Named for its spiky appearance in mutated fruit fly embryos, the Hedgehog pathway is one of several key developmental cell-signaling networks whose aberrant activation in adult tissues can lead to cancer.
Thus far, more than 30 years of exploration have yielded two small-molecule inhibitors for the treatment of patients with metastatic or locally advanced basal cell carcinoma (BCC). The FDA approved vismodegib (Erivedge) in January 2012 and sonidegib (Odomzo) in July 2015, both for indications in recurrent disease after surgery and radiotherapy.
The successful development of these two agents has validated the Hedgehog pathway as a bona fide therapeutic target, and clinical trials are under way to determine whether similar inhibition strategies can be employed against other tumor types including breast, prostate, brain, and gastrointestinal cancers. Thus far, the most promising target in the pathway has proved to be the Smoothened (Smo) receptor (Table)
Table. Smoothened Inhibitors in Clinical Development
aTrial is ongoing, but not recruiting participants.
bMonoclonal antibody that targets insulin-like growth factor-1 receptor. AML indicates acute myeloid leukemia; BCC, basal cell carcinoma; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; JAK, Janus kinase; MDS, myelodysplastic syndrome; RT, radiation therapy; SCLC, small cell lung cancer; TNBC, triple-negative breast cancer.
At the same time, researchers have acknowledged many deficits in our understanding of this highly complex signaling network including the importance of delineating mechanisms of resistance to currently available therapies.
Hedgehog Signaling Enigmas
The key players in the Hedgehog pathway are the transmembrane receptor Patched (Ptch), its three ligands (Sonic, Indian, and Desert Hedgehog); Smo, a second receptor that is structurally similar to G-protein–coupled receptors; and a family of three glioma-associated transcription factors (Gli1, Gli2, and Gli3).
In mammals, canonical Hedgehog signaling occurs predominantly in the primary cilium, an antenna-like structure that protrudes from the surface of most cells. In its “off” state, when no ligand is present, Ptch inhibits Smo by mechanisms that are not yet clear. In the “on” state, ligand binding to Ptch causes it to release its inhibition on Smo, which is then free to move into the primary cilium and propagate the signal downstream.
This culminates in the activation of the Gli transcription factors, which regulate the activity of Hedgehog target genes that control vital cellular processes necessary for embryonic development, including cell proliferation, migration, metabolism, and determination of cell fate.
Hedgehog ligands are morphogens, produced by specialized secreting cells and, acting in either an autocrine (on the same cell) or paracrine (on a different cell) fashion; their concentration at the target cell determines the response that is elicited from that cell. This graded response is achieved in part by impacting the proteolytic processing of the Gli proteins. Depending on the strength of the Hedgehog signal, different ratios of full-length active Gli isoforms to truncated suppressive isoforms are generated and regulate the strength of the transcriptional response.
The steps between Smo and Gli are poorly defined, but one protein that has been identified is Suppressor of Fused (SuFu), which plays an important role in the graded response to Hedgehog signals by mediating processing and degradation of the Gli proteins.
Although this description has become the established view of Hedgehog signaling, there is a growing body of evidence that the pathway can be activated in other ways. In so-called noncanonical signaling, the components of the pathway may be able to regulate basic cellular processes seemingly independently of the full pathway. These routes of activation may have a particularly important role in the development of cancer.
Although the Hedgehog pathway plays a critical role in embryonic development, the network is mostly inactive in adults, though it does have important functions in regenerating tissue and in regulating the growth of stem cells, particularly in the brain.