A Vancouver team led by TFRI-funded investigator Dr. David Huntsman has discovered an important therapeutic target for treating small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). This is a rare, but extremely lethal, ovarian cancer in young women with no effective treatment.
The present study, published in The Journal of Pathology (June 2017), suggests that SCCOHT tumour cells need the activity of an enzyme called EZH2 for their survival. This enzyme adds methyl groups to the dedicated site of histones, a group of proteins that maintain the proper structure of DNA, and thereby controls which genes to turn on or off.
Two EZH2 inhibitors (GSK126 and EPZ-6438), in various trials, displayed robust pre-clinical activities against SCCOHT tumour, and are therapeutic targets with the potential to help patients living with this disease. The median age of diagnosis is 24; most women succumb within two years.
Further, the synthetic lethality between the deficiencies in a multi-protein complex called SWI/SNF chromatin remodeling complex and EZH2 inhibition has been proposed. The present study provided solid evidence supporting this notion in the context of a rare ovarian cancer that is fully driven by complete loss of the enzymatic activity of SWI/SNF complex. The findings also suggest that the deficiency of SWI/SNF complex alone is not sufficient to predict cellular sensitivity to EZH2 inhibition and the cellular context does play an important role.
Looking forward, the team is working to identify "molecular markers" to predict the response of SCCOHT tumours to EZH2 inhibitors. By seeing which markers are present in patients, researchers can determine the SCCOHT patients that will benefit from the treatment. One of the biggest risks of treating cancer patients with a single drug is the almost inevitable development of resistance to that drug. With this in mind, the group will develop strategies that can improve the efficacy of EZH2 inhibitor treatment alone.
Study: The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.
Authors: Yemin Wang, Shary Yuting Chen, Anthony N Karnezis, Shane Colborne, Nancy Dos Santos, Jessica D Lang, William PD Hendricks, Krystal A Orlando, Damian Yap, Friedrich Kommoss, Marcel B Bally, Gregg B Morin, Jeffrey M Trent, Bernard E Weissman and David G Huntsman.
Funding: This study was funded in part by the Terry Fox Research Institute’s New Frontiers Program Project Grant in the genomics of forme fruste tumours; new vistas on cancer biology and treatment.