Mouse models for mesothelioma drug discovery and development

Our plain-English summary of Mouse models for mesothelioma drug discovery and development, by K.P. Seastedt, N. Pruett, C.D. Hoang (Expert Opinion on Drug Discovery, 2021).

The study

• Authors: K.P. Seastedt, N. Pruett, C.D. Hoang
• Journal: Expert Opinion on Drug Discovery
• Published: 2021;16(6):697-708
• Type of article: Review
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a review article on mouse models used for mesothelioma drug discovery and development, written with an accompanying expert opinion section. The authors grouped the available models into asbestos-induction models, genetically engineered mouse (GEM) models, and graft models (cell line transplants and patient-derived xenografts), and set out the advantages and disadvantages of each. They reported that inhalation asbestos models in Balb/c mice more often produced lung adenocarcinoma than tumours resembling malignant pleural mesothelioma and required latency of at least 12 months, while intraperitoneal asbestos injection gave latency of 7 months or more with fewer than 30% of mice developing tumours. Among GEM models with intraperitoneal asbestos, the authors reported figures such as 85% tumour development in Nf2 heterozygous mice after 12 months, and delayed disease in mice treated with the IL1 receptor antagonist anakinra (33 weeks versus 23 weeks untreated). For one patient-derived xenograft study, the engraftment rate was 40% overall. The authors concluded that no single model precisely represents the human condition.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review with an expert opinion section, covering mouse models of mesothelioma
• Who was studied: published mouse models of mesothelioma (mainly malignant pleural mesothelioma); no new patients or animals were studied by the authors
• Exposure: asbestos given to mice by inhalation or by intraperitoneal injection, alone or in genetically engineered mice; also genetic knockouts/knockins without asbestos, and transplanted mouse or human tumour cells and patient tumour fragments
• Main results:
  • In the asbestos inhalation model, Balb/c mice more often developed lung adenocarcinoma than MPM-like tumours, with latency of at least 12 months
  • The intraperitoneal asbestos injection model had long latency and low tumour yield
  • In Tp53 knockout mice given intraperitoneal asbestos, not all mice developed mesothelioma; 13% of homozygous and 76% of heterozygous mice did
  • In Nf2 heterozygous knockout mice given intraperitoneal asbestos, 85% developed mesothelioma but needed 12 months
  • In Nf2;Cdkn2a double knockout mice given intraperitoneal asbestos, median latency was 24 weeks, versus 38 weeks for Nf2 heterozygous and 45 weeks for wild-type mice
  • In the same double knockout model, the IL1 receptor antagonist anakinra delayed mesothelioma, but all treated mice eventually developed tumours
  • In Bap1 heterozygous knockout mice given intraperitoneal asbestos, 36-60% developed mesothelioma depending on asbestos dose, mostly sarcomatoid
  • In the SV40 TAg (MexTAg) model with intraperitoneal asbestos, all exposed mice developed mesothelioma at 20-40 weeks
  • In the patient-derived xenograft example, 7 of the 10 PDX models treated with chemotherapy (cisplatin and pemetrexed) showed significant growth inhibition
  • In the same patient-derived xenograft example, engraftment was 40% overall, 32% for epithelioid histology and 29% for patients who had received neoadjuvant radiation
• The authors' conclusion: The authors concluded that no single mouse model precisely represents human mesothelioma, but that the models remain essential for expanding knowledge and testing therapeutic principles; they anticipated CRISPR-Cas editing and humanized patient-derived xenograft models as future directions
• Limitations the authors state:
  • The authors stated that aspects of human MPM have not been fully replicated in any of these in vivo models, so drugs effective in mice can fail in humans
  • The authors stated that asbestos-inoculated mouse tumours do not carry the same common mutations as human mesothelioma
  • The authors stated that immunodeficient xenograft and PDX models preclude evaluation of immune-based therapies
  • The authors stated that humanized PDX models have not yet been reported for MPM

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Discovery, Inflammation, Carcinogenesis, Tumor Microenvironment, Asbestos Exposure.

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