Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Autor: Charlotte Gatzweiler, Johannes Ridinger, Sonja Herter, Xenia F. Gerloff, Dina ElHarouni, Yannick Berker, Roland Imle, Lukas Schmitt, Sina Kreth, Sabine Stainczyk, Simay Ayhan, Sara Najafi, Damir Krunic, Karen Frese, Benjamin Meder, David Reuss, Petra Fiesel, Kathrin Schramm, Mirjam Blattner-Johnson, David T. W. Jones, Ana Banito, Frank Westermann, Sina Oppermann, Till Milde, Heike Peterziel, Olaf Witt, Ina Oehme
Rok vydání: 2022
Předmět:
Zdroj: Cancers; Volume 14; Issue 3; Pages: 849
Cancers, Vol 14, Iss 849, p 849 (2022)
ISSN: 2072-6694
DOI: 10.3390/cancers14030849
Popis: The survival rate among children with relapsed tumors remains poor, due to tumor heterogeneity, lack of directly actionable tumor drivers and multidrug resistance. Novel personalized medicine approaches tailored to each tumor are urgently needed to improve cancer treatment. Current pediatric precision oncology platforms, such as the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study, reveal that molecular profiling of tumor tissue identifies targets associated with clinical benefit in a subgroup of patients only and should be complemented with functional drug testing. In such an approach, patient-derived tumor cells are exposed to a library of approved oncological drugs in a physiological setting, e.g., in the form of animal avatars injected with patient tumor cells. We used molecularly fully characterized tumor samples from the INFORM study to compare drug screen results of individual patient-derived cell models in functional assays: (i) patient-derived spheroid cultures within a few days after tumor dissociation; (ii) tumor cells reisolated from the corresponding mouse PDX; (iii) corresponding long-term organoid-like cultures and (iv) drug evaluation with the corresponding zebrafish PDX (zPDX) model. Each model had its advantage and complemented the others for drug hit and drug combination selection. Our results provide evidence that in vivo zPDX drug screening is a promising add-on to current functional drug screening in precision medicine platforms.
Databáze: OpenAIRE
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