Translating mesothelioma molecular genomics and dependencies into precision oncology-based therapies

Our plain-English summary of Translating mesothelioma molecular genomics and dependencies into precision oncology-based therapies, by T.K. Hinz, L.E. Heasley (Seminars in Cancer Biology, 2020).

The study

• Authors: T.K. Hinz, L.E. Heasley
• Journal: Seminars in Cancer Biology
• Published: 2020;61:11-22
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare, yet lethal asbestos-induced cancer and despite marked efforts to reduce occupational exposure, the incidence has not yet significantly declined. Since 2003, combined treatment with a platinum-based agent and pemetrexed has been the first-line therapy and no effective or approved second-line treatments have emerged. The seemingly slow advance in developing new MPM treatments does not appear to be related to a low level of clinical and pre-clinical research activity. Rather, we suggest that a key hurdle in successfully translating basic discovery into novel MPM therapeutics is the underlying assumption that as a rare cancer, it will also be molecularly and genetically homogeneous. In fact, lung adenocarcinoma and melanoma only benefitted from precision oncology upon full appreciation of the high degree of molecular heterogeneity inherent in these cancers, especially regarding the diversity of oncogenic drivers. Herein, we consider the recent explosion of molecular and genetic information that has become available regarding MPM and suggest ways in which the unfolding landscape may guide identification of novel therapeutic vulnerabilities within subsets of MPM that can be targeted in a manner consistent with the tenets of precision oncology.

Copyright © 2019. Published by Elsevier Ltd.

In plain English

This review examined research on the genetics of malignant pleural mesothelioma (MPM) and how it might guide targeted treatment ("precision oncology"). Besides summarizing earlier studies and trials, the authors analyzed public data on 87 pleural mesotheliomas in the Cancer Genome Atlas (TCGA) and on MPM cell lines screened in two laboratory projects. In the TCGA tumors, deep deletion of the CDKN2A gene was the most common alteration (46%), and about 25% had no changes in any of five common tumor suppressor genes. The authors counted a tumor as positive when its FGFR1 mRNA was at or above the average and its mRNA for at least one known FGFR1 ligand (FGF2, FGF9 or FGF18) was above that ligand's average. By this measure, 24 of 87 tumors (28%) were positive for both. Of those 24, 11 (46%) had BAP1 changes, versus 32% overall, a difference that was not statistically significant (p = 0.124). Cell lines with normal TP53 were more sensitive to the drug Nutlin 3a. The authors concluded the field should move away from treating all patients alike and toward precision oncology. They noted that available cell lines are unlikely to fully reflect the disease. The article did not study asbestos exposure.

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: Review of genomic, laboratory and clinical trial research on malignant pleural mesothelioma, including the authors' own analyses of publicly available datasets (TCGA, DepMap, GDSC)
• Who was studied: Published literature on MPM; 87 pleural mesothelioma tumors in the Cancer Genome Atlas (TCGA); human MPM cell lines screened in the DepMap and GDSC projects
• Exposure: Not studied. The authors state that the minerals and substances linked with MPM, and efforts to limit occupational and environmental exposure, are outside the scope of this review.
• Main results:
  • In the 87 TCGA pleural mesotheliomas, deep deletion of CDKN2A was the most common alteration, found in 46%
  • About 25% of the TCGA tumors had no alterations in any of the five most common tumor suppressor genes (CDKN2A, BAP1, NF2, LATS2, TP53)
  • FGFR1-positive tumors were those with FGFR1 mRNA expression greater than or equal to the mean
  • Among FGFR1-positive tumors, those also with expression above the mean for FGF2, FGF9 or FGF18 numbered 24 of 87 TCGA tumors (28%). This is an expression measure, not a direct measure of pathway activity.
  • Among the 24 FGFR1-FGF high tumors, 11 (46%) had BAP1 mutations or deletions, compared with 32% in the whole TCGA cohort
  • The difference in BAP1 alteration frequency was not statistically significant (Fisher's exact test, p = 0.124)
  • In GDSC data, MPM cell lines with wild-type TP53 were more sensitive to the MDM2 inhibitor Nutlin 3a than lines with missense TP53 mutations or low TP53 expression
  • In DepMap, MPM cell lines ranked 7th of 33 cancer categories for dependency on FGFR1
  • An 18-gene interferon gamma-related immune signature calculated for the 87 TCGA tumors did not obviously correlate with tumor histology or with alterations in NF2, BAP1, TP53 or CDKN2A
• The authors' conclusion: The authors concluded that MPM is molecularly heterogeneous and that the field should move away from "all comers" treatment strategies toward precision oncology guided by pre-clinical studies and molecular biomarkers.
• Limitations the authors state:
  • The MPM cell lines screened in DepMap and GDSC are unlikely to fully reflect the diversity of the disease
  • FGFR1 and FGF expression levels are continuous measures and are harder to use as biomarkers than simple mutation or copy number changes

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Occupational Exposure, Pemetrexed (Alimta), First-line Therapy, Discovery, Lung Adenocarcinoma.

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