Cichowski, PhD  and Thomas DeRaedt, PhD

Karen Cichowski, PhD and Thomas DeRaedt, PhD

A research team led by Karen Cichowski, PhD, and Thomas DeRaedt, PhD, BWH Division of Genetics, identified a tumor suppressor that is mutated in nervous system malignancies, brain tumors and melanoma. By counteracting the effects of this mutation, the team developed a promising new therapy for cancers such as malignant peripheral nerve sheath tumors (MPNST).

The researchers first performed genetic studies on MPNST tumors that lacked a functional NF1 gene. Similar NF1 mutations are found in human melanoma, lung and brain cancers. NF1 helps turn off Ras signaling, a cell-signaling pathway that promotes cell growth and survival. Without regulation, Ras is hyperactivated and can drive cancer.

DeRaedt and Cichowski found that two genes in the polycomb group complex 2 (PRC2), SUZ12 and EED, are often deleted or mutated in NF1-mutant cancers. Moreover, mice carrying SUZ12 and NF1 mutations together developed more tumors and developed MPNSTs and brain cancers more quickly. They showed that SUZ12 mutations make NF1 mutations worse, by amplifying the genetic program triggered by NF1-loss.

The researchers found that SUZ12 loss increases binding of bromodomain proteins to DNA, which amplify transcription caused by hyperactivated Ras. Noting that these effects might be sensitive to bromodomain inhibitors, the researchers treated mice with the bromodomain inhibitor JQ1. JQ1 slowed cancer growth, however tumors dramatically shrank when JQ1 was combined with a direct Ras pathway inhibitor.

“To develop effective therapies we may need to counteract NF1 and SUZ12 mutations simultaneously. Fortunately both types of drugs are being evaluated in clinical trials. We aim to develop trials combining these agents, which may hold promise for patients with MPNSTs and other genetically similar cancers,” said Cichowski.

The study was published online August 13, 2014 in Nature.