Zebrafish Patient-Derived Xenografts Identify Chemo-Response in Pancreatic Ductal Adenocarcinoma Patients

Usai, Alice; Franco, Gregorio Di; Piccardi, Margherita; Cateni, Perla; Pollina, Luca Emanuele; Vivaldi, Caterina; Vasile, Enrico; Funel, Niccola; Palmeri, Matteo; Dente, Luciana; Falcone, Alfredo; Giunchi, Dimitri; Massolo, Alessandro; Raffa, Vittoria; Morelli, Luca

doi:10.3390/cancers13164131

Cited by 12 publications

(17 citation statements)

References 49 publications

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“…This study very elegantly used small pieces of stained tissue and transplanted these pieces into the yolk of zebrafish embryos [40,58]. The model was predictive if compared to the response rates of the tumor to the different chemotherapy protocols known from the literature and was further validated in a prospective study with PDAC patients [59]. From 16 zPDX models, the chemosensitivity profile was compared to the clinical response to adjuvant chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…From 16 zPDX models, the chemosensitivity profile was compared to the clinical response to adjuvant chemotherapy. The model predicted relapse/no relapse within one year after surgery for 12 out of 16 patients and was able to identify those patients who responded to chemotherapy [59]. A co-clinical trial (ClinicalTrials.gov Identifier:NCT00070213) is currently running to test the zPDX model with more solid cancers [58].…”

Section: Discussionmentioning

confidence: 99%

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Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Gatzweiler

Ridinger

Herter

et al. 2022

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Gatzweiler

Ridinger

Herter

et al. 2022

Cancers

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“…As first described by our team for PDAC co-clinical trial [ 15 ], a Linear Mixed effect Model (LMM) [ 18 ] was adopted to analyze the treatment effects on zPDX tumor and to investigate the zPDX specific response. The xenografted tumor was considered as a spherical object, according to the circularity analysis (see Supplementary Materials ).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, our aim is to evaluate the possibility to use zPDXs for patients with colorectal cancer. After the encouraging results that we have already reported about the first zebrafish larval co-clinical trial (XenoZ, NCT03668418) for patients with pancreatic ductal adenocarcinoma (PDAC) [ 15 , 16 ], we are now presenting the results obtained with the zPDX of patients that underwent surgical resection for colorectal cancer. Instead of using the procedure of isolated cancer cells xenografts, we decided to use the approach in which pieces of the patient’s tumor tissue are directly xenotransplanted into zebrafish embryos, taking advantage that they have not yet developed an adaptive immune response.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients

et al. 2022

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The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine.

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“…Avatars were created using tissues from 24 patients affected by pancreatic, colon, and gastric cancers, and different chemotherapeutic regimens were tested to measure the fragments area regression [ 208 ]. The samples belonged to patients enrolled in NCT03668418 (xenoZ) co-clinical trials, an observational prospective study based on the xenotransplantation of primary hepato–biliary–pancreatic and gastro–intestinal cancer samples in zebrafish embryos [ 209 ]. The XenoZ model demonstrated the prediction of the patient’s clinical outcomes, discriminating between responders and non-responders patients.…”

Section: Precision Medicine In Hnsccsmentioning

confidence: 99%

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

Miserocchi

Spadazzi

Calpona

et al. 2022

JPM

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Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.

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Zebrafish Patient-Derived Xenografts Identify Chemo-Response in Pancreatic Ductal Adenocarcinoma Patients

Cited by 12 publications

References 49 publications

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

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