Mesothelioma BAP1 Mutations Might Represent a Promising Target for Epigenetic Therapy

Epigenetic EZH2 inhibitors show preclinical promise against mesothelioma tumors that harbor BRCA1 associated protein-1 (BAP1) mutations, according to research published in Nature Medicine.¹

“Mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies,” reported senior author Ross Levine, MD, and coauthors at Memorial Sloan Kettering Cancer Center in New York.¹

BAP1 is a tumor-suppressor gene involved in regulating epigenetic transcription repression and gene silencing. It is deleted in several cancer types, including uveal melanoma, clear cell renal carcinoma, and mesothelioma.²

Inherited germline BAP1 mutations are rare, but Memorial Sloan Kettering Cancer Center’s Marc Ladanyi, MD, who first discovered them in 2011, has found that up to 60% of mesotheliomas harbor these mutations.

Using knockout mice with mutated BAP1, a team of Memorial Sloan Kettering Cancer Center researchers found that BAP1 inactivation is followed by increased expression of the enhancer of zeste homolog 2 (EZH2) enzyme. EZH2 mediates the epigenetic silencing of genes involved in tumor suppression.

“When BAP1 is knocked out and EZH2 levels go up, it leads to inappropriate modification of a particular histone, which is the mechanism by which cells are able to proliferate out of control,” explained study coauthor Scott Armstrong, MD, PhD, head of Memorial Sloan Kettering’s Center for Epigenetics Research.²

Expression of another gene, SETD8, can reduce EZH2 levels, and “abrogates the proliferation of BAP1-mutant cells,” the coauthors noted.¹

Researchers at Memorial Sloan Kettering Cancer Center and the biotechnology company, Epizyme, are working together to study EZH2 inhibition in patients diagnosed with BAP1-harboring mesotheliomas.

Mesothelioma is “highly lethal” and difficult to manage, noted Memorial Sloan Kettering Cancer Center medical oncologist Marjorie Zauderer, MD. “EZH2 inhibitors already exist in the world of drug development, and some of them have already completed early-stage trials that showed they are safe to use. Now that there’s a biological rationale for why these drugs work in mesothelioma, this could be a tremendous innovation for patients.”

“Until this past June when the drug bevacizumab was shown to benefit patients, there hadn’t been a new drug for it in more than ten years,” Dr. Zauderer noted. “Although targeted therapies have been successful in many other cancers, one problem with mesothelioma has been that there aren’t many alterations that we can target,” she said. “Now that is changing.”

References:

• LaFave LM, Béguelin W, Koche R, et al. (2015). Loss of BAP1 function leads to EZH2-dependent transformation. Nature Medicine, Oct 5. doi: 10.1038/nm.3947.
• Grisham J. (2015). Collaborative Research Suggests Targeting BAP1 May Help Treat Mesothelioma. Memorial Sloan Kettering Cancer Center.