Top

Published in:

01-06-2019 | Itraconazole | Review Article

Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma

Authors: Ralf Gutzmer, James A. Solomon

Published in: Targeted Oncology | Issue 3/2019

Abstract

Globally, basal cell carcinoma is the most commonly diagnosed cancer. While most cases are amenable to surgery, treatment options for advanced basal cell carcinoma, including locally advanced basal cell carcinoma and metastatic basal cell carcinoma, have proved more difficult. Recent advances regarding the role of hedgehog signaling in the pathogenesis of basal cell carcinoma and the identification of hedgehog pathway inhibitors have facilitated the development of treatment options with improved clinical outcomes. The hedgehog signaling pathway regulates development, cell proliferation, and tissue repair. The pathway is tightly regulated under normal physiological conditions. However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation. Subsequently, inhibitors blocking hedgehog signaling either at the level of Smo (i.e., vismodegib, sonidegib, patidegib, and itraconazole) or via an unknown mode of action (arsenic trioxide) were identified. The hedgehog inhibitor vismodegib is approved for the treatment of locally advanced basal cell carcinoma and metastatic basal cell carcinoma while sonidegib is approved for the treatment of locally advanced basal cell carcinoma in the USA and Europe; and for locally advanced basal cell carcinoma and metastatic basal cell carcinoma in Switzerland and Australia. The most common treatment-emergent adverse events associated with approved hedgehog inhibitors include muscle spasms, dysgeusia, and alopecia. This review addresses the challenges associated with appropriately diagnosing locally advanced basal cell carcinoma, provides an overview of hedgehog signaling in basal cell carcinoma, and discusses the pharmacology of hedgehog inhibitors and their efficacy, and adverse events associated with hedgehog inhibitor use, and their management.

Tay EY, Teoh YL, Yeo MS. Hedgehog pathway inhibitors and their utility in basal cell carcinoma: a comprehensive review of current evidence. Dermatol Ther (Heidelb). 2019;9(1):33–49. https://doi.org/10.1007/s13555-018-0277-7.CrossRefPubMed

Migden MR, Chang ALS, Dirix L, Stratigos AJ, Lear JT. Emerging trends in the treatment of advanced basal cell carcinoma. Cancer Treat Rev. 2018;64:1–10. https://doi.org/10.1016/j.ctrv.2017.12.009.CrossRefPubMed

Cross SS, Bury JP. The hedgehog signalling pathways in human pathology. Curr Diagn Histopathol. 2004;10(2):157–68. https://doi.org/10.1016/j.cdip.2003.11.005.CrossRef

Pak E, Segal RA. Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev Cell. 2016;38(4):333–44. https://doi.org/10.1016/j.devcel.2016.07.026.CrossRefPubMedPubMedCentral

Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo H-W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel). 2016;8(2):22. https://doi.org/10.3390/cancers8020022.CrossRefPubMedCentral

Heo JS, Lee MY, Han HJ. Sonic hedgehog stimulates mouse embryonic stem cell proliferation by cooperation of Ca²⁺/protein kinase C and epidermal growth factor receptor as well as Gli1 activation. Stem Cells. 2007;25(12):3069–80. https://doi.org/10.1634/stemcells.2007-0550.CrossRefPubMed

Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the hedgehog pathway in cancer. Nat Med. 2013;19(11):1410–22. https://doi.org/10.1038/nm.3389.CrossRefPubMed

Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110(6):885–8. https://doi.org/10.1046/j.1523-1747.1998.00222.x.CrossRefPubMed

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. https://doi.org/10.1158/0008-5472.can-14-1666.CrossRefPubMedPubMedCentral

10.

American Joint Committee on Cancer. AJCC cancer staging manual. 8th ed. Chicago: Springer International Publishing; 2018.

11.

Lear JT, Corner C, Dziewulski P, Fife K, Ross GL, Varma S, et al. Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective. Br J Cancer. 2014;111(8):1476–81. https://doi.org/10.1038/bjc.2014.270.CrossRefPubMedPubMedCentral

12.

