Originally identified as a gene involved in embryogenesis, specifically, in brain development of vertebrates, scientists from the University of Surrey and the University of Bradford in the UK detailed a mechanism by which Engrailed-2 (EN2) may provide a mode of communication between prostate cancer cells and the surrounding stroma.
The EN2 protein was detected in several prostate cancer cell lines and in one cell line, the protein was observed to be secreted and taken up by adjacent cells.
Future of prostate cancer
This cell–cell contact begs the question of what message the cancer cells are spreading, and what potential consequences it may have for target cells.
One potential effect the authors observed was a dose-dependent increase in the protein MX dynamin-like GTPase2 (MX2); although the consequences of this gene expression are unknown, it was hypothesized that this may provide some resistance to the immune killing of tumours, as the MX2 protein prevents viral infection and transmission.
Although this “infectious” mechanism appears to be an anomaly, perhaps the most interesting feature is EN2’s potential clinical applications in the fight on prostate cancer.
Future of prostate cancer: diagnosis
One unmet need for prostate cancer that could be addressed by EN2 is the need for a better diagnostic and prognostic biomarker. Currently, men may request to be tested for prostate-specific antigen (PSA), a protein that is notorious for its low sensitivity and specificity, often picking up false positives that cause undue stress on patients, require further testing, and impact healthcare budgets.
A better diagnostic test is necessary to continue routine screening of men, and while the study authors reported no EN2 expression on normal prostate cancer cells, they also were unable to identify EN2 expression on all prostate cancer cell lines, suggesting that this test may suffer from the opposite problem of false negatives.
However, a clinical investigation of prostate cancer biopsies will be necessary to determine what proportion of tumours express this protein and whether its expression is heterogeneous within an individual tumour.
Future of prostate cancer: research
The Prostate Project, a registered UK charity, has funded research into EN2 as a diagnostic biomarker, and results have shown that up to 66% of men may be accurately identified using this protein. A large advantage of this test is that it is not invasive, requiring only a urine sample, with confirmation through biopsy.
It will be important for researchers to determine what percentage of patients express the EN2 protein and at what level, as it may have an application as a therapeutic target in men who express the protein or as a prognostic marker, especially if it is not universally expressed among prostate cancers.
Importantly, the study authors localized the protein on the cell surface. As an embryonic gene not generally expressed in normal adult tissue, it may prove a good target to direct chemotherapy to the correct cells, saving normal tissues from its toxic effects.
This strategy, termed antibody-drug conjugates, or ADCs, has been exploited by multiple companies already, with notable approvals for Adcetris (brentuximab vedotin) for Hodgkin’s lymphoma and Mylotarg (gemtuzumab ozogamicin) for acute myeloid leukaemia.
The case is still open for EN2 as investigators learn more about this unusual protein and determine whether there are any clinical uses to its expression in cancer. Prostate cancer patients could greatly benefit from either of the identified applications, as early identification and treatment can greatly improve clinical outcomes.
Overall, survival rates for early-stage prostate cancer are high, but patients with metastatic disease still lack options and are mostly dependent upon hormonal agents. Such research studies continue to provide hope to men afflicted by this common cancer.
GlobalData (2019). Prostate Cancer: Global Drug Forecast and Market Analysis to 2028, to be published.