A model of Zebrafish Avatar for co-clinical trials

Abstract

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...

Zebrafish for Personalized Regenerative Medicine; A More Predictive Humanized Model of Endocrine Disease

“…For example, difficulty in the evaluation of engraftment in the early steps, the adverse effects of irradiation regimes, prolonged engraftment assessing procedures, special maintenance requirements for immunosuppressed animals, and restriction in the number of animals that can be screened which consequently raise the overall cost and duration. All of these, are limitations that justify substituting more qualified alternatives ( 11 , 70 ). It has now become clear that Zebrafish has many advantages over mice.…”

“…It has now become clear that Zebrafish has many advantages over mice. Embryo transparency that enables in-vivo imaging of engrafted cells, high permeability to small molecules of chemotherapy drugs, providing a rejection-free environment with high proliferation rate of xenotransplanted cancer cells, enabling multiple drug tests with low cost housing and faster maturation and reproduction rate, less ethical issues along with similar chemo-sensitive responses with mice are what makes zebrafish a better avatar for personalized medicine in cancer studies ( 11 , 12 ). Additionally, Zebrafish has a relatively identical genetic profile to humans that makes it a perfect tool for genetic manipulation.…”

“…Since many kidney diseases are caused by mono/polygenic mutations, zebrafish is used to both reveal the underlying genetic mutation and pathophysiology and model for drug screening in the hopes of personalized medicine) ( 71 – 73 ). On the other hand, zebrafish is distinctly useful in personalized medicine when treatment options are abundant, etiologies are not well-established, or the abnormality is rare; like endocrine disorders, cancers, and Duchene muscular dystrophy ( 11 , 74 , 75 ). Regarding endocrine and metabolic diseases, zebrafish is reported to have great potential as a model for investigating thyroid diseases including thyroid cancer, thyroid hormones, and its receptors defects.…”

“…Taken together, it can be concluded that unique features of zebrafish like high regenerative capacity, easier disease induction, low-cost housing, high maturation rate, and fecundity along with the utility of zebrafish in modeling endocrine and metabolic disorders, make it a better choice for developing personalized regenerative treatment. Treatments developed with zebrafish modeling are available faster and to a larger group of patients since this method produces faster results with lower cost ( 11 , 63 , 66 ).…”

“…Regarding this given capacity, it is used for different models of injury for example in cardiovascular, neurological, and metabolic diseases ( 9 , 10 ). Additionally, zebrafish is used as an animal model in personalized medicine for studying different diseases like cancers as avatars due to its beneficial advantages which are discussed in this review ( 11 , 12 ). Moreover, it is mentioned that zebrafish was used in investigating one of the unique features in humans, the gut microbiota, in order to find the associations between metabolic disorders and intestinal microbiota ( 13 ).…”