Mesothelioma, a cancer that usually occurs in the lining of the lung, is largely associated with exposure to asbestos, a building material widely used until the 1970s. The disease is aggressive and has historically been very difficult to treat. Now research conducted at Memorial Sloan Kettering has led to an approach that could benefit about half of all mesothelioma patients.
The cancer has been linked to both inherited and acquired mutations in a gene called BAP1. Discovered in 2011 by MSK experimental pathologist Marc Ladanyi, BAP1 mutations are also associated with inherited forms of uveal melanoma, a rare eye cancer, and a type of kidney cancer called clear cell renal cell carcinoma. Although only a small number of people with mesothelioma carry BAP1 mutations in their germline (meaning that they inherited it from their parents), Dr. Ladanyi found that 50 to 60 percent of all mesothelioma tumors have BAP1 mutations, making BAP1 a promising target for drug therapy.
“Mesothelioma is a disease that is highly lethal,” says MSK medical oncologist Marjorie Zauderer, who specializes in treating it. “Until this past June when the drug bevacizumab (Avastin®) was shown to benefit patients, there hadn’t been a new drug for it in more than ten years. Although targeted therapies have been successful with many other cancers, one problem with mesothelioma has been that there aren’t many alterations that we can target. Now that is changing.”
Research Using Knockout Mice
In a new study, published recently in Nature Medicine, a team led by MSK physician-scientist Ross Levine created a mouse with a mutated form of BAP1. They found that when BAP1 was knocked out or inactivated due to mutations, the levels of an enzyme called EZH2 went up, allowing mesothelioma cells to grow out of control. The investigators then showed in mouse models and in mesothelioma cells that blocking EZH2 could inhibit the growth of these tumors.
“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,” Dr. Zauderer says. “Now that there’s a biological rationale for why these drugs would work in mesothelioma, this could be a tremendous innovation for patients.”Back to top
Blocking Epigenetic Changes
The drugs that block EZH2 are among a new class of drugs that target the epigenetic changes in cancer cells. Epigenetics is a growing field that’s based on the study of genetic changes that are not part of the DNA code. In this case, the drugs target changes in histones, the proteins that DNA strands wrap around in the nucleus of the cell and that determine which genes are available to instruct the manufacture of proteins.
“When BAP1 is knocked out and EZH2 levels goes up, it leads to inappropriate modification of a particular histone, which is the mechanism by which cells are able to proliferate out of control,” says physician-scientist Scott Armstrong, head of MSK’s Center for Epigenetics Research and one of the study’s co-authors.
The investigators are now interested in extending their laboratory observations to the clinic and are working in coordination with the biotechnology firm Epizyme to study EZH2 inhibitors in mesothelioma patients.
“Because of the way MSK works and the way we all collaborate together, Dr. Levine was able to connect with Dr. Ladanyi, physician-scientist and thoracic surgeon Prasad Adusumilli, and me to rapidly translate his findings into a clinical approach for mesothelioma,” Dr. Zauderer says. “This is a great story because it represents how we can work together to translate laboratory research into something that could benefit patients.”Back to top