Hillen U, Ulrich M, Alter M, Becker JC, Gutzmer R, Leiter U, et al. Cutaneous squamous cell carcinoma: a review with consideration of special patient groups [in German]. Hautarzt. 2014;65(7):590–9.CrossRefPubMed

13.

Edge SB, Byrd DR, Compton CC, Firtz AG, Greene FL, Trotti A III. Cutaneous squamous cell carcinoma and other cutaneous carcinomas. In: Edge SB, Compton CC, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. p. 301–14.

14.

Maly TJ, Sligh JE. Defining locally advanced basal cell carcinoma. J Drugs Dermatol. 2014;13(5):528–9.PubMed

15.

Fecher LA, Sharfman WH. Advanced basal cell carcinoma, the hedgehog pathway, and treatment options: role of smoothened inhibitors. Biologics. 2015;9:129–40. https://doi.org/10.2147/BTT.S54179.CrossRefPubMedPubMedCentral

16.

Amici JM, Battistella M, Beylot-Barry M, Chatelleir A, Dalac-Ra S. Defining and recognising locally advanced basal cell carcinoma. Eur J Dermatol. 2015;25(6):586–94.PubMed

17.

Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, Scales SJ, et al. Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site. J Biol Chem. 2010;285(34):26570–80. https://doi.org/10.1074/jbc.M110.112284.CrossRefPubMedPubMedCentral

18.

Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. Itraconazole, a commonly used anti-fungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388–99. https://doi.org/10.1016/j.ccr.2010.02.027.CrossRefPubMedPubMedCentral

19.

Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455(7211):406–10. https://doi.org/10.1038/nature07275. https://www.nature.com/articles/nature07275#supplementary-information.

20.

Whitson RJ, Lee A, Urman NM, Mirza A, Yao CY, Brown AS, et al. Noncanonical hedgehog pathway activation through SRF–MKL1 promotes drug resistance in basal cell carcinomas. Nat Med. 2018;24(3):271–81. https://doi.org/10.1038/nm.4476. https://www.nature.com/articles/nm.4476#supplementary-information.

21.

Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell. 2012;151(2):414–26. https://doi.org/10.1016/j.cell.2012.09.021.CrossRefPubMed

22.

Atwood SX, Chang AL, Oro AE. Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol. 2012;199(2):193–7. https://doi.org/10.1083/jcb.201207140.CrossRefPubMedPubMedCentral

23.

Dentice M, Luongo C, Huang S, Ambrosio R, Elefante A, Mirebeau-Prunier D, et al. Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci USA. 2007;104(36):14466–71. https://doi.org/10.1073/pnas.0706754104.CrossRefPubMedPubMedCentral

24.

Hasegawa D, Ochiai-Shino H, Onodera S, Nakamura T, Saito A, Onda T, et al. Gorlin syndrome-derived induced pluripotent stem cells are hypersensitive to hedgehog-mediated osteogenic induction. PLoS One. 2017;12(10):e0186879. https://doi.org/10.1371/journal.pone.0186879.CrossRefPubMedPubMedCentral

25.

Evans DG, Oudit D, Smith MJ, Rutkowski D, Allan E, Newman WG, et al. First evidence of genotype–phenotype correlations in Gorlin syndrome. J Med Genet. 2017;54(8):530–6. https://doi.org/10.1136/jmedgenet-2017-104669.CrossRefPubMed

26.

Adolphe C, Hetherington R, Ellis T, Wainwright B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res. 2006;66(4):2081–8. https://doi.org/10.1158/0008-5472.CAN-05-2146.CrossRefPubMed

27.

Shih S, Urso BA, Domozych R, Updyke KM, Laughlin AI, Solomon JA. Chromosome 9 mutations reported absent in some patients with basal cell carcinoma nevus syndrome. J Eur Acad Dermatol Venereol. 2018;32(5):e179–81. https://doi.org/10.1111/jdv.14689.CrossRefPubMed

28.

Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90–2. https://doi.org/10.1038/34201.CrossRefPubMed

29.

Callahan CA, Ofstad T, Horng L, Wang JK, Zhen HH, Coulombe PA, et al. MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev. 2004;18(22):2724–9. https://doi.org/10.1101/gad.1221804.CrossRefPubMedPubMedCentral

30.

Shih S, Dai C, Ansari A, Urso BA, Laughlin AI, Solomon JA. Advances in genetic understanding of Gorlin syndrome and emerging treatment options. Expert Opin Orphan Drugs. 2018;6(7):413–23. https://doi.org/10.1080/21678707.2018.1483233.CrossRef

31.

Yang SH, Andl T, Grachtchouk V, Wang A, Liu J, Syu LJ, et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta3-catenin signaling. Nat Genet. 2008;40(9):1130–5. https://doi.org/10.1038/ng.192.CrossRefPubMedPubMedCentral

32.

Cooper MK, Porter JA, Young KE, Beachy PA. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science. 1998;280(5369):1603–7. https://doi.org/10.1126/science.280.5369.1603.CrossRefPubMed

33.

Heretsch P, Tzagkaroulaki L, Giannis A. Cyclopamine and hedgehog signaling: chemistry, biology, medical perspectives. Angew Chem Int Ed Engl. 2010;49(20):3418–27. https://doi.org/10.1002/anie.200906967.CrossRefPubMed

34.

Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC, et al. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem. 2009;52(14):4400–18. https://doi.org/10.1021/jm900305z.CrossRefPubMed

35.

Jimeno A, Weiss GJ, Miller WHJ, Gettinger S, Eigl BJC, Chang ALS, et al. Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res. 2013;19(10):2766–74. https://doi.org/10.1158/1078-0432.Ccr-12-3654.CrossRefPubMedPubMedCentral

36.

Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, et al. GDC-0449: a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett. 2009;19(19):5576–81. https://doi.org/10.1016/j.bmcl.2009.08.049.CrossRefPubMed

37.

Gould SE, Low JA, Marsters JCJ, Robarge K, Rubin LL, de Sauvage FJ, et al. Discovery and preclinical development of vismodegib. Expert Opin Drug Discov. 2014;9(8):969–84. https://doi.org/10.1517/17460441.2014.920816.CrossRefPubMed

38.

Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med Chem Lett. 2010;1(3):130–4. https://doi.org/10.1021/ml1000307.CrossRefPubMedPubMedCentral

39.

Epstein EH, Lear J, Saldanha G, Tang JY, Harwood C. Hedgehog pathway inhibition by topical patidegib to reduce BCC burden in patients with basal cell nevus (Gorlin) syndrome. J Clin Oncol. 2018;36(15_Suppl.):e21626-e. https://doi.org/10.1200/jco.2018.36.15_suppl.e21626.CrossRef

40.

Lauressergues E, Heusler P, Lestienne F, Troulier D, Rauly-Lestienne I, Tourette A, et al. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol Res Perspect. 2016;4(2):e00214. https://doi.org/10.1002/prp2.214.CrossRefPubMedPubMedCentral

41.

Ueno H, Kondo S, Yoshikawa S, Inoue K, Andre V, Tajimi M, et al. A phase I and pharmacokinetic study of taladegib, a Smoothened inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs. 2018;36(4):647–56. https://doi.org/10.1007/s10637-017-0544-y.CrossRefPubMed

42.

Bendell JC, Andre VA, Ho AL, Kudchakar R, Migden MR, Infante JR, et al. Phase 1 study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment naive and previously treated basal cell carcinoma. Clin Cancer Res. 2018;24(9):2082–91. https://doi.org/10.1158/1078-0432.Ccr-17-0723.CrossRefPubMedPubMedCentral

43.

Erivedge^®. US prescribing information. San Francisco (CA): Genentech. USA, Inc.; 2019.

44.

Odomzo^®. US prescribing information. Cranbury (NJ): Sun Pharmaceutical Industries, Inc.; 2017.

