A Model of a Zebrafish Avatar for Co-Clinical Trials

Abstract

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).

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

“…The hypoxic conditions might explain why any BCP-ALL cells transplanted into the yolk sac survived. Our flow cytometric methods to assess total cell proliferation (CellTrace Violet) and viability (annexin V/7AAD) more accurately and independently quantify proliferation and viability in engrafted cells than the almost ubiquitously used microscopy-based methods applied to zebrafish xenograft models [20,31,[33][34][35][36][37].…”

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.…”

“…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).…”