Vismodegib and the Hedgehog Pathway Inhibitors: A Historical Perspective to Current Clinical Application

May 2018 | Volume 17 | Issue 5 | Original Article | 506 | Copyright © May 2018


Jennifer C. Tang MD,a C. William Hanke MD,a Ivor Caro MDb

aLaser and Skin Surgery Center of Indiana, Carmel, IN bGenentech, Inc, San Francisco, CA

Abstract
Vismodegib (Erivedge, Genentech-Roche) is the first in class of Hedgehog pathway inhibitors approved for treatment of metastatic basal cell carcinoma (BCC), or locally advanced BCC that has recurred after surgery or is not amenable to surgery or radiation. Its path to discovery has been unique and traces its origin to corn lilies, sheep, Drosophila flies, and the Hedgehog signaling pathway. J Drugs Dermatol. 2018;17(5):506-508.

INTRODUCTION

Vismodegib (Erivedge, Genentech-Roche) is the first in class of Hedgehog pathway inhibitors approved for treatment of metastatic basal cell carcinoma (BCC), or locally advanced BCC that has recurred after surgery or is not amenable to surgery or radiation. The path to discovery traces its origins to corn lilies, sheep, and Drosophila flies. The unifying theme of seemingly divergent concepts is the Hedgehog signaling pathway. 

Corn Lilies and Cyclopia 

In the 1950s, Idaho sheep ranchers first noticed lambs born with deformities including cyclopia, holoprosencephaly, and limb defects after sheep grazed on certain alpine meadows during the breeding season.1 These events were unpublicized until an epidemic in 1957 prompted investigation. Scientists from a plant research lab studied the flocks and determined Veratrum californicum, known as the Western corn lily, as the culprit. Pregnant sheep that fed on this vibrant plant in early gestation, days 10-15, had disrupted embryonic development in their offspring. In 1968, cyclopamine, a steroidal alkaloid, was finally identified as the component of the corn lily that caused congenital abnormalities yet left the mothers unharmed.2 However, pathophysiology of cyclopamine induced defects would remain unknown for 30 years. 

The Hedgehog Pathway 

In the interim, Christiane Nüsslein-Volhard and Eric F. Wischaus of Germany, would discover the Hedgehog (Hh) pathway. In the 1970s, they were screening for genes in Drosophila (fruit fly) embryos that controlled segment development of fruit fly larvae.3 They would ultimately win the 1995 Nobel Prize for Physiology or Medicine for their work. Normal Hh patterns in larval Drosophila are comprised of segmented bands of denticles. It was noticed that one gene mutation presented as disorganized denticles in all directions resembling a hedgehog’s spines, thus its name (Figures 1 and 2). The Hh signaling pathway conserved in both flies and vertebrates contributes to cellular proliferation and differentiation, as well as tissue patterns including the neural tube. Its role during embryogenesis is well understood. However, the role of the Hh pathway in adult tissue is less clear. There is evidence that the Hh pathway contributes to growth and maintenance of adult tissue, dermal appendages including hair and teeth, and the reproductive system.4–6In the absence of circulating Hh protein the 12-pass cell surface receptor patched 1 (PTCH1), inhibits a second downstream transmembrane protein, SMO. Upon Hh binding, the inhibitory activity of PTCH1 is turned off, leading to activation of SMO to transmit an intracellular signal cascade. The ultimate effector of the Hh pathway is the GLI1 transcription factor which leads to changes in gene expression. The first observation of Hh pathway’s association with human disease was the basal cell nevus syndrome with inactivating mutations of PTCH1.7,8 Dysfunction of PTCH1 or SMO has been observed in the majority of sporadic basal cell carcinomas as well.9,10 Medulloblastoma is another tumor associated with mutations in the Hh pathway occurring in 30% of all cases.11 

Cyclopamine: The Bridge to Hedgehog Inhibition

In 1998, Incardona et al. elucidated cyclopamine’s role in teratogenesis.12 After administering cyclopamine to chick embryos, they observed facial malformations including cyclopia and holoprosencephaly. They concluded that cyclopamine interrupts hedgehog dependent patterns of the ventral neural tube and body segments. In 2002, Beachy et al. discovered that cyclopamine binds directly to SMO using mouse assays.13 Cyclopamine’s ability to inhibit this pathway suggested the potential for pharmacologic antagonists as potential therapies for BCC and medulloblastoma. This paved the path for Lee Rubin at Curis, Inc to begin investigating small