cur-61414 and Skin-Neoplasms

Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed.

Topics: Administration, Cutaneous; Animals; Carcinoma, Basal Cell; Hedgehog Proteins; Humans; Itraconazole; Mice; Skin Neoplasms; Tissue Distribution

Basal cell carcinomas (BCC) are slow-growing skin tumors that rarely metastasize but frequently recur, most often around the face, head and neck. Currently, surgery is the only treatment practice, which can be painful and leave scars. However, several years ago it was discovered that almost all forms of BCC result from mutations in a signaling pathway controlled by a protein called Hedgehog (Hh). Recently, a novel small-molecule drug candidate, CUR-61414, has been identified that blocks this pathway and could potentially be effective for the treatment of BCC. CUR-61414 was reported to prevent the proliferation and selectively induce the death of the tumor cells, while not harming adjacent normal skin cells in two different models of BCC. These findings directly demonstrate that the use of Hh inhibitors could be a valid novel therapeutic approach for treating BCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Basal Cell; Carrier Proteins; Dioxoles; Humans; Membrane Glycoproteins; Mutation; Piperazines; Signal Transduction; Skin Neoplasms

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.. In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days.. In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study.. Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Carcinoma, Basal Cell; Dioxoles; Double-Blind Method; Drug Delivery Systems; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piperazines; Placebos; Receptors, G-Protein-Coupled; Skin Neoplasms; Small Molecule Libraries; Smoothened Receptor; Treatment Outcome

The link between basal cell carcinoma (BCC) and aberrant activation of the Hedgehog (Hh) signaling pathway has been well established in humans and in mouse models. Here we report the development of assays, including two novel in vitro BCC models, which allowed us to screen for Hh inhibitors and test their validity as potential treatments for BCC. We identified a novel small molecule Hh inhibitor (CUR61414) that can block elevated Hh signaling activity resulting from oncogenic mutations in Patched-1. Moreover, CUR61414 can suppress proliferation and induce apoptosis of basaloid nests in the BCC model systems, whereas having no effect on normal skin cells. These findings directly demonstrate that the use of Hh inhibitors could be a valid therapeutic approach for treating BCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Basal Cell; Cell Line; Chick Embryo; Dioxoles; Drug Screening Assays, Antitumor; Hedgehog Proteins; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Knockout; Mice, Transgenic; Patched Receptors; Patched-1 Receptor; Piperazines; Receptors, Cell Surface; Signal Transduction; Skin; Skin Neoplasms; Trans-Activators; Veratrum Alkaloids