Novel Approaches in Non-Melanoma Skin Cancers—A Focus on Hedgehog Pathway in Basal Cell Carcinoma (BCC)

Abstract

Basal cell carcinoma (BCC) is one of the most common neoplasms in the population. A good prognosis and mainly non-aggressive development have made it underdiagnosed and excluded from the statistics. Due to the availability of efficient surgical therapy, BCC is sometimes overlooked in the search for novel therapies. Most clinicians are unaware of its complicated pathogenesis or the availability of effective targeted therapy based on Hedgehog inhibitors (HHI) used in advanced or metastatic cases. Nevertheless, the concomitance and esthetic burden of this neoplasm are severe. As with other cancers, its pathogenesis is multifactorial and complicated with a network of dependencies. Although the tumour microenvironment (TME), genetic aberrations, and risk factors seem crucial in all skin cancers, in BCC they all have become accessible as therapeutic or prevention targets. The results of this review indicate that a central role in the development of BCC is played by the Hedgehog (Hh) signalling pathway. Two signalling molecules have been identified as the main culprits, namely Patched homologue 1 (PTCH1) and, less often, Smoothened homologue (SMO). Considering effective immunotherapy for other neoplastic growths being introduced, implementing immunotherapy in advanced BCC is pivotal and beneficial. Up to now, the US Food and Drug Administration (FDA) has approved two inhibitors of SMO for the treatment of advanced BCC. Sonidegib and vismodegib are registered based on their efficacy in clinical trials. However, despite this success, limitations might occur during the therapy, as some patients show resistance to these molecules. This review aims to summarize novel options of targeted therapies in BCC and debate the mechanisms and clinical implications of tumor resistance.

Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

“…In addition, miR-138 or miR-346 can also promote QCCs from a quiescent state to a proliferative state in metastatic lesions and mediate the metastatic reactivation of breast cancer in mice [ 55 ], suggesting that modulating the expression levels of miRNAs could stimulate a transition from quiescence to proliferation. Basal cell carcinoma, the most common cancer in humans, results from the constitutive activation of the Hedgehog pathway [ 56 ]. Vismodegib, a smoothened inhibitor (Smoi), causes basal cell carcinoma shrinkage in most patients; however, a small fraction of tumor cells persists and causes tumor recurrence when treatment is stopped [ 57 , 58 ].…”

Clinical Characteristics of Basal Cell Carcinomas of the Scrotum: An Institutional Retrospective Review

“…In advanced or metastatic diseases, surgical treatment does not provide radical excision, so its implementation is limited in these cases. As indicated, targeting hedgehog pathway signifcantly afects BCC progression and patient outcomes [27]. Since many elements may interact in the Hh pathway, these drugs can be divided into groups: SHH inhibitors, SMO antagonists, and GLI inhibitors.…”

Dermoscopic Clues of Histopathologically Aggressive Basal Cell Carcinoma Subtypes

“…Overall, the increased tendency of histopathologically aggressive BCCs to recur after surgery justifies a more careful surgical approach with micrographically controlled techniques or wider margins as compared to the low-risk subtypes, that can be adequately cured with conventional surgery with 3–4 mm safety margins, at least when located on non-critical anatomic sites [ 3 , 4 , 5 ].…”