Patient-derived organoid analysis of drug resistance in precision medicine: is there a value?

Abstract

Cancer is the main health problem with high morbidity and mortality. The worldwide annual incidence and deaths from cancers are estimated in millions [1,2]. Hence, cancer therapy must be continuously promoted and developed. Cancer study, like in other diseases, highly depends on representative and reliable models. However, the tumor is not uniform, but rather a heterogenic and highly variable and complex than other diseases, rendering its study extremely difficult, expensive [3]. The most common treatment methods for cancers are based on surgery [4], chemotherapy [5], radiotherapy [6], and immunotherapy [7]. The response of cancers to these various treatment strategies differs according to tumor subtype, clinical stage, and associated risk factors and unfortunately fails to limit the progression of cancer in various cases. Even the same tumor of the same organ or tissue differs in response to therapy among patients and the recurrence and metastasis which are associated with high resistance to therapy are main issues [8]. Also, chemotherapy affects the quality of life because of its potential side effects and therefore disfavored by many patients. Therefore, suitable models to expect the treatment response with high precision are of extreme need toward more personalized treatment of patients. Experimental models are assigned to understand the pathobiology, identify diagnostic and prognostic biomarkers of cancer progression and establish novel potent and effective therapies. To date, the available treatment protocols seem inadequate to prevent the resistance to therapy as well as the recurrence and progression of cancer. Therefore, several experimental models of to study cancer development and progression including rats and mice as well as the in vitro culture models of cell line, 2D cell, induced pluripotent stem cell (iPSCs) lines, spheroids, 3D organoids, organotypic tissue slice cultures, patient-derived tumor xenografts are developed [9–11] and certainly, they confer valuable tools for preclinical pharmacological assessment. Cancer stem cells (CSCs) are tumor-initiating cells capable of conserving cellular heterogeneity, self-renewal, epithelial to mesenchymal transition, differentiation to form all kind cells in a given tumor [12] and drive the tumor growth, metastasis and most importantly, the resistance to conventional anticancer agents [13–22]. Therefore, the total eradication of CSCs is crucial for the successful treatment of cancers. Thus, understanding the mechanism of response and resistance of CSCs to therapy and developing personalized therapy is the cornerstone for treatments of cancer in cancer patients. Currently, the selection of the correct tool to use in the laboratory to elucidate the mechanism of CSCs’ resistance to therapy can depend on the question on hand, but also on the resources (and knowledge) available. Among them, organoids constitute the more reasonable method in recapitulating the in vivo microenvironment of the tumor, and easier handling as well as high throughput screening than slice cultures or xenografts. During the past decade, researchers have made substantial progress in the field of organoid biology, and organoid systems have already been reviewed in detail elsewhere [21,23,24].