Anticancer drug discovery using multicellular tumor spheroid models

ABSTRACT

Introduction: Despite the increasing financial outlay on cancer research and drug discovery, many advanced cancers remain incurable. One possible strategy for increasing the approval rate of new anticancer drugs for use in clinical practice could be represented by three-dimensional (3D) tumor models on which to perform in vitro drug screening. There is a general consensus among the scientific community that 3D tumor models more closely recapitulate the complexity of tumor tissue architecture and biology than bi-dimensional cell cultures. In a 3D context, cells are connected to each other through tissue junctions and show proliferative and metabolic gradients that resemble the intricate milieu of organs and tumors.

Areas covered: The present review focuses on available techniques for generating tumor spheroids and discusses current and future applications in the field of drug discovery. The article is based on literature obtained from PubMed.

Expert opinion: Given the relative simplicity of spheroid models with respect to clinical tumors, we must be careful not to overestimate the reliability of their drug-response prediction capacity. The next challenge is to combine our knowledge of co-culture methodologies with high-content imaging and advanced microfluidic technologies to improve the readout and biomimetic potential of spheroid-based models.

KEYWORDS:

• Anticancer drug discovery
• high throughput assay
• in vitro 3D models
• preclinical drug evaluation
• tumor spheroids

Article highlights

● Despite significant time and effort dedicated to the area of drug discovery, the approval rate of new anticancer drugs remains low (≤5%).

● Three-dimensional (3D) tumor models represent a potential strategy to improve the approval rate for anticancer drugs as they bridge the gap between in vitro testing, animal models and clinical trials.

● 3D in vitro tumor models better recapitulate the complex architectural and biological scenario of the tumor microenvironment compared to bidimensional (2D) cell cultures.

● Among 3D in vitro models, multicellular tumor spheroids have become popular as preclinical drug screening platforms due to their potential flexibility and capability to recapitulate major clinical tumor features.

● Numerous techniques are available to generate tumor spheroids and to analyze the effects of physical or chemical anticancer drug treatments.

● Although some issues still need to be addressed, there is great potential for improving 3D spheroid-based drug screening platforms to better recapitulate the 3D pathophysiological environment of clinical tumors.

● Looking ahead, the combination of the techniques for the generation of patient-derived tumor organoids with the technologies for spheroid assembly in HTC assays appear a promising, albeit challenging, solution to bridge the gap between the results from preclinical models and clinical trials.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Gráinne Tierney of the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori for their editorial assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.