Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies

Abstract

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.

Keywords::

• basal cell carcinoma
• hedgehog
• locally advanced
• metastatic
• vismodegib

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Currently, we have few therapeutic tools for the treatment of locally advanced and/or metastatic basal cell carcinoma, so in recent years, it has emerged the need for finding new therapeutic targets.

• The discovery of the Hedgehog pathway, when aberrant plays an important role in the development of multiple malignancies, has allowed the development of new targeted drugs.

• Vismodegib is the first drug approved by US FDA for the treatment of locally advanced and metastatic basal cell carcinoma, that acts as a inhibitor of smoothened receptor, an important component of the Hh pathway, whose activation is linked with cellular and neoplasic proliferation.

• The first clinical trials published show moderate efficacy of vismodegib, and we need more experience in clinical practice in order to asses their long-term effectiveness and safety.

• Another important aspect is the development of acquired drug resistance, which is not fully understood and their understanding will enable to development of better strategies to overcome this problem.