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

Abstract

Cancer frequency and prevalence have been increasing in the past decades, with devastating impacts on patients and their families. Despite the great advances in targeted approaches, there is still a lack of methods to predict individual patient responses, and therefore treatments are tailored according to average response rates. "Omics" approaches are used for patient stratification and choice of therapeutic options towards a more precise medicine. These methods, however, do not consider all genetic and non-genetic dynamic interactions that occur upon drug treatment. Therefore, the need to directly challenge patient cells in a personalized manner remains. The present review addresses the state of the art of patient-derived in vitro and in vivo models, from organoids to mouse and zebrafish Avatars. The predictive power of each model based on the retrospective correlation with the patient clinical outcome will be considered. Finally, the review is focused on the emerging zebrafish Avatars and their unique characteristics allowing a fast analysis of local and systemic effects of drug treatments at the single-cell level. We also address the technical challenges that the field has yet to overcome.The arrival of precision medicine and immunotherapy are giving hope to finally manage cancer treatment. Many advances were made possible due to the discovery of molecular pathways in tumor cells and on their interaction with the surrounding tumor microenvironment (TME) [1], leading to the development of many new therapies. The latest successes in HER2-targeted therapy and the discovery of immune checkpoint inhibitors are great examples of this [2]. However, not all patients respond and many are not eligible for these "new therapies". Thus, nowadays, the majority of patients are still treated with traditional chemo/radiotherapy and surgery according to clinical guidelines, which are developed and approved based on average efficacy rates.As a result of this "one-size-fits-all" approach, treatments may prove to be efficient for some patients but not for others. For example, in the international therapeutic guidelines (NCCN and ESMO) for advanced colorectal cancer (CRC) there are two main chemotherapeutic arms (FOLFOX and FOLFIRI), which show very similar response rates of~50% [3,4]. In other words,~50% of patients respond to treatment while~50% do not. Clinicians do not know in which group patients will fall, as there is no predictive screening test to provide this information. Thus, patients that start with FOLFOX and do not respond change to FOLFIRI, and vice-versa. This applies for CRC and many other cancers, being especially relevant in the metastatic scenario when oncology therapy guidelines reach branch

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

“…Within this approach, treatment response to olaparib has been extensively studied in in vivo mouse models, through analysis of tumor size and survival rates [53,[83][84][85][86][87]. Even though the mouse model is the gold standard, mouse patient derived xenografts take about~2-4 months for sample engraftment and expansion, which makes it unfeasible for clinical decision-making [32].…”

“…The zebrafish model presents numerous advantages and has been used in several experimental approaches, including drug screenings and the generation of patient-derived zebrafish Avatars, using embryonic-larval stages or even adult zebrafish [30,31,33,[88][89][90][91]. The optical transparency and single-cell resolution allow for the evaluation of different readouts apart from the classically used tumor size analysis [32,91].…”

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

“…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.…”

“…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 ).…”

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

“…In recent years, the zebrafish embryo and adult received increasing attention as an avatar for human cancer cells, but mostly originating from solid tumors. Many cell lines derived from human cancers, including breast cancer [14], melanoma [15] or gastric cancer [16] among others, have successfully been transplanted into zebrafish embryos (reviewed in [17]). The first successful PDX performed in 2-day old zebrafish embryos engrafted gastrointestinal human tumors [18], and were followed by xenografting patient-derived samples of neuroendocrine tumors [19] and colorectal cancers [20].…”