Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond

Abstract

Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling-related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm. Some of these pathways could be regulated by noncoding microRNA. Altered microRNA expression profile is recognized with the progression of these lesions. Stopping treatment with Smoothened (SMO) inhibitors often leads to tumor reoccurrence in the patients with basal cell nevus syndrome, who develop 10–100 of BCCs. In addition, the initial effectiveness of these SMO inhibitors is impaired due to the onset of mutations in the drug-binding domain of SMO. These data point to a need to develop strategies to overcome tumor recurrence and resistance and to enhance efficacy by developing novel single agent-based or multiple agents-based combinatorial approaches. Immunotherapy and photodynamic therapy could be additional successful approaches particularly if developed in combination with chemotherapy for inoperable and metastatic BCCs.

Understanding the Molecular Genetics of Basal Cell Carcinoma

“…Verteporfin, a second-generation photosensitizer approved by the FDA for the treatment of age-related macular degeneration, has been shown to inhibit the proliferation of hepatocellular carcinoma and retinoblastoma cells by inhibiting the YAP pathway [ 109 , 110 ]. Bakshi et al [ 111 ] are currently investigating the effects of verteprofin administered as monotherapy and in combination with SMO inhibitors in BCC tumor regression.…”

“…Monoclonal antibodies that block immune checkpoint proteins, as anti- programmed cell death-1 (PD-1) and PD-Ligand-1 (PD-L1), thus enhancing the anti-tumor immune response, have demonstrated remarkable efficacy against multiple cancers, including melanoma [ 111 ]. Several immune-related markers have been implicated in BCC pathogenesis [ 112 , 113 , 114 , 115 , 116 , 117 ], suggesting that immunotherapy may be a valuable therapeutic option for this tumor.…”

Mixed signals from the cell's antennae: primary cilia in cancer

“…Looking at the extensive list of studies linking PC, Hh signaling, and tumorigenesis, it is not surprising that this pathway became an interesting cancer drug target. Smo inhibitors are FDA‐approved for treatment of advanced BCC and tested in clinical trials in medulloblastoma patients . The success of those therapeutics was, however, limited due to the development of drug resistance.…”

Treatment of Basal Cell Cancer With a Pulsed Copper Vapor Laser: A Case Series

“…[3][4][5] So far the pathogenesis of BCC is associated with both dysfunction of keratinocytes and melanocytes of the basal layer of the epidermis and the abnormal transformation of the vascular bed in the BCC underlying papillary dermal layer. [6][7][8] According to the data reported in recent bench-to-bedside investigations, the pathogenetic treatment of BCC must provide the elimination of both all-malignant keratinocytes and melanocytes supporting the progression of the malignant process in the basal layer of the epidermis and the pathological vascular dysplastic bed in the adjacent dermal papillary layer. Up to the present, there has been appeared a number of reports concerning the sound application of such laser systems as pulsed dye laser, diode, Nd:YAG, and CO2 laser system for the treatment of BCC.…”