Itraconazol, an Antifungal and a Hedgehog Pathway Inhibitor for Treatment of Prostate Cancer

A commonly used antifungal, Itraconazole targets a pathway that is also upregulated in human prostate cancer. Itwas observed that Itraconazole synergizes with cyclopamine to induce superior therapeutic effects. Cyclopamine istoxic, however, when combined with itraconazole the dose requirement for each drug was considerably reduced.This combination therefore has the potential to be more effective and at the same time less toxic. The mostimportant aspect of this finding is that these are existing drugs whose safety and toxicological profiles are known.This project sought to investigate the efficacy of Itraconazol in combination with cyclopamine against prostatecancer with an intention to accelerate their rapid translation into human clinical trials. Treatment of prostate cancercells with the combination of itraconazole and cyclopamine led to increased cell growth inhibition that was greaterthan the sum of the individual agents alone suggesting synergism. We also analyzed the effect of the combinationon the growth of tumors in vivo conditions using athymic nude mice. In control animals, targeted tumor volume of1200 mm3 was reached at 6 weeks post cell inoculation and significantly later time in animals treated withitraconazole alone (9 weeks) and cyclopamine alone (8 weeks). Notably, tumor volumes stayed under 165 mm^{3} inmice that received both itraconazole and cyclopamine. In the prostate specific Pten knockout mice combination ofitraconazole and cyclopamine produced 57 percent inhibition of tumor growth compared to 30 percent in cyclopamine aloneand 45 percent in itraconazole alone treated mice. These data show that a combination of itraconazole and cyclopamineis considerably more efficient in inhibiting tumor growth.