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

Abstract

It is increasingly evident the necessity of new predictive tools for the treatment of pancreatic ductal adenocarcinoma in a personalized manner. We present a co-clinical trial testing the predictiveness of zPDX (zebrafish patient-derived xenograft) for assessing if patients could benefit from a therapeutic strategy (ClinicalTrials.gov: XenoZ, NCT03668418). zPDX are generated xenografting tumor tissues in zebrafish embryos. zPDX were exposed to chemotherapy regimens commonly used. We considered a zPDX a responder (R) when a decrease ≥50% in the relative tumor area was reported; otherwise, we considered them a non-responder (NR). Patients were classified as Responder if their own zPDX was classified as an R for the chemotherapy scheme she/he received an adjuvant treatment; otherwise, we considered them a Non-Responder. We compared the cancer recurrence rate at 1 year after surgery and the disease-free survival (DFS) of patients of both groups. We reported a statistically significant higher recurrence rate in the Non-Responder group: 66.7% vs. 14.3% (p = 0.036), anticipating relapse/no relapse within 1 year after surgery in 12/16 patients. The mean DFS was longer in the R-group than the NR-group, even if not statistically significant: 19.2 months vs. 12.7 months, (p = 0.123). The proposed strategy could potentially improve preclinical evaluation of treatment modalities and may enable prospective therapeutic selection in everyday clinical practice.

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

“…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.…”

“…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].…”

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

“…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 ).…”

“…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.…”

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

“…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.…”