Chapter 16 Hedgehog Signaling Pathway Inhibitors as Cancer Therapeutics

Publisher Summary This chapter describes the mechanism of action of the Hedgehog (Hh) inhibitors. The Hh pathway directs the development of multiple tissues during embryonic development and contributes to tissue homeostasis in adults. The inactivation of the pathway during embryonic development causes birth defects, whereas abnormal activation is linked to tumorigenesis in several cancers. Genetic validation of this pathway in human tumors comes from the observations that patients with a germ line mutation in Patched (Ptch1)—a component of the Hh pathway—have activated Hh signaling and develop Gorlin syndrome, also known as “nevoid basal cell carcinoma (BCC).” In addition, the aberrant activation of the Hh pathway without known mutation is implicated in a number of additional tumor types, including small cell lung cancer, gut-related tumors, and pancreatic and prostate cancer. The inhibition of the Hh pathway in either tumor cells directly or non-malignant stromal cells, which as part of the tumor microenvironment support tumor growth, has emerged as an attractive target in anticancer therapy.