A new study has identified the RNA helicase DDX5 as an important driver of myeloproliferative neoplasms (MPNs), blood cancers often caused by the JAK2V617F mutation. The research suggests that targeting DDX5 with the small-molecule drug FL118 could help eliminate cancer cells that current treatments fail to destroy.
MPNs such as polycythemia vera and myelofibrosis are commonly treated with the JAK1/2 inhibitor Ruxolitinib, which can reduce symptoms and shrink an enlarged spleen. However, the drug usually does not eliminate the malignant cell population and may cause low blood cell counts with long-term use.
Researchers found that the JAK2V617F mutation stabilizes DDX5, allowing it to act as a structural protein that supports cancer cell survival. DDX5 activates the mTOR growth pathway and increases levels of anti-apoptotic proteins that prevent cancer cells from dying.
The team tested FL118, a drug derived from Camptothecin, and discovered that it binds to DDX5 and triggers its destruction inside the cell. Removing DDX5 shut down growth signals and caused large numbers of cancer cells to die.
In mouse studies, oral FL118 significantly suppressed tumor growth and reduced enlarged liver and spleen size without major toxicity. The drug also worked even better when combined with Ruxolitinib, suggesting a potential new treatment strategy for patients with MPNs.