Fishing for cures: The alLURE of using zebrafish to develop precision oncology therapies

Abstract

Zebrafish have proven to be a valuable model to study human cancer biology with the ultimate aim of developing new therapies. Danio rerio are amenable to in vivo imaging, high throughput drug screening, mutagenesis, and transgenesis, and they share histological and genetic similarities with Homo sapiens. The significance of zebrafish in the field of precision oncology is rapidly emerging. Indeed, modeling cancer in zebrafish has already been used to identify tumor biomarkers, define therapeutic targets and provide an in vivo platform for drug discovery. New zebrafish studies are starting to pave the way to direct individualized clinical applications. Patient-derived cancer cell xenograft models have demonstrated the feasibility of using zebrafish as a real time avatar of prognosis and drug response to identify the most ideal therapy for an individual patient. Genetic cancer modeling in zebrafish, now facilitated by rapidly evolving genome editing techniques, represents another innovative approach to recapitulate human oncogenesis and develop individualized treatments. Utilizing zebrafish to design customizable precision therapies will improve the clinical outcome of patients afflicted with cancer.

Zebrafish Avatars towards Personalized Medicine—A Comparative Review between Avatar Models

“…The absence of the adaptive immune response until 8dpf [125] is also an important feature of the zebrafish larval model that allows xenograft engraftment. Therefore, human tumor cells usually are not rejected until that time point, avoiding the need of immunosuppressing agents or radiation, in contrast with murine models [128]. Other characteristics such as the small size; the ability to absorb compounds through the water, avoiding the burden of administering drugs to each animal individually (although is also possible to locally or systemically inject compounds that are not so easily absorbed); the reduced amounts of drugs required per test; the possibility to have a statistically-significant number of animals per assay; less ethics constrains and low costs of husbandry, make the zebrafish larvae a very attractive and promising in vivo model for human cancer studies.…”

“…Regarding zebrafish larval xenografts using patient-derived samples, few studies have been published so far (see Table S1). Nevertheless, these studies show promising results and the reliability of the zPDX model to establish different cancer types, as it is able to overcome some of the disadvantages of the murine PDXs such as the time required to develop an assay, as well as number of cells needed for implantation [106,115,[128][129][130][131].…”

“…Another critique of the model is its incubation temperature. Since zebrafish are typically reared at 28-29 • C, and human cells thrive at 37 • C, the compromise usually adopted is to raise zebrafish xenografts at 33-35 • C, which can have an impact on the physiology of the fish and the biology of the tumor cells [128]. Lastly, another limitation of the zebrafish could be the pharmacokinetics and pharmacodynamics of some drugs.…”

“…It does not, however, consider each individual patient. In personalized medicine, on the contrary, patient-derived live cells are challenged with specific drugs, and responses can be evaluated in real time and directly transposed to the clinic [128]. However, not all possible therapeutic options can be tested in Avatars due to the restricted amount of patient material.…”

Selective Inhibition of Kras Signaling by Combination of Low Dose Rapamycin and Paclitaxel in Vivo

“…В этом случае опухоль просто не успевает сфор-мироваться из-за быстрой элиминации потенциально онкогенных клеток. Это предположение косвенно под-тверждается тем, что другие модели, основанные на экспрессии онкогена KRAS в тканях, которые ограни-чены внутренней средой организма рыб, способны приводить на определенном этапе к развитию типичных злокачественных опухолей различных локализаций [11,12]. Тем не менее эти модели имеют ряд ограничений для практического использования, обусловленных длительным (несколько месяцев) латентным периодом и отсутствием синхронности развития новообразо-ваний.…”