Animal "avatars" and co-clinical trials are being developed for possible use in personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient's tumor are xenotransplanted into the animal avatar for drug efficacy studies, and the data collected in the animal trial are used to plan the best drug treatment in the patient trial. Zebrafish have recently been proposed for implementing avatar models, however the lack of a general criterion for the chemotherapy dose conversion from humans to fish is a limitation in terms of conducting co-clinical trials. Here, we validate a simple, reliant and cost-effective avatar model based on the use of zebrafish embryos. By crossing data from safety and efficacy studies, we found a basic formula for estimating the equivalent dose for use in co-clinical trials which we validated in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, NCT03668418).

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Glaucoma and other optic neuropathies are characterized by a loss of retinal ganglion cells (RGCs), a cell layer located in the posterior eye segment. Several preclinical studies demonstrate that neurotrophins (NTs) prevent RGC loss. However, NTs are rarely investigated in the clinic due to various issues, such as difficulties in reaching the retina, the very short half-life of NTs, and the need for multiple injections. We demonstrate that NTs can be conjugated to magnetic nanoparticles (MNPs), which act as smart drug carriers. This combines the advantages of the self-localization of the drug in the retina and drug protection from fast degradation. We tested the nerve growth factor and brain-derived neurotrophic factor by comparing the neuroprotection of free versus conjugated proteins in a model of RGC loss induced by oxidative stress. Histological data demonstrated that the conjugated proteins totally prevented RGC loss, in sharp contrast to the equivalent dose of free proteins, which had no effect. The overall data suggest that the nanoscale MNP-protein hybrid is an excellent tool in implementing ocular drug delivery strategies for neuroprotection and therapy.Electronic supplementary materialThe online version of this article (10.1007/s00018-017-2691-x) contains supplementary material, which is available to authorized users.

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.

24Animal ''Avatars'' and co-clinical trials represent an emerging concept for 25 implementing schemes of personalized medicine in oncology. In a co-clinical 26 trial, the cancer cells of the patient tumor are xenotransplanted in the animal 27 Avatar for drug efficacy studies and data collected in the animal trial are used 28 to plan the best drug treatment in the patient trial. Recently, zebrafish has 29 been proposed for implementing Avatar models but the lack of a general 30 criterion for chemotherapy dose conversion from humans to fishes represents 31 a limitation for conducting co-clinical trials. 32Here, we validate a simple, reliant and cost-effective Avatar model based on 33 the use of zebrafish larvae; by crossing data from safety and efficacy studies, 34 we found a basic formula for the estimation of the dose to be used for running 35 co-clinical trials and we validate it in a clinical study enrolling 24 adult patients 36 with solid cancers (XenoZ, NCT03668418). 37 ABBREVIATIONS 38 5-FU, 5-Fluorouracil; dpf, days post fertilization; DMEM, Dulbecco's modified 39 Eagle's medium; FBS, fetal bovine serum; ECF, 5-Fluorouracil + Cisplatin + 40 Epirubicin; FLOT, 5-Fluorouracil + Lederfolin + Oxaliplatin + Docetaxel; 41 FOLFIRI, 5-Fluorouracil + Lederfolin + Irinotecan; FOLFOX, 5-Fluorouracil + 42 Lederfolin + Oxaliplatin; FOLFOXIRI, 5-Fluorouracil + Lederfolin + Oxaliplatin 43 + Irinotecan; GEM, Gemcitabine; GEMCIS, Gemcitabine + Cisplatin; 44 GEM/nab-P, Gemcitabine + nab-Paclitaxel; GEMOX, Gemcitabine + 45 Oxaliplatin; hpf, hours post fertilization; hpi, hours post injection 48Precision medicine refers to the approaches for tailoring a medical treatment 49 to the individual characteristics of each patient (1). In particular, the "Mouse 50 Avatar" is an emerging approach of precision medicine in oncology that has 51 recently grown in importance (2); it implicates the xenotransplantation of 52 cancer cells from patient tumor sample in mouse models to use them in drug 53 efficacy studies. Mouse Avatars can be used to run "co-clinical trials" (3). In a 54 co-clinical trial, the patient and murine trials are concurrently conducted and 55 the drug efficacy response of the mouse study provides data to plan the best 56 drug treatment of the patient tumor (4). The advantage of this approach is that 57 each patient has his/her own tumor growing in an in vivo system, thereby 58 allowing the identification of a personalized therapeutic approach. Nowadays, 59 there are companies providing mouse Avatar generation and drug testing 60 services to patients at a cost of tens thousands of dollars (5). The high cost is 61 directly associated to the time-consuming process and the requirement of 62 immunosuppressed strains (6). Unfortunately, this makes Avatars a cutting-63 edge technology available only for few people, posing a serious threat to the 64 equal right to health for everyone. Recently, it has been proposed the use of 65 zebrafish to make Avatars available for every patient and the approach 66 sustainable for N...