US-based biopharmaceutical firm Epizyme has reported positive pre-clinical data from its Phase I/II trial of EPZ-6438 (E7438), its oral, small molecule inhibitor of EZH2, in models of synovial sarcoma, a soft tissue sarcoma that typically affects young adults.
EZH2 is a histone methyltransferase (HMT), which is expected to play a potentially oncogenic role in a number of cancers such as germinal centre (GC) non-Hodgkin lymphomas, INI1-deficient cancers such as synovial sarcoma and malignant rhabdoid tumours, and a range of other solid tumours.
Synovial sarcomas are characterised by a translocation of chromosomes X and 18, generating an SS18-SSX fusion protein that creates a state of deficiency of the INI1 protein.
Epizyme Biological Sciences director Heike Keilhack said: "These data show that EPZ-6438 induced anti-proliferative activity in three of four pre-clinical models of synovial sarcoma tested.
"The data continue to reinforce the importance of EZH2 inhibition in INI1-deficient malignancies, and warrant further investigation of EPZ-6438 in these genetically defined cancers."
During the trial, synovial sarcoma cell lines and patient-derived xenograft models were evaluated for their sensitivity to EZH2 inhibition in vitro and in vivo.
The trial also evaluated histone methylation, changes in gene expression and histology endpoints.
The results showed that EPZ-6438 induced dose-dependent inhibition of cell growth and cell death specifically in SS18-SSX fusion-positive cells in vitro.
The company said that treatment of mice with either a cell line xenograft or two patient-derived xenograft models led to dose-dependent tumour growth inhibition, while treatment in a fourth xenograft model did not reflect such results.
The company along with its partner Eisai is developing EPZ-6438), a small molecule inhibitor of EZH2 created with our proprietary product platform, to treat patients with non-Hodgkin lymphoma.
Eisai secured worldwide license to EPZ-6438 (E7438), subject to Epizyme’s right to opt in for co-development, co-commercialisation and profit share arrangement.
Image: Micrograph of a monophasic synovial sarcoma. Photo: courtesy of Nephron.