Skip to main content

Advertisement

SpringerLink
Log in

The Role of Vismodegib in the Management of Advanced Basal Cell Skin Cancers: A Review

  • Medical Surgery (J Thiele, Section Editor)
  • Published:
Current Dermatology Reports Aims and scope Submit manuscript

Abstract

Basal cell carcinoma (BCC) is the most common occurring skin malignancy. Until recently, the treatment options for advanced BCC (locally advanced and metastatic BCC) and patients with Basal Cell Nevus Syndrome (BCNS) have been limited. However, the discovery of the Hedgehog (HH) pathway and its role in BCC has led to the development of a first-in-class systemic HH pathway inhibitor, vismodegib (GDC-0449, Erivedge), and has revolutionized the treatment of advanced BCC. In this review, we discuss the current progress on the role of vismodegib for the treatment of advanced BCC and important clinical questions on the mechanisms of vismodegib resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kim RH, Armstrong AW. Nonmelanoma skin cancer. Dermatol Clin. 2012;30(1):125–39. ix.

    Article  CAS  PubMed  Google Scholar 

  2. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005;353(21):2262–9.

    Article  CAS  PubMed  Google Scholar 

  3. Gulleth Y, Goldberg N, Silverman RP, Gastman BR. What is the best surgical margin for a Basal cell carcinoma: a meta-analysis of the literature. Plast Reconstr Surg. Oct 2010;126(4):1222–31.

    Google Scholar 

  4. Wysong A, Aasi SZ, Tang JY. Update on metastatic Basal cell carcinoma: a summary of published cases from 1981 through 2011. JAMA Dermatol (Chicago, Ill). 2013;149(5):615–6.

    Article  Google Scholar 

  5. Sobanko JF, Okman J, Miller C. Vismodegib: a hedgehog pathway inhibitor for locally advanced and metastatic basal cell carcinomas. J Drugs Dermatol: JDD. 2013;12(10 Suppl):s154–155.

    CAS  PubMed  Google Scholar 

  6. Galioto S, Lucioni M, Pastori M, Arecchi A, di Petrillo A. Metastatic basal cell carcinoma: two cases involving the maxillofacial area. Int J Dermatol. 2012;51(9):1097–100.

    Article  PubMed  Google Scholar 

  7. Snow SN, Sahl W, Lo JS, et al. Metastatic basal cell carcinoma. Report of five cases. Cancer. 1994;73(2):328–35.

    Article  CAS  PubMed  Google Scholar 

  8. Guthrie Jr TH, McElveen LJ, Porubsky ES, Harmon JD. Cisplatin and doxorubicin. An effective chemotherapy combination in the treatment of advanced basal cell and squamous carcinoma of the skin. Cancer. 1985;55(8):1629–32.

    Article  PubMed  Google Scholar 

  9. Guthrie Jr TH, Porubsky ES, Luxenberg MN, Shah KJ, Wurtz KL, Watson PR. Cisplatin-based chemotherapy in advanced basal and squamous cell carcinomas of the skin: results in 28 patients including 13 patients receiving multimodality therapy. J Clin Oncol Off J Am Soc Clin Oncol. 1990;8(2):342–6.

    Google Scholar 

  10. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743–54.

    Article  CAS  PubMed  Google Scholar 

  11. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–9. This was one of the first studies to show efficacy of vismodegib in advanced basal cell carcinoma.

    Article  CAS  PubMed  Google Scholar 

  12. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180–8. This was the first study showing that vismodegib can reduce the number of surgically eligible basal cell carcinoma’s in basal cell nevus syndrome patients.

    Article  CAS  PubMed  Google Scholar 

  13. Merchant AA, Matsui W. Targeting Hedgehog–a cancer stem cell pathway. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(12):3130–40.

    Article  CAS  Google Scholar 

  14. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.

    Article  CAS  PubMed  Google Scholar 

  15. Fan H, Khavari PA. Sonic hedgehog opposes epithelial cell cycle arrest. J Cell Biol. 1999;147(1):71–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–51.

    Article  CAS  PubMed  Google Scholar 

  17. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science (New York, NY). 1996;272(5268):1668–71.

    Article  CAS  Google Scholar 

  18. Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90–2.

    Article  CAS  PubMed  Google Scholar 

  19. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173–8.

    Article  CAS  PubMed  Google Scholar 

  20. LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(8):2502–11. This phase I study demonstrated the recommended phase II dose of vismodegib should be 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose.

    Article  CAS  Google Scholar 

  21. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164–72. This phase I study was one of the first to show that vismodegib (GDC-0449) has antitumor activity in locally advanced or metastatic basal-cell carcinoma.

