Mouse models for mesothelioma drug discovery and development

ABSTRACT

Introduction

Mesothelioma is an aggressive mesothelial lining tumor. Available drug therapies include chemotherapeutic agents, targeted molecular therapies, and immune system modulators. Mouse models were instrumental in the discovery and evaluation of such therapies, but there is need for improved understanding of the role of inflammation, tumor heterogeneity, mechanisms of carcinogenesis, and the tumor microenvironment. Novel mouse models may provide new insights and drive drug therapy discovery that improves efficacy.

Areas covered

This review concerns available mouse models for mesothelioma drug discovery and development including the advantages and disadvantages of each. Gaps in current knowledge of mesothelioma are highlighted, and future directions for mouse model research are considered.

Expert opinion

Soon, CRISPR-Cas gene-editing will improve understanding of mesothelioma mechanisms foundational to the discovery and testing of efficacious therapeutic targets. There are at least two likely areas of upcoming methodology development. One is concerned with precise modeling of inflammation - is it a causal process whereby inflammatory signals contribute to tumor initiation, or is it a secondary passenger process driven by asbestos exposure effects? The other area of methods improvement regards the availability of humanized immunocompromised mice harboring patient-derived xenografts. Combining human tumors in an environment with human immune cells will enable rapid innovation in immuno-oncology therapeutics.

KEYWORDS:

• Drugs
• inflammation
• mesothelioma
• mouse
• therapeutics
• xenograft

Article highlights

• Many drug therapies have been tested against mesothelioma with overall poor survival results necessitating the discovery of novel agents with improved efficacy

• Several mouse models are available: 1) asbestos induction, 2) genetically engineered models, and 3) graft models, including patient-derived xenografts

• No single model accurately represents human disease, and each model has its advantages and disadvantages

• Current gaps in our knowledge of mesothelioma include the role of inflammation, tumor heterogeneity, mechanisms of carcinogenesis, and the tumor microenvironment

• Novel mouse models are needed to better understand the pathophysiology of mesothelioma, with CRISPR genome editing and humanized patient-derived xenograft models as likely future avenues for innovative drug testing and development

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

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

Additional information

Funding

The authors are funded by the National Institutes of Health Intramural Research Program (ZIA BC 011657) provided to CD Hoang.