Vismodegib

Brand Name: Erivedge

Vismodegib is used to treat adults with metastatic or locally advanced basal cell carcinoma.1

How Does Vismodegib Work?

A primary cilium is a single tail-like structure that protrudes out of most cells in our body.2 It functions as a signaling hub that receives and transmits a variety of signals inside and outside the cell. Most notably, it plays a key role in cellular growth and development though the hedgehog pathway3, and the dysfunction in this pathway is implicated in many diseases including cancer.4,5,6

Three key proteins are involved in the hedgehog pathway: smoothened (SMO), patched (PTCH), and hedgehog (HH).3 In normal conditions, PTCH reside on the surface of the cell near the primary cilium, while SMO reside within the cell.7 Through mechanisms that are not fully understood, PTCH prevents SMO from translocating to the primary cilium.

However, when HH binds to PTCH, PTCH is inactivated and is transported within the cell. This allows SMO to translocate to the primary cilium, where it is able to transmit signal for the cell to grow.7 Since this process is dependent on the presence of HH, it is a controllable one - when cellular growth is no longer needed, the production of HH simply ceases.

However, SMO or PTCH are mutated in certain types of cancer that allows SMO to bypass PTCH or for PTCH to be unable to block SMO.4,8 This allows SMO-mediated growth signal to be transmitted uncontrollably even without hedgehog. These cancer cells rely on growth signal from the constitutively active hedgehog pathway to proliferate.6

Vismodegib is a drug that binds to SMO and inactivates it.9 This turns off the growth signal transmitted by SMO, and as a result, cancer growth is halted.10,11

References

1. ERIVEDGE. U.S. Food and Drug Administration (2012).

2. Macarelli, V., Leventea, E. & Merkle, F. T. Regulation of the length of neuronal primary cilia and its potential effects on signalling. Trends in Cell Biology 33(11), 979-990 (2023).

3. Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nature Reviews Genetics 11, 331-344 (2010).

4. Gailani, M. R. et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nature Genetics 14, 78-81 (1996).

5. Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851-856 (2003).

6. Wicking, C., Smyth, I. & Bale, A. The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18, 7844-7851 (1999).

7. Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 Regulates Hedgehog Signaling at the Primary Cilium. Science 317(5836), 372-376 (2007).

8. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90-92 (1998).

9. Byrne, E. F. X. et al. Structural basis of Smoothened regulation by its extracellular domains. Nature 535, 517-522 (2016).

10. Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406-410 (2008).

11. Von Hoff, D. D. et al. Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma. The New England Journal of Medicine 361, 1164-1172 (2009).