What value do zebrafish have to anticancer drug discovery?

Figures & data

Figure 1. Zebrafish’s application in drug discovery and development. The chart outlines the steps of the drug discovery and development pipeline, with the unique strengths of zebrafish described in the shaded boxes.

Table 1. Advances in drug discovery, validation, and personalized medicine using zebrafish.

Drugs	Targets	Modality of Screening	Indications	Stage of Clinical Development/Status	Clinical Trial Identifier	Major References
			Target Identification
Marizomib	20S proteasome	Systemic angiogenesis assays in zebrafish embryos	Glioblastoma multiforme	Phase III/Active, not recruiting	NCT03345095	Wang and Miao, 2013
ProHema (Chemical derivative of PGE2)	PGE2 receptor	Chemical genetic screens using zebrafish embryos to identify effectors of stem cell induction	Hematologic malignancies Hematologic malignancies Inherited metabolic disorders Hematologic malignancies	Phase I/Terminated Phase I/Completed Phase I/Terminated Phase II/Terminated	NCT02354417 NCT00890500 NCT02354443 NCT01627314	North et al. 2007
Devimistat	Pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complex in the TCA cycle	Genetic screens that identified the TCA cycle enzyme as the drug target based on leukemia-suppressing phenotypes in adult zebrafish	Relapsed or refractory Burkitt Lymphoma/Leukemia or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 Relapsed/refractory acute myeloid leukemia Relapsed or refractory clear cell sarcoma of soft tissue Locally advanced pancreatic cancer Relapsed or refractory T-Cell Non-Hodgkin lymphoma Metastatic adenocarcinoma of the pancreas Advanced unresectable biliary tract cancer Advanced or metastatic bile duct cancer that cannot be removed by surgery Relapsed or refractory acute myeloid leukemia Relapsed or refractory acute myeloid leukemia or granulocytic sarcoma Advanced chemorefractory solid tumors	Phase II/Active, not recruiting Phase III/Terminated Phase I/II/Completed Phase I/II/Active, not recruiting Phase II/Recruiting Phase II/Completed Phase I/II/Recruiting Phase I/II/Completed Phase II/Not yet recruiting Phase II/Completed Phase II/Recruiting	NCT03793140 NCT03504410 NCT04593758 NCT03699319 NCT04217317 NCT03504423 NCT04203160 NCT01766219 NCT05854966 NCT02484391 NCT05733000	Anderson et al. 2016
			Drug Repurposing
Leflunomide (FDA-approved treatment for Rheumatoid Arthritis)	dihydroorotate dehydrogenase	Chemical genetic screens for compounds impacting neural crest cell development, self-renewal, and lymphatic activity in zebrafish embryos	Previously treated metastatic triple negative breast cancer PTEN-null advanced solid malignancies Relapsed or refractory multiple myeloma High-risk smoldering myeloma Multiple endocrine neoplasia type 1 syndromes	Phase I/II/Recruiting Phase I/Recruiting Phase II/Recruiting Phase II/Recruiting Cancer Prevention study/Recruiting	NCT03709446 NCT04997993 NCT04508790 NCT05014646 NCT05605587	White et al. 2011 Santoriello et al. 2020 Astin et al. 2014 Seda et al. 2019
Rosuvastatin (FDA-approved treatment for hypercholesterolemia)	HMG-CoA reductase	Chemical genetic screens using zebrafish embryos to identify small molecules that inhibit angiogenesis with minimal toxicities	Clonal cytopenia of undetermined significance and myelodysplastic syndromes Early endometrial carcinoma Metastatic prostate cancer Rectal cancer Advanced solid malignancies with focus on squamous cell carcinomas and NSCL	Phase II/Not yet recruiting Phase II/Recruiting Phase IV/Completed Phase II/Completed Phase II/Completed	NCT05483010 NCT04491643 NCT04776889 NCT02569645 NCT00966472	Wang et al. 2010 Kumar et al. 2020 Kumar et al. 2022 Han et al. 2022
All-Trans-Retinoic Acid (FDA-approved treatment for AML, APML, Immune Thrombocytopenia) 13-cis-Retinoic Acid	Retinoic acid receptor alpha	Chemical genetic screens using pluripotent zebrafish blastomere culture system to identify suppressors of c-myb in adenoid cystic cancers	Advanced adenoid cystic carcinoma Neuroblastoma Brain cancers	Phase II/Completed Phase II/Completed Phase II/Completed	NCT03999684 NCT00135135 NCT00528437	Mandelbaum et al. 2018
			Cancer Avatars
Olaparib Temozolomide	Poly(ADP‐ribose) polymerase DNA (alkylating agent)	Combination therapies assessed in optically-clear, immunodeficient adult zebrafish engrafted with established human sarcoma cell lines. Validation of zebrafish patient-derived xenografts (zPDXs) using patient-derived cancers	Ewing’s sarcoma Rhabdomyosarcoma	Phase I/Recruiting	NCT01858168	Yan et al. 2019
Fluorouracil Lederfolin Oxaliplatin Irinotecan Docetaxel Cisplatin Epirubicin Gemcitabine Nab paclitaxel	Approved chemotherapy drugs	Prediction of patient responses to chemotherapy regimens using embryo zPDXs	Liver cancer Pancreatic cancer Gastric cancer Esophageal cancer Colorectal cancer Gall bladder cancer Biliary tract cancer	Observational/Unknown status	NCT03668418	Di Franco et al. 2020 Usai et al. 2021 Di Franco et al. 2022
Gastric Cancer drugs	Approved chemotherapy drugs	Prediction of patient responses to chemotherapy regimens using zPDXs; fish stage not specified	Gastric cancer	Observational/Not yet recruiting	NCT05616533	Jin, Zhejiang University