Monophasic synovial sarcoma

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.

"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.

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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.