Ferreting Out the Hedgehog Pathway Emerges as Ripe Target for Cancer Drug Development

Jane de Lartigue, PhD
Published: Friday, May 13, 2011
In 1995, the Nobel Prize in Medicine was jointly awarded to Edward B. Lewis, Christiane Nüsslein- Volhard, and Eric F. Wieschaus for discoveries relating to the “genetic control of embryonic development” that began with a series of experiments in the fruit fly some 20 years earlier.

The researchers were interested in understanding how the newly fertilized fruit fly egg develops into a segmented embryo and, after testing mutations in approximately 20,000 fly genes, identified 150 involved in early embryonic development, 15 of which, if mutated, caused defects in body segmentation.

Among them was a gene that caused the fly embryo to develop as a spiny ball reminiscent of a hedgehog. Thus, the Hedgehog gene, HH, was discovered.

How the Hh Signaling Pathway Works

We now know that Hh is an intracellular signaling ligand that initiates the Hh pathway, which is important in the regulation of embryo development from flies to humans. In the embryo, Hh acts as a morphogen, generating different responses from cells, depending on its concentration. It drives developing cells to different fates, thereby controlling the formation of many organs, including the central nervous system, limbs, lungs, heart, and eyes, and the development of left-right asymmetry in the body.

Although Hh activity is significantly reduced in adults, recent evidence suggests that it may also have important functions later on in life, in regulating the growth of some stem cells, including those in the adult brain, and in tissue regeneration.

In human beings, there are 3 Hh proteins: sonic hedgehog (SHH), Indian hedgehog (IHH), and desert hedgehog (DHH). Essentially, the Hh signaling pathway involves the binding of Hh ligand to membrane receptors known as Patched (Ptch) on the surface of target cells, either the same cell (autocrine signaling) or different cells (paracrine signaling). There are 2 Ptch receptors in humans, Ptch-1 and Ptch-2.

In the absence of the Hh ligand, Ptch suppresses the expression of the downstream protein Smoothened, Smo; therefore, when Hh binds Ptch, Smo becomes activated. Smo is subsequently free to activate the Gli family of transcription factors, which initiate Hh-target gene expression in the nucleus. In mammals, there are 3 Gli proteins: Gli1 and Gli2 activate target gene expression, while Gli3 represses it.

Hh Signaling Plays Major Role in Cancer

The first link between the Hh pathway and cancer stemmed from the discovery that Gorlin syndrome, a condition in which people are prone to the development of numerous basal cell carcinomas (BCCs) and other forms of cancer, is caused by an inherited mutation in Ptch-1.

Accumulating evidence suggests that aberrant Hh signaling, caused either by mutations in the molecular components of the pathway (ligandindependent signaling) or by overexpression of the Hh protein (ligand-dependent signaling), is involved in a variety of different cancers.

The former is implicated in 2 main forms of cancer: BCC, the most common form of cancer among white people, and medulloblastoma, the most common malignant brain tumor in children, both of which have an unmet need for improved treatments.

Ligand-independent signaling most commonly occurs as a result of inactivating mutations in Ptch- 1 (identified in the majority of cases of sporadic BCC and approximately 10% of medulloblastomas), or activating mutations of Smo (found in approximately 10% of sporadic BCCs). Both of these mutations lead to activation of the pathway even in the absence of ligand.

The first case of ligand-dependent signaling was identified in small-cell lung carcinoma. Since then, Hh-overexpression has been demonstrated in numerous other solid tumors, including gastrointestinal, pancreatic, ovarian, and breast cancers. Overall, improper Hh signaling is thought to be involved in as many as one-third of all cancers and this number is growing with the identification of more Hh-overexpressing tumors.

In 1889, the British surgeon Stephen Paget proposed his visionary “seed and soil” hypothesis that the normal cells, or microenvironment, surrounding the tumor are also capable of supporting tumor growth and metastasis. Since Hh ligands can also act in a paracrine fashion on surrounding cells (sometimes at a substantial distance from the Hh-producing cell), an Hh-overexpressing tumor cell may also promote tumor growth and metastasis via modifi cation of the microenvironment.

hedgehog gene overexpression example
Arrows show the sequence of events promoting
the overexpression of the Hedgehog gene.

A Hot New Drug Target

Given the role of Hh signaling in cancer initiation and progression, much importance has been placed on the search for ways to block its effects. A Smo inhibitor called cyclopamine, a naturally occurring chemical isolated from the corn lily plant, has historically been used to elucidate the function of Hh signaling in vertebrates. This compound, however, is not a viable therapeutic agent given its structural complexity, scarcity, and poor solubility and stability. Thus, a search began for small-molecule inhibitors with improved therapeutic viability.

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