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Published on: May 17, 2017
Rapid In Vivo Validation of HDAC Inhibitor-Based Treatments in Neuroblastoma Zebrafish Xenografts
Jagoda K Wrobel1,2, Sara Najafi1,2,3, Simay Ayhan1,2,4
1Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany.
Abstract:
The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing models are urgently needed. Zebrafish are a powerful vertebrate model in preclinical cancer research. Here, we describe a zebrafish neuroblastoma yolk sac model to evaluate efficacy and toxicity of histone deacetylase (HDAC) inhibitor treatments. Larvae were engrafted with fluorescently labeled, genetically diverse, established cell lines and short-term cultures of patient-derived primary cells. Engrafted tumors progressed locally and disseminated remotely in an intact environment. Combination treatments involving the standard chemotherapy doxorubicin and HDAC inhibitors substantially reduced tumor volume, induced tumor cell death, and inhibited tumor cell dissemination to the tail region. Hence, this model allows for fast, cost-efficient, and reliable in vivo evaluation of toxicity and response of the primary and metastatic tumor sites to drug combinations.
Insights
New zebrafish models offer a fast and cost-effective way to test neuroblastoma treatments. Combining chemotherapy with histone deacetylase (HDAC) inhibitors shows promise in reducing tumor growth and spread in preclinical studies.
Area of Science:
- Oncology
- Zebrafish Models
- Drug Discovery
Background:
- Relapsed neuroblastoma in children has a poor survival rate, necessitating novel therapeutic strategies.
- Reliable preclinical models are crucial for identifying effective new treatments for neuroblastoma.
Purpose of the Study:
- To develop and validate a zebrafish neuroblastoma yolk sac model for evaluating histone deacetylase (HDAC) inhibitor efficacy and toxicity.
- To assess the therapeutic potential of combining HDAC inhibitors with standard chemotherapy in a preclinical setting.
Main Methods:
- Engraftment of zebrafish larvae with fluorescently labeled neuroblastoma cell lines and patient-derived primary cells.
- Utilizing a zebrafish neuroblastoma yolk sac model to observe tumor progression and metastasis in vivo.
- Evaluating combination treatments with doxorubicin and HDAC inhibitors on tumor volume, cell death, and dissemination.
Main Results:
- The zebrafish model successfully recapitulated local tumor progression and remote dissemination.
- Combination therapy significantly reduced tumor volume and induced tumor cell death.
- Treatment inhibited the dissemination of neuroblastoma cells to distant sites.
Conclusions:
- The developed zebrafish model provides a fast, cost-efficient, and reliable platform for in vivo drug testing in neuroblastoma.
- Combination treatments involving HDAC inhibitors and doxorubicin demonstrate therapeutic efficacy against primary and metastatic neuroblastoma.
- This model aids in the evaluation of drug toxicity and treatment response for neuroblastoma.
