Advanced Cellular Models for Preclinical Drug Testing: From 2D Cultures to Organ-on-a-Chip Technology

SIMPLE SUMMARY: Novel strategies that aim at personalizing cancer therapy are in rapid evolution. In the past decade, new methods to test for the efficacy of either standard-of-care medicines or novel targeted compounds have been implemented. In this review, we introduce the reader to experimental studies that employ patient-derived material to produce spheroids, organoids, or organs-on-a-chip as platforms that allow a more accurate representation of cancer complexity compared to bidimensional cell cultures. We discuss on the versatility and reliability of these model systems, provide evidence of their usage in drug screenings, and describe potential downfalls. The open question is whether or not tumor mimicry in vitro will be, in the near future, advanced enough to prospectively inform about treatment outcome on a certain patient. ABSTRACT: Cancer is a complex disease arising from a homeostatic imbalance of cell-intrinsic and microenvironment-related mechanisms. A multimodal approach to treat cancer that includes surgery, chemotherapy, and radiation therapy often fails in achieving tumor remission and produces unbearable side effects including secondary malignancies. Novel strategies have been implemented in the past decades in order to replace conventional chemotherapeutics with targeted, less toxic drugs. Up to now, scientists have relied on results achieved in animal research before proceeding to clinical trials. However, the high failure rate of targeted drugs in early phase trials leaves no doubt about the inadequacy of those models. In compliance with the need of reducing, and possibly replacing, animal research, studies have been conducted in vitro with advanced cellular models that more and more mimic the tumor in vivo. We will here review those methods that allow for the 3D reconstitution of the tumor and its microenvironment and the implementation of the organ-on-a-chip technology to study minimal organ units in disease progression. We will make specific reference to the usability of these systems as predictive cancer models and report on recent applications in high-throughput screenings of innovative and targeted drug compounds.