Precision Therapy for Mesothelioma: Feasibility and New Opportunities.

Sean Dulloo,Dean Anthony Fennell,Aleksandra Bzura

doi:10.3390/cancers13102347

Sean Dulloo, Dean Anthony Fennell + Show 1 more

Open Access

https://doi.org/10.3390/cancers13102347

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Abstract

Simple SummaryMesothelioma remains a lethal cancer. Personalized treatment is lacking. Emerging insights into the genomic and epigenomic landscape of mesothelioma highlight promising opportunities for precision therapy, where are discussed.Malignant pleural mesotheliomas (MPMs) are characterised by their wide variation in natural history, ranging from minimally to highly aggressive, associated with both interpatient and intra-tumour genomic heterogeneity. Recent insights into the nature of this genetic variation, the identification of drivers, and the emergence of novel strategies capable of targeting vulnerabilities that result from the inactivation of key tumour suppressors suggest that new approaches to molecularly strategy therapy for mesothelioma may be feasible.

Highlights

Over the last decade, multiple landmark next-generation sequencing studies of Malignant pleural mesotheliomas (MPMs) have shed light on the spectrum of recurrently mutated cancer genes [1,2,3,4]
Preclinical studies demonstrated a correlation between merlin loss and upregulation of focal adhesion kinase (FAK); inhibition of FAK was associated with the selective killing of merlin deficient cell lines, highlighting a potential synthetic lethal relationship [24,25]
The primary endpoint for this trial was 12-week disease control which was met with a disease control rate of 58% with evidence of durable partial responses lasting more than a year, with manageable toxicity

Summary

Targeting Hippo Pathway Mutations—Disrupting an Oncogenic Pathway?

One of the most frequent pathways to be inactivated in MPM involves Hippo signalling, a pathway that regulates organ size. Preclinical studies demonstrated a correlation between merlin loss and upregulation of focal adhesion kinase (FAK); inhibition of FAK was associated with the selective killing of merlin deficient cell lines, highlighting a potential synthetic lethal relationship [24,25]. This concept was tested in a merlin-stratified, global randomised phase 2 trial called COMMAND [26,27,28], comparing maintenance defactinib or placebo. TEAD signalling upregulates ferroptosis modulators ACSL4 and TFRC, leading to enhanced sensitivity to agents such as sorafenib or sulphasalazine that can modify glutamate transport and cellular redox state [33,34]

BAP1 Inactivation

PTCH-1

Findings

Conclusions