The VDA called DMXAA works well against several types of human cancers and is currently in phase II clinical trials. But there are no clues from clinical studies to explain why this drug has succeeded where others have failed.

Experiments in mice have hinted at its downstream targets: DMXAA prods mouse macrophages to secrete interferon (IFN)-ß and other cytokines that promote vessel permeability. IFN-ß is also induced by activation of certain pattern recognition receptors (PRRs), such as the Toll-like receptors and the RNA helicases. But Roberts et al. now find that DMXAA's path to gene induction bypasses all known PRRs. The drug instead potently activates the tank binding kinase (TBK)-1, leading to high levels of an activated transcription factor called IFN regulatory factor (IRF)-3.

Besides IFN-ß, IRF-3 also turns on genes that cause the apoptosis and senescence of tumor cells. The functional diversity of the downstream targets of DMXAA might explain the high efficacy of this drug against human cancers.

Recombinant IFN-ß has been used for years in the clinic to treat a number of malignancies including chronic myelogenous leukemia and malignant melanoma. Thus, Roberts et al. now tie DMXAA to this preeminent tumor-fighting system.

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The chemotherapeutic agent DMXAA potently and specifically activates the TBK1–IRF-3 signaling axis

Zachary J. Roberts, Nadege Goutagny, Pin-Yu Perera, Hiroki Kato, Himanshu Kumar, Taro Kawai, Shizuo Akira, Ram Savan, David van Echo, Katherine A. Fitzgerald, Howard A. Young, Lai-Ming Ching, and Stefanie N. Vogel
J. Exp. Med. 2007 204: 1559-1569. [Abstract] [Full Text] [PDF]