Small Molecule Inhibitors of the Hedgehog Pathway in the Treatment of Basal Cell Carcinoma of the Skin

Abstract

Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway. As a result, identification of drugs that inhibit the receptor Smoothened (SMO) in the HH pathway has resulted in novel therapeutic approaches to treating patients with advanced BCC. These HH-pathway inhibiting medications have shown efficacy in clinical trials, and two medications, vismodegib and sonidegib, have received FDA approval. However, several limitations of these drugs have been identified, including treatment-limiting adverse events, drug resistance, and the formation of additional malignancies. This paper aims to summarize the clinical trials leading to the approval of SMO inhibitors, as well as reviewing potential mechanisms driving tumor resistance and the formation of cutaneous squamous cell carcinomas. Strategies to overcome some of these challenges, including the development of drugs that inhibit other downstream targets in the HH pathway, are the subject of ongoing clinical trials.

YAP‐TEAD signaling promotes basal cell carcinoma development via a c‐JUN/AP1 axis

“…Basal cell carcinoma (BCC) is a skin tumor initiated and driven by activating mutations in the Hedgehog signaling pathway (Reifenberger et al , ; Epstein, ). Although the vast majority of BCC are curable with resection, vismodegib (SMO inhibitor) therapy, or a combination of both, the projected increase in BCC incidence over coming decades will result in a surge of advanced and vismodegib‐resistant cases (Danhof et al , ). Additionally, emerging findings suggest that advanced BCC could transdifferentiate into squamous cell carcinoma (SCC) with a much more aggressive phenotype (Orouji et al , ; Ransohoff et al , ; Zhao et al , ).…”

“…In the clinic, the biggest challenge for BCC remains treatment of patients with advanced or metastatic disease, of which only about 50% respond to vismodegib therapy (Puig & Berrocal, ; Danhof et al , ). The mechanisms of resistance vary from emergence of the SMO ‐mutant BCC clones and activation of kinase pathways to amplification of the GLI signaling via other mechanisms (Atwood et al , , ; Sharpe et al , ).…”

“…Strong genetic evidence and near 100% mutation frequency of the Hedgehog pathway in basal cell nevus syndrome and BCC have led to successful development of the SMO inhibitor, vismodegib, for the treatment of these diseases. However, locally advanced and metastatic BCCs frequently (~50% recurrence) escape Hedgehog pathway inhibition, predominantly via the mutation of SMO within the drug‐binding pocket or the alternative potentiation of GLI signaling (Atwood et al , , ; Sharpe et al , ; Zhao et al , ; Danhof et al , ). The development of new approaches to inhibit BCC tumor growth in parallel with vismodegib therapy would provide significant clinical benefits for patients with advanced BCC.…”

Cutaneous basal cell carcinoma with lymph node and pulmonary metastases

“…Until January 2012, no specific systemic therapy was available for patients with locally advanced or metastatic BCC. Patients were treated with chemotherapy, most frequently platinum-based or with more than one chemotherapy agent with mixed responses [1,2,8].…”

Managing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor vismodegib: a single centre experience

“…Managing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor vismodegib: a single centre experience Editor Locally advanced basal cell carcinoma (laBCC) represents an uncommon, difficult to treat form of skin cancer. 1,2 The approval of hedgehog inhibitor (HHI) vismodegib in 2012 opened a novel therapeutic option. [2][3][4][5][6][7][8][9][10] "Drug holidays" have been proposed to increase patients' compliance and adherence which is poor due to the high frequency of adverse effects (AE's) of HHI, [3][4][5] however, up to date, the effect of dose reduction during HHI treatment has not been reported.…”