Discovery and Exploitation of Novel Targets by Approved Drugs
Authors: Luc Dirix
Journal: Journal of Clinical Oncology (2014)

The Hedgehog (Hh) signaling pathway is essential for the development of multicellular organisms. Given that this pathway controls a number of key developmental processes, it comes as no surprise that several congenital malformations are caused by genetic alterations in the Hh pathway. Hh signaling is primarily critically active at the developmental stage, less so in adult life. The Hh family of proteins is also involved in the development of cancer. This was first recognized with the discovery that a mutation in the PTCH1 gene was causal for the basal cell nevus syndrome, also known as Gorlin-Goltz syndrome, a condition associated with skeletal, skin, and neural abnormalities as well as with the development of multiple basal cell carcinomas (BCCs) and an increased risk for medulloblastoma. Different mechanisms drive the Hh pathway activation in cancer: ligand-dependent or paracrine activation and ligand-independent or mutation-driven activation. Mutation-driven, ligand-independent signaling involves inappropriate activation of the Hh pathway resulting from loss-offunction mutations in the tumor suppressor gene PTCH1 or activating mutations in SMO. Their presence is the rule in BCCs, both in the Gorlin-Goltz–associated BCCs and in sporadic BCCs. The majority of BCCs are treated effectively with surgical resection, including Mohs’ surgery, and/or a variety of other local treatment options. In some rare cases, BCCs progress to advanced BCC (aBCC), which groups both locally advanced (as in inoperable) BCC and the even more seldom metastatic BCC. If surgery is not considered possible or appropriate for patients with locally aBCC, radiotherapy remains an effective option. aBCC is a rare disease. Both the US Food and Drug Administration and European Medicines Agency have approved a new drug, vismodegib, for the treatment of patients with aBCC. Vismodegib is the first orally bioavailable, small-molecule inhibitor of the Hh pathway; it introduces Hhpathway inhibitors as a new anticancer drug class. Vismodegib targets SMO, the central mediator of the Hh signaling pathway, and inhibits both ligand-dependent and mutation-driven SMO-mediated signaling. On the basis of pharmacokinetic properties as well as the observed efficacy, the lowest dose from the phase I study (150 mg once per day of vismodegib) was chosen for phase II evaluation. Dosing regimens of three times per week or once per week for vismodegib failed to achieve sufficient unbound plasma concentrations. The Hh pathway has been shown to act as an on/off switch for tumor growth in xenograft studies, suggesting that small changes in vismodegib exposure— and therefore pathway suppression—could result in important changes in antitumor activity. Additionally, increasing the daily dose from 150 mg to 270 or 540 mg did not result in higher steady-state plasma concentrations. Vismodegib is now available at the lowest dose investigated in the phase I study, and changing the schedule by dosing on alternate days is clearly not effective. Responses in patients with aBCC are frequent and reasonably durable, but resistance to treatment is the rule. The different SMO mutations that interfere with drug binding are some of the mechanisms responsible for drug resistance. Adverse events are frequent, and although rarely severe, they are often the reason for discontinuing drug treatment. The typical class-related adverse effects are muscle spasms, dysgeusia, weight loss, fatigue, alopecia, and nausea. In the article that accompanies this editorial, Kim et al report on the activity of another drug for the same indication. These investigators previously identified itraconazole, an antifungal agent, in a screening program of previously tested drugs as a potent antagonist of the Hh signaling pathway. Its mechanism of action was shown to be clearly distinct from itsinhibitoryeffectonfungalergosterolsynthesis.Itraconazolealsoactson SMO—although by a mechanism distinct from that of cyclopamine and other SMO antagonists—but similarly prevents the ciliary accumulation of SMO after Hh stimulation. Systemically administered itraconazole was shown to suppress Hh pathway activity and the growth of medulloblastomainananimalmodel.Inpreclinicalstudies,thiswasachievedatserum levels comparable to those in patients undergoing antifungal therapy. In this investigator-initiated, short-exposure (1 to 2.3 months), exploratory phase II study of itraconazole, patients with BCC both with (n 3) and without prior vismodegib (n 16) exposure were enrolled. Patients receivedeitheroral itraconazole200mgtwiceperdayor100mgtwiceper day. The primary end point was the change in Hh pathway–related biomarkers and in tumor cell proliferation in paired tumor biopsies. The investigators succeeded in collecting tumor biopsies and having them evaluated in an independent facility. Itraconazole reduced cell proliferation by 45%, Hh pathway activity by 65%, and tumor area by 24%. Of eight evaluable patients, four had a partial response and four had stable disease after 1 month of treatment. Tumors from the three patients with documented disease progression on vismodegib showed no significant changes in either proliferation or tumor size. This study clearly confirms the preclinically anticipated activity of itraconazole. It also confirms the modeofactionofitraconazoleasanHhpathwayantagonistbydecreasing GLI expression intratumorally. The absence of the typical on-target spectrum of adverse events of the other SMO antagonists is striking (eg, hair loss, muscle cramps, dysgeusia). The primary question of this study was answered, and the authors are to be congratulated for pursuing their JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 8 MARCH 1