    Article  Google Scholar 

  22. Chang AL, Solomon JA, Hainsworth JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014;70(1):60–9. This is the most recently published study of 119 patients with advanced BCC who were treated with vismodegib. They showed that response was negatively associated with prior systemic therapy in patients with locally advanced BCC.

    Article  CAS  PubMed  Google Scholar 

  23. Wolfe CM, Green WH, Cognetta Jr AB, Hatfield HK. Basal cell carcinoma rebound after cessation of vismodegib in a nevoid basal cell carcinoma syndrome patient. Dermatol Surg Off Publ Am Soc Dermatol Surg [et al]. 2012;38(11):1863–6.

    CAS  Google Scholar 

  24. Aldabagh B, Yu J, Perkocha LA, Arron S. Histologic changes in basal cell carcinoma after treatment with vismodegib. Dermatol Surg Off Publ Am Soc Dermatol Surg [et al.]. Jul 23 2013.

  25. Ally MS, Wysong A, Tang JY, Aasi S. Comment on basal cell carcinoma rebound after cessation of vismodegib in an individual with basal cell nevus syndrome. Dermatol Surg Off Publ Am Soc Dermatol Surg [et al.]. May 17 2013.

  26. Chang AL, Atwood SX, Tartar DM, Oro AE. Surgical excision after neoadjuvant therapy with vismodegib for a locally advanced Basal cell carcinoma and resistant Basal carcinomas in gorlin syndrome. JAMA Dermatol (Chicago, Ill). 2013;149(5):639–41.

    Article  Google Scholar 

  27. Kahana A, Worden FP, Elner VM. Vismodegib as eye-sparing adjuvant treatment for orbital basal cell carcinoma. JAMA Ophthalmol. Aug 1 2013.

  28. Abstracts of the 2013 International Investigative Dermatology Meeting. May 8–11, 2013. Edinburgh, Scotland, United Kingdom. J Investig Dermatol. May 2013;133 Suppl 1:S1–311.

  29. Teperino R, Amann S, Bayer M, et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell. 2012;151(2):414–26.

    Article  CAS  PubMed  Google Scholar 

  30. Iarrobino A, Messina JL, Kudchadkar R, Sondak VK. Emergence of a squamous cell carcinoma phenotype following treatment of metastatic basal cell carcinoma with vismodegib. J Am Acad Dermatol. 2013;69(1):e33–34.

    Article  PubMed  Google Scholar 

  31. Gill HS, Moscato EE, Chang AL, Soon S, Silkiss RZ. Vismodegib for periocular and orbital Basal cell carcinoma. JAMA Ophthalmol. 2013;131(12):1591–4.

    Article  CAS  PubMed  Google Scholar 

  32. Aasi S, Silkiss R, Tang JY, et al. New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol (Chicago, Ill). 2013;149(2):242–3.

    Article  Google Scholar 

  33. Atwood SX, Whitson RJ, Oro AE. “Patch”ing up our tumor signaling knowledge. J Investig Dermatol. 2013;133(5):1131–3.

    Article  CAS  PubMed  Google Scholar 

  34. Wakabayashi Y, Mao JH, Brown K, Girardi M, Balmain A. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature. 2007;445(7129):761–5.

    Article  CAS  PubMed  Google Scholar 

  35. Chang AL, Oro AE. Initial assessment of tumor regrowth after vismodegib in advanced Basal cell carcinoma. Arch Dermatol. 2012;148(11):1324–5. This study addresses the mechanisms of resistance in basal cell carcinoma to vismodegib and other smoothened inhibitors.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Atwood SX, Chang AL, Oro AE. Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol. 2012;199(2):193–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Dijkgraaf GJ, Alicke B, Weinmann L, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011;71(2):435–44.

    Article  CAS  PubMed  Google Scholar 

  38. Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 2011;71(15):5057–61.

    Article  CAS  PubMed  Google Scholar 

  39. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A. 2007;104(20):8455–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23(1):23–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

MS Ally declares no conflicts of interest.

SZ Aasi reports serving on the scientific advisory panel for Genentech in October 2013.

Human and Animal Rights and Informed Consent

All studies by SZ Aasi and MS Ally involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

Author information

Authors and Affiliations

  1. Department of Dermatology, Stanford University, 450 Broadway Street, Redwood City, CA, 94063, USA

    Mina S. Ally & Sumaira Z. Aasi

Authors
  1. Mina S. Ally
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sumaira Z. Aasi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sumaira Z. Aasi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ally, M.S., Aasi, S.Z. The Role of Vismodegib in the Management of Advanced Basal Cell Skin Cancers: A Review. Curr Derm Rep 3, 98–102 (2014). https://doi.org/10.1007/s13671-014-0073-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13671-014-0073-2

Keywords

Search

Navigation