PUBLICATION

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Authors
Varanda, A.B., Martins-Logrado, A., Ferreira, M.G., Fior, R.
ID
ZDB-PUB-200708-21
Date
2020
Source
Cancers   12(7): (Journal)
Registered Authors
Ferreira, Miguel Godinho, Fior, Rita
Keywords
BRCA1/2, PARP, breast cancer, ionizing radiation, olaparib, radiotherapy, xenografts, zebrafish
MeSH Terms
none
PubMed
32630796 Full text @ Cancers
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping