Pathway of the Day: Hedgehog

Luc Dirix

Luc Dirix, Sint Augustinus Hospital, Antwerp, Belgium

Article extracted from the ESMO 2014 onsite newspaper.

The hedgehog pathway (see Figure) has a key role in cell proliferation, differentiation and organ formation during embryonic development. Although it also has a role in the maintenance of some adult tissues (e.g. proliferating cell populations), deregulation of the hedgehog pathway in adults is associated with cancer development. Hedgehog pathway mutations are associated with basal cell carcinoma (BCC) and medulloblastomas.

The hedgehog pathway consists of a number of critical trough evolution highly conserved components. Among these are the patched (PTCH) and smoothened (SMO) proteins, which are each encoded by multiple genes. PTCH is a membrane-associated receptor protein that actively suppresses the pathway by inhibiting SMO. It is the receptor for the hedgehog proteins. Mammalian hedgehog genes are split into three families: Sonic, Indian and Desert, and Sonic is the most studied ligand for PTCH. Binding of a hedgehog ligand to PTCH results in de-inhibition of SMO, leading to activation of the pathway.

Abnormal activation of the hedgehog pathway is associated with the development of cancers, with the type of activation being linked to particular cancer types. For example, ligand-independent signalling driven via inactivating mutations, e.g. ligand receptor, PTCH, or activating mutations in SMO, is associated with BCC and medulloblastoma. Most individuals with BCC have intratumour mutations, either inactivating mutations in the PTCH1 gene or activating mutations in the SMO gene so that the SMO gene is no longer inhibited by PTCH1. PTCH1 therefore appears to be the linchpin in the development of most BCCs. Research into tumours thought to be driven by ligand overexpression has progressed more slowly.

Vismodegib, an SMO receptor antagonist, was the first agent targeting the hedgehog pathway to receive regulatory approval. It is indicated for BCC that has metastasised, relapsed after surgery or cannot be treated with surgery or radiotherapy. Sonidegib (or erismodegib) is another SMO receptor antagonist in clinical development for advanced solid tumours, which featured in a presentation by Dr Quincy Siu-Chung Chu from the University of Alberta Cross Cancer Institute, Edmonton, Canada in a Proffered Paper Session on Developmental Therapeutics (Saturday 27 September 2014). Dr Chu described the results of a dose-escalation, phase Ib study of sonidegib/buparlisib combination in adults with metastatic breast or colorectal cancer, pancreatic cancer or recurrent glioblastoma. The combination was tolerable, with dose-limiting toxicities (primarily elevations of alanine aminotransferase and creatine phosphokinase) consistent with those reported in other phase I studies. The recommended dose for expansion was sonidegib 400 mg/buparlisib 80 mg. Further investigation of this combination will follow.  

Hedgehog

Hedgehog (Hh); Sonic Hedgehog (Shh) signalling is activated in both autocrine and paracrine pathways.
Adapted from World J Gastroenterol 2014 March 7; 20(9): 2335-2342