Hedgehog

The Hedgehog (Hh) pathway was first uncovered in 1980 by researchers Christiane Nusslein-Volhard and Eric F. Weischaus while screening for genetic mutations implicated in disrupting the Drosophila larval body plan. They chose the term `Hedgehog` for the resulting phenotype produced by mutating the Hh gene as the Drosophila larvae were characterized by a short and spiked stature. This discovery led to research illustrating the role Hh signalling pathway plays in processes related to embryonic development, a stage in which it controls the growth and patterning of various tissues and the development of organs, by sending signals that act as both mitogens and morphogens. As morphogens, Hh signals act in a dose-dependent manner to induce distinct cells fates within a targeted region, while as mitogens they regulate the formation of organ development by controlling cell proliferation.

The key components of the Hh signalling pathway includes: (1) the ligands, (2) the receptors, (3) the effectors, (4) the regulators, and (5) the transcriptional effectors.  Activation of the Hh signalling pathway occurs by the interaction between Hh ligands (either Sonic Hh (SHh), Indian, Hh, and Desert Hh) and the corresponding receptor, known as the Patched receptor (PTCH) that exists as two isoforms, PTCH-1 and PTCH-2.ii, iii  The consequence of this interaction at the cell membrane results in the discontinuation of repression activity by PTCH on Smoothened (SMO). As a consequence, downstream signalling by SMO is permitted as it becomes activated by various kinases including G-protein-coupled receptor kinase (GRK) which results in β-arrestin recruitment.ii, iii Facilitating the signalling cascade in the cytoplasm, that ensues upon SMO activation, is the interaction between SMO and the Suppressor fused (Sufu) that is bound to the glioma-associated oncogene homolog (Gli) transcription factors (Gli 1-3).iii This interaction liberates Sufu from Gli and permits transactivation of Hh-responsive genes whose products are involved in activities related to tissue patterning, growth and differentiation, and tissue homeostasis. In vertebrates, SMO enrichment occurs in the primary cilium from which it plays its role in signal transduction. When the Hh pathway is inactive, Gli2/Gli3 exist in their repressed form, also known as GliR, while its active companion Gli1(GliA) is inhibited by SuFu. When the Hh pathway is activated the phosphorylation and translocation of GliA to the nucleus is observed.

Aberrant Hh signalling is observed in a wide range of cancer types, although the aberrant activity associated with tumors varies by cancer type. In general, abnormal Hh signalling can be categorized as ligand-dependent or ligand-independent.iii The latter mode of aberrant Hh signaling is subdivided into two additional mechanisms: (a) ligand-dependent signaling in tumor cells, and (b) ligand-dependent signaling between the tumor and the microenvironment. Ligand-dependent drivers of Hh signalling activity includes the overexpression of Hh ligands by the drug-resistant and metastatic tumors or stromal cells (using autocrine or paracrine mechanisms). Examples of ligand-dependent activation in several solid tumors includes: lung, pancreatic, prostate, digestive tract, hepatocellular, glioblastoma, melanoma, bone/cartilage, colorectal, ovarian, breast, and haematological malignancies (multiple myeloma, chronic myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphomas). In contrast, ligand-independent mechanisms are noted where mutations can occur at various points along the activation pathway. For instance, in basal cell carcinoma and medulloblastomas it is observed that gain-of-function SMO mutations or PTCH loss-of-function are implicated in disease progression. A mutation of SUFU, while less common, is another possibility in addition to downregulation of micro RNAs that inhibit SUFU or Gli1.^[2][3] Over the past decade a number of Hh pathway inhibitors have been discovered, including a Curis-Genentech collaboration on a new SMO inhibitor called GDC-0449. In 2009, the two companies announced GDC-0449 showed promising results in the anti-cancer treatment of BCC and medulloblastomas in a Phase I study. Since then the compound has advanced to a number of Phase II clinical trials that are currently in recruitment.^[1]