A new investigational compound targeting a specific protein that is frequently mutated and malfunctioning in lymphoma and melanoma patients has shown promising results in mice cancer models. The study, “An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation,” was recently published in the journal Nature Medicine.
Data from several types of cancer suggest that dysregulation of polycomb group complexes that control a high number of genes involved in cell fate can lead to cells changing to a malignant state. EZH2, a protein in one of these complexes, has often been found to be highly expressed or to bear specific mutations in certain types of B-cell tumors. Similar alterations have also been described in other tumor types, including non-small cell lung, prostate, and colon cancer, and in melanoma.
Researchers from University of North Carolina (UNC) School of Medicine and UNC Lineberger Comprehensive Cancer Center developed mouse models of B-cell lymphoma and melanoma with a specific EZH2 mutation. The mutation is known to occur in about 20 percent of B-cell lymphoma patients and 5 percent of those with melanoma. Although a mutation in EZH2 gene alone is sufficient to induce B-cell lymphoma, the investigators found it only induces melanoma when mutations on the BRAF gene, which occur in about 50 percent of melanoma patients, are also present.
The team, led by Norman Sharpless, MD, director of UNC Lineberger and the Wellcome Distinguished Professor of Cancer Research, also reported that a new investigational compound (JQEZ5) inhibits the function of the protein encoded by the EZH2 gene — with highly effective results in decreasing tumor growth and minimal toxicity.
“We have shown that the biology of tumors driven by this mutation are distinct from other types of lymphoma and melanoma, and that these tumors require persistent malfunction of EZH2 for growth,” Dr. Sharpless said in a press release. “And with our collaborators, we have shown that a potential new drug designed to target EZH2 mutations in such cancers is very active in our laboratory models.”
Results also suggested that EZH2 inhibitors, like JQEZ5, might be used to enhance the responses to melanoma therapies already approved by the U.S. Food and Drug Administration (FDA), such as BRAF inhibitors.
“While there has been significant progress in recent years against cancers such as lymphoma and melanoma, many patients still fail these newer therapies and need further options for therapy,” Dr. Sharpless said. “Given that EZH2 malfunction is a common event in many types of cancer beyond lymphoma and melanoma, we are hopeful that well-tolerated inhibitors of this enzyme will benefit a large group of patients with cancer.”
