation while inducing differentiation in RB. Sunitinib was a more effective suppressor of proliferative tumor cones in RB organoids and had lower toxicity in normal retinal organoids than either melphalan or topotecan. Conclusion: The efficacy and retinal toxicity profiles of sunitinib suggest that it could potentially be repurposed for local chemotherapy of RB.