Advertisement

Sonic Hedgehog Pathway Inhibition in the Treatment of Advanced Basal Cell Carcinoma

  • Erica Leavitt
  • Gary Lask
  • Stephanie MartinEmail author
Skin Cancer (T Ito, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Skin Cancer

Opinion statement

Advanced basal cell carcinoma (BCC) represents a small proportion of BCCs that are not amenable to standard therapies due to lack of efficacy, high recurrence risk, and excessive morbidity. Implication of the Sonic hedgehog (Shh) pathway in the development of BCC has led to the development of systemic Shh pathway inhibitors, providing patients with advanced BCCs new treatment options and improved survival. There are currently two Food and Drug Administration (FDA)–approved Shh inhibitors, vismodegib and sonidegib, for advanced basal cell carcinomas. Vismodegib has approval for locally advanced BCCs (laBCC) and metastatic BCC (mBCC), while sonidegib has approval for laBCC. These agents have also been used for prevention in nevoid basal cell carcinoma syndrome and as neoadjuvant therapy before surgery, and we feel that there is a growing role of Shh inhibitors in these settings. Head-to-head randomized controlled trials comparing vismodegib to sonidegib are lacking. Adverse events can limit the utility of these medications by leading to treatment discontinuation in a large proportion of patients, and it is thus essential that prescribers be able to anticipate and manage the most frequent side effects of muscle spasms, alopecia, dysgeusia, nausea, and weight loss. Other Shh inhibitors, including the antifungal itraconazole, have been investigated in small trials, but further research is needed before recommending their routine clinical use. Additionally, there are several new agents under investigation that may have improved efficacy for resistant tumors by utilizing different mechanisms of action than the two currently approved medications.

Keywords

Sonic hedgehog Vismodegib Sonidegib Advanced basal cell carcinoma Metastatic basal cell carcinoma Smoothened inhibitors 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

