Revealing Recurrence Risk

When diagnosed with cancer, most patients are pleased to hear that their disease is early-stage or low-grade – and most doctors are equally happy to deliver the news. But in endometrial cancer, that information doesn’t always bring the relief it would with other diagnoses. That’s because a subset of patients with early-stage, low-grade disease experience recurrence for unknown reasons, and those recurrences tend to resist further treatment. How do we know which patients are at risk of a return? We’ve had no way to tell – until now. Martina Bazzaro and her colleagues at the Masonic Cancer Center have uncovered a biomarker that could potentially predict these recurrences (1).

Deubiquitinating enzymes (DUBs) are important modulators of pathways regulating cell proliferation and chemoresistance. They’ve previously been linked to cancer initiation, progression and chemoresistance – but now, Bazzaro’s research suggests that high levels of a particular DUB known as USP14 indicate a seven-fold higher likelihood of recurrence, meaning that USP14 may be able to serve as a biomarker for recurrence risk. “USP14 is important in regulating the β-catenin pathway, as well as the epithelial-to-mesenchymal transition, both of which are related to chemoresistance in endometrial cancer,” Bazzaro explains. Examining a newly diagnosed patient’s USP14 levels could lead to more aggressive treatment and follow-up for those at higher risk, ultimately saving lives. It could also offer a potential treatment avenue – not only does USP14 serve as a marker of recurrence likelihood, but when targeted with the FDA-approved inhibitor VLX1570, the viability of chemoresistant endometrial cancer cells was found to decrease.

“The clinical test using USP14 as a biomarker would be staining for it in clinical specimens at the time of surgery and prior to chemotherapy,” says Bazzaro. Immunohistochemistry is the simplest way of testing for the enzyme, and the team anticipate that clinical trials will start within the next 18 months. “We will first assess USP14 as a marker for recurrence in prospective clinical trials, and then conduct clinical trials using VLX1570 in recurrent endometrial cancer resistant to conventional carboplatin chemotherapy.” Bazzaro also suggests that, because of the similarities between recurrent endometrial cancer and certain types of aggressive ovarian cancer, USP14 testing may eventually be recommended for ovarian cancer too.