Cancer Cell publishes Epizyme and collaborators' breakthrough research on MLL

Epizyme, Inc., a company leading the discovery and development of personalized therapeutics for genetically-defined cancer and rare disease patients, and its collaborators announced the publication in Cancer Cell of breakthrough research in the treatment of MLL-rearranged leukemia (MLL), a genetically-defined subset of acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML).

This seminal research demonstrates for the first time that a small molecule histone methyltransferase inhibitor (HMTi) can:

• selectively kill genetically-defined MLL tumors in vitro, with little effect on non-MLL leukemia cells, and
• drive a statistically significant anti-tumor survival benefit in an in vivo model.

HMTs are a class of epigenetic enzymes that regulate entire pathways of gene expression. Many members of this 100-member target class have strong genetic associations with the underlying causes of human diseases, including cancer and orphan diseases. In MLL, chromosomal rearrangements of the MLL gene result in aberrant recruitment of the DOT1L HMT, which drives the expression of genes that are leukemogenic in the affected patients. Researchers exposed leukemic cells in vitro to Epizyme's potent and DOT1L-targeted HMTi, selectively killing genetically-defined cells bearing the MLL rearrangement. When Epizyme's compound was administered in vivo in an aggressive disseminated mouse model of MLL, the treatment led to statistically significant extension of survival at every dose tested.

"MLL is a devastating disease that affects both pediatric and adult patients. Inhibiting DOT1L with potent, targeted small molecules like Epizyme's HMTi represents a promising new therapeutic avenue for the treatment of this specific and genetically-defined subset of leukemia," said Bruce Chabner, M.D., the Director for Clinical Research at the Massachusetts General Hospital Cancer Center, former head of the Division of Cancer Treatment at the National Cancer Institute, and Epizyme SAB member.

"Our ability to create targeted small molecules that selectively inhibit the enzymatic activity of DOT1L in vitro and in vivo is a breakthrough for the field of epigenetic drug discovery," said Roy Pollock, Ph.D., Director of Biological Sciences at Epizyme and corresponding author on the paper.

Dr. Robert A. Copeland, EVP of R&D and CSO, said, "The findings published today are a giant step forward in the translation of HMT science to the development of targeted epigenetic therapies through the demonstration of anti-tumor activity in an in vivo model. Our DOT1L program's progress is an example of the power of Epizyme's approach to creating personalized therapeutics for patients with genetically-defined diseases. In addition to DOT1L, Epizyme is pursuing a rich pipeline of proprietary and partnered HMTi therapeutic programs, all of which are directed to patient-defined targets."  

Soure: Epizyme