Editors' ChoiceCancer

Itraconazole: From Histoplasmosis to Hedgehog Signaling

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Science Translational Medicine  21 Apr 2010:
Vol. 2, Issue 28, pp. 28ec62
DOI: 10.1126/scitranslmed.3001163

Although great strides have been made in oncology through the synthesis and development of new anticancer agents, copious amounts of time and money have been lost along the way. This underscores the need to streamline the process by which agents with anticancer properties may be introduced into testing in cancer patients. Using a high-throughput screen of a chemical library of 2400 drugs that were either FDA-approved or in early clinical testing, Kim et al. now identify that the antifungal agent itraconazole inhibits tumor growth through disruption of the Hedgehog signaling pathway, which is commonly activated in human cancer.

Hedgehog pathway activation in human tumors commonly occurs because of loss of function of the Patched (PTCH) protein, a negative regulator of the Smoothened (SMO) protein, which activates downstream signaling pathways. Pharmacological compounds that interfere with SMO function have been developed, and early phase trials show promising results. The researchers now demonstrate that the antifungal itraconazole, at concentrations achievable in man, also inhibits Hedgehog signaling and tumor growth but through a mechanism different from SMO antagonists—the prevention of ciliary accumulation of SMO. Additionally, they demonstrate that combining itraconazole with SMO antagonists leads to synergistic effects on Hedgehog pathway inactivation and tumor growth suppression, which underscores the promise of itraconazole alone or in combination with other Hedgehog pathway antagonists.

The approach of Kim et al. demonstrates the feasibility and utility of screening therapies approved for other diseases in order to identify “new” anticancer agents. Although the results with itraconazole are exciting, we await clinical trials with itraconazole in cancer patients in order to determine whether itraconazole’s activity against fungi like histoplasmosis will be matched by its activity against cancers with Hedgehog signaling.

J. Kim et al., Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388–399 (2010). [Full Text]

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