Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives

Abstract

The Hedgehog pathway (HhP) plays an important role in normal embryonic development and its abnormal function has been linked to a variety of neoplasms. Recently, the complex mechanisms involved in this pathway have been deciphered and the cross talks with other important pathways involved in carcinogenesis have been characterized. This knowledge has led to the development of targeted therapies against key components of HhP, which culminated in the approval of vismodegib for the treatment of advanced basal cell carcinoma in 2012. Since then, other compounds have been developed and evaluated in preclinical and clinical studies with interesting results. Today, several medications against components of the HhP have demonstrated clinical activity as monotherapies and in combination with cytotoxic treatment or other targeted therapies against mitogenic pathways that are linked to the HhP. This review aims to clarify the mechanism of the HhP and the complex crosstalk with others pathways involved in carcinogenesis and to discuss both the evidence associated with the growing number of medications and combined therapies addressing this pathway and future perspectives.

Eupatilin regulates proliferation and cell cycle of cervical cancer by regulating hedgehog signalling pathway

“…There were already existing clinically successful approaches of cancer therapies targeting at hedgehog signalling, such as some small molecules that can eliminate the activity of SMO, named SMO inhibitors. SMO antagonists showed potent therapeutic efficacy typically in skin and brain cancer patients .…”

Real-Life Effectiveness of Vismodegib in Patients with Metastatic and Advanced Basal Cell Carcinoma: Characterization of Adverse Events and Assessment of Health-Related Quality of Life using the Dermatology Life Quality Index (DLQI) Test

“…Vismodegib, an oral sonic hedgehog signaling pathway inhibitor, has recently been approved by the Food and Drug Association for the treatment of locally advanced, metastatic, and recurrent basal cell carcinomas that are ineligible for surgery or radiotherapy [4]. Several studies have demonstrated the efficacy and safety of this small molecule which selectively connects to the Smoothened protein and blocks intracellular signaling, deactivating the hedgehog pathway and thus inhibiting tumor growth [7]. As reported in our results, muscle spasms, dysgeusia, weight loss, and alopecia are the most frequently described adverse events associated with vismodegib therapy.…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…Hedgehog pathway signaling activates the glioblastoma Gli1/2/3 genes (named so because they were initially identified in glioblastomas [478]) through a complex epistatic pathway of negative regulators [479]. Targeting of the hedgehog pathway in cancer cells has been an efficient way to inhibit tumor growth [480][481][482][483].…”