Esterase enzymes are a subclass of hydrolase enzymes that function to break ester bonds. There are many known esterases, which differ in their substate specificity and biological function. Hydrolase enzymes have been shown to be highly expressed in cancer cells and have been implicated in cancer development [1, 2]. As such, the expression of esterase enzymes may be dysregulated in cancer cells and may differ in their selectivity compared with esterases in healthy tissue [3-6].
As novel peptide-drug conjugates are developed, which rely on intracellular enzymes for the selective release of a toxic ‘payload’ in cancer cells, interest in metabolic enzyme expression is growing [7, 8]. Esterase hydrolysis represents an interesting potential strategy for selective activation of anti-cancer drugs within cancer cells that overexpress esterases, or which express esterases with different specificities, while minimising toxic effects on healthy cells and tissues.
In our recently published study (https://www.nature.com/articles/s41416-020-01237-1) we compared esterase gene expression from samples taken from newly diagnosed MM patients (NDMM) with samples taken from patients who had relapsed/refractory MM (RRMM). For validation, our results were compared to data obtained from the Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) study .
We found that individual esterase genes exhibited relatively high or low expression in samples taken from patients with MM. Interestingly, the expression profiles of several esterase genes appeared different in samples taken from NDMM patients compared with RRMM patients. In our dataset we found that high expression levels of platelet-activating factor acetylhydrolase 1B2 (PAFAH1B2) and sialic acid acetyl esterase (SIAE) were associated with significantly poorer prognosis, versus patients with lower expression. Similarly, low expression levels of PCED1B were associated with poorer prognosis versus higher expression. High expression of PAFAH1B3 and SIAE, and low expression of PCED1B were validated as markers of poor prognosis in MM using the CoMMpass dataset, suggesting a role for these esterase enzymes in myeloma biology. We also identified further esterase genes where differing expression levels were associated with poorer prognosis in our dataset, which were not validated by the CoMMpass dataset, but have been previously reported to be dysregulated in cancer cells and may warrant further investigation.
This is the first time that individual esterase genes have been demonstrated to exhibit high or low expression in MM. We have also shown that esterase gene expression profiles not only change as patients progress from NDMM to RRMM, but that expression of specific esterases may be predictive of patient outcome in MM. Further work should aim to better understand the role of these esterases in myeloma biology, and how these differences in esterase gene expression could be used to promote activation of anti-cancer drugs in tumour cells, and as potential biomarkers of MM progression and treatment.
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- Fukami, T. and T. Yokoi, The emerging role of human esterases. Drug metabolism and pharmacokinetics, 2012: p. DMPK-12-RV-042.
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- Yamazaki, Y., et al., Difference between cancer cells and the corresponding normal tissue in view of stereoselective hydrolysis of synthetic esters. Biochimica et Biophysica Acta (BBA)-General Subjects, 1995. 1243(3): p. 300-308.
- Yamazaki, Y., Y.-i. Kageyama, and H. Okuno, Direct evaluation of stereoselectivity of cancer esterases by polyacrylamide gel electrophoresis coupled with activity staining with chiral naphthyl esters. Analytical biochemistry, 1995. 231(2): p. 295-300.
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- Wickström, M., et al., Melflufen-a peptidase-potentiated alkylating agent in clinical trials. Oncotarget, 2017. 8(39): p. 66641.
- Chauhan, D., et al., In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clinical Cancer Research, 2013. 19(11): p. 3019-3031.
- MMRF. Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) study. 2019; Available from: https://research.themmrf.org/.