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

  1. 1.
    Armstrong P, Martin S, Lask G. Sonic hedgehog pathway inhibition in the treatment of advanced basal cell carcinoma. In: Yamauchi P, editor. Biologic and systemic agents in dermatology. Berlin: Springer; 2018. p. 541–8.CrossRefGoogle Scholar
  2. 2.
    Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev. 2004;23(3–4):389–402.PubMedCrossRefGoogle Scholar
  3. 3.
    Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B. 2001;63(1–3):8–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009;10(3):207–17.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. 2004;6(6):530–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Athar M, Li C, Kim AL, Spiegelman VS, Bickers DR. Sonic hedgehog signaling in basal cell nevus syndrome. Cancer Res. 2014;74(18):4967–75.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    de Zwaan SE, Haass NK. Genetics of basal cell carcinoma. Australas J Dermatol. 2010;51(2):81–92 quiz 3-4.Google Scholar
  8. 8.
    Lo JS, Snow SN, Reizner GT, Mohs FE, Larson PO, Hruza GJ. Metastatic basal cell carcinoma: report of twelve cases with a review of the literature. J Am Acad Dermatol. 1991;24(5 Pt 1):715–9.PubMedCrossRefGoogle Scholar
  9. 9.
    von Domarus H, Stevens PJ. Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol. 1984;10(6):1043–60.CrossRefGoogle Scholar
  10. 10.
    Prescribing information: ERIVEDGE (vismodegib) capsule for oral use 2015 [Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2Available from: 015/203388s005s006s007s008lbl.pdf.
  11. 11.
    Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, et al. Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2019;19(1):366.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.•
    Dréno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol. 2017;18(3):404–12 Study investigating intermittent vismodegib dosing regimens for BCC reduction in patients with multiple BCCs including NBCC syndrome.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Chang AL, Solomon JA, Hainsworth JD, Goldberg L, McKenna E, Day BM, 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.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.••
    Basset-Séguin N, Hauschild A, Kunstfeld R, Grob J, Dréno B, Mortier L, et al. Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334–48 Largest trial of over 1000 patients with advanced BCC treated with vismodegib.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    ODOMZO (sonidegib) capsules, for oral use 2015 [Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205266s000lbl.pdf.
  17. 17.
    Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716–28.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Dummer R, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016;75(1):113–25.e5.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.•
    Lear JT, Migden MR, Lewis KD, Chang ALS, Guminski A, Gutzmer R, et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2018;32(3):372–81 Final update from the largest trial treating patients with sonidegib for advanced BCC.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Xie P, Lefrançois P. Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: a systematic review and meta-analysis. J Am Acad Dermatol. 2018;79(6):1089–100.e17.PubMedCrossRefGoogle Scholar
  21. 21.
    Vogt M, Sethi A, Brocato J, Squittieri N. Notes and comments on efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: a systematic review and analysis. J Am Acad Dermatol. 2019.Google Scholar
  22. 22.
    Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol. 2016;152(5):527–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Bhutani T, Abrouk M, Sima CS, Sadetsky N, Hou J, Caro I, et al. Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib. J Am Acad Dermatol. 2017;77(4):713–8.PubMedCrossRefGoogle Scholar
  24. 24.•
    Lacouture ME, Dréno B, Ascierto PA, Dummer R, Basset-Seguin N, Fife K, et al. Characterization and management of hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. Oncologist. 2016;21(10):1218–29 Review and proposed management algorithm of adverse evenets from Shh inhibitors.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Grunewald S, Jank A. New systemic agents in dermatology with respect to fertility, pregnancy, and lactation. J Dtsch Dermatol Ges. 2015;13(4):277–89 quiz 90.PubMedGoogle Scholar
  26. 26.
    Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Tang JY, Ally MS, Chanana AM, Mackay-Wiggan JM, Aszterbaum M, Lindgren JA, et al. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1720–31.PubMedCrossRefGoogle Scholar
  28. 28.
    Skvara H, Kalthoff F, Meingassner JG, Wolff-Winiski B, Aschauer H, Kelleher JF, et al. Topical treatment of basal cell carcinomas in nevoid basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol. 2011;131(8):1735–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Calienni MN, Febres-Molina C, Llovera RE, Zevallos-Delgado C, Tuttolomondo ME, Paolino D, et al. Nanoformulation for potential topical delivery of vismodegib in skin cancer treatment. Int J Pharm. 2019;565:108–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Olesen UH, Clergeaud G, Lerche CM, Andresen TL, Haedersdal M. Topical delivery of vismodegib using ablative fractional laser and micro-emulsion formulation in vitro. Lasers Surg Med. 2019;51(1):79–87.PubMedCrossRefGoogle Scholar
  31. 31.
    Ally MS, Aasi S, Wysong A, Teng C, Anderson E, Bailey-Healy I, et al. An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):904–11.e1.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    González AR, Etchichury D, Gil ME, Del Aguila R. Neoadjuvant vismodegib and Mohs micrographic surgery for locally advanced periocular basal cell carcinoma. Ophthalmic Plast Reconstr Surg. 2019;35(1):56–61.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Mortier L, Bertrand N, Basset-Seguin N, Saiag P, Dupuy A, Dalac-Rat S, et al. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: first results of a multi center, open-label, phase 2 trial (VISMONEO study). J Clin Oncol. 2018;36(15):9509.CrossRefGoogle Scholar
  34. 34.
    Alcalay J, Tauber G, Fenig E, Hodak E. Vismodegib as a neoadjuvant treatment to Mohs surgery for aggressive basal cell carcinoma. J Drugs Dermatol. 2015;14(3):219–23.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Chang AL, Oro AE. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol. 2012;148(11):1324–5.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pricl S, Cortelazzi B, Dal Col V, Marson D, Laurini E, Fermeglia M, et al. Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Mol Oncol. 2015;9(2):389–97.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2(51):51ra70.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Biehs B, Dijkgraaf GJP, Piskol R, Alicke B, Boumahdi S, Peale F, et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature. 2018;562(7727):429–33.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Kuonen F, Huskey NE, Shankar G, Jaju P, Whitson RJ, Rieger KE, et al. Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma. J Invest Dermatol. 2019;139:1439–48.PubMedCrossRefGoogle Scholar
  41. 41.
    Kim J, Tang JY, Gong R, Lee JJ, Clemons KV, Chong CR, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388–99.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, Chandra K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32(8):745–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Ally MS, Ransohoff K, Sarin K, Atwood SX, Rezaee M, Bailey-Healy I, et al. Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma. JAMA Dermatol. 2016;152(4):452–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Girardi D, Barrichello A, Fernandes G, Pereira A. Targeting the Hedgehog pathway in cancer: current evidence and future perspectives. Cells. 2019;8(2).PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Chen B, Trang V, Lee A, Williams NS, Wilson AN, Epstein EH, et al. Posaconazole, a second-generation triazole antifungal drug, inhibits the Hedgehog signaling pathway and progression of basal cell carcinoma. Mol Cancer Ther. 2016;15(5):866–76.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    List A, Beran M, DiPersio J, Slack J, Vey N, Rosenfeld CS, et al. Opportunities for Trisenox (arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia. 2003;17(8):1499–507.PubMedCrossRefGoogle Scholar
  48. 48.
    Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148–60.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim J, Lee JJ, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107(30):13432–7.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    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.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of DermatologyUCLALos AngelesUSA
  2. 2.ILR DermatologyEncinoUSA
  3. 3.Department of DermatologyGreater Los Angeles VALos AngelesUSA

Personalised recommendations