Genomic determinants of drug sensitivity in malignant pleural mesothelioma

Hypothesis:

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and poor outcomes. Epithelial-mesenchymal transition (EMT) has been implicated as a key mechanism of chemotherapy resistance in MPM, potentially sensitizing tumours to oxidative stress. Targeting EMT via PRX3 inhibition presents a promising therapeutic strategy.

Aims:

1)To determine the correlation of EMT with chemotherapy responses using transcriptomic interrogation.

2)Explore the clinical efficacy of a first in human PRX3 inhibitor which demonstrates reversal of EMT and to determine whether EMT and response to PRX3 inhibition is correlated.

Methods:

Patients enrolled under the MEDUSA study who subsequently progressed following extended pleurectomy decortication and went on to receive standard of care pemetrexed and carboplatin chemotherapy, will be studied with regards to obtaining chemotherapy and radiology data. Further analysis of RNA sequencing data and gene set enrichment analysis (GSEA) to examine the relationship between EMT gene expression and clinical outcome will be carried out. GSEA on cell lines treated with platinum/pemetrexed was also carried out to cross validate. Coordination of a first in human PRX3 inhibitor study (MITOPE) and to explore whether EMT is correlated with response.

Results:

EMT was enriched in resistant patients and cell lines giving us cross validation. Interferon signalling in responders was an unexpected finding opening up an avenue for further research. PRX3 inhibitor RSO-021 reverses EMT in an explant study in our laboratory, suggesting that sarcomatoid transformation exhibits adaption to hypoxia via a TGF-β/TEAD/EMT axis which is reversible by PRX3 inhibition.