45.

Wahid M, Jawed A, Dar SA, Mandal RK, Haque S. Differential pharmacology and clinical utility of sonidegib in advanced basal cell carcinoma. Onco Targets Ther. 2017;10:515–20. https://doi.org/10.2147/OTT.S97713.CrossRefPubMedPubMedCentral

46.

Sporanox^®: prescribing information. Beerse: Janssen Pharmaceuticals I, 2017.

47.

Sharma MR, Karrison TG, Kell B, Wu K, Turcich M, Geary D, et al. Evaluation of food effect on pharmacokinetics of vismodegib in advanced solid tumor patients. Clin Cancer Res. 2013;19(11):3059–67. https://doi.org/10.1158/1078-0432.CCR-12-3829.CrossRefPubMedPubMedCentral

48.

European Medicines Agency. Odomzo: summary of product characteristics. London: European Medicines Agency; 2015.

49.

Jain S, Song R, Xie J. Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. Onco Targets Ther. 2017;10:1645–53. https://doi.org/10.2147/OTT.S130910.CrossRefPubMedPubMedCentral

50.

Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother. 2005;56(Suppl_1):i17–22. https://doi.org/10.1093/jac/dki220.CrossRefPubMed

51.

Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017;17(1):332. https://doi.org/10.1186/s12885-017-3286-5.CrossRefPubMedPubMedCentral

52.

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. https://doi.org/10.1056/NEJMoa1113713.CrossRefPubMedPubMedCentral

53.

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. https://doi.org/10.1111/jdv.14542.CrossRefPubMed

54.

Ernst D. Patidegib gets breakthrough and orphan designation for Gorlin syndrome. 2017. Available from: https://www.empr.com/patidegib-gets-breakthrough-and-orphan-designation-for-gorlin-syndrome/printarticle/708449/. Accessed 6 Feb 2018.

55.

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. https://doi.org/10.1016/j.ejca.2017.08.022.CrossRefPubMed

56.

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. https://doi.org/10.1016/S1470-2045(17)30072-4.CrossRefPubMed

57.

Migden MR, Lewis KD. 42-month follow-up of sonidegib efficacy and safety in advanced basal cell carcinoma: final analysis from BOLT. J Clin Oncol. 2018;36(15_Suppl.):9551. https://doi.org/10.1200/jco.2018.36.15_suppl.9551.CrossRef

58.

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. https://doi.org/10.1016/j.jaad.2016.02.1226.CrossRefPubMed

59.

Lewis KD, Migden MR. Effects of sonidegib dose reduction or delay in locally advanced basal cell carcinoma: 42-month data from BOLT. J Clin Oncol. 2018;36(Suppl.):abstract no. 9573.

60.

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. https://doi.org/10.1016/S1470-2045(15)70100-2.CrossRefPubMed

61.

National Cancer Institute. Trial of patidegib gel 2%, 4%, and vehicle to decrease the number of surgically eligible basal cell carcinomas (BCC) in Gorlin syndrome patients (BCC). 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT02762084. Accessed 5 Feb 2018.

62.

National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Bethesda (MD): U.S. Department of Health and Human Services, National Institutes of Health; 2010.

63.

Chang ALS, Solomon JA, Hainsworth JD, Goldberg L, McKenna E, Day B-M, 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. https://doi.org/10.1016/j.jaad.2013.09.012.CrossRefPubMed

64.

Dummer R, Basset-Seguin N, Hansson J, Grob JJ, Kunstfeld R, Dréno B, et al. Impact of treatment breaks on vismodegib patient outcomes: exploratory analysis of the STEVIE study. J Clin Oncol. 2015;33(15_Suppl.):9024. https://doi.org/10.1200/jco.2015.33.15_suppl.9024.CrossRef

65.

Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway. J Invest Dermatol. 2005;125(4):638–46. https://doi.org/10.1111/j.0022-202X.2005.23867.x.CrossRefPubMed

66.

Monderer RS, Wu WP, Thorpy MJ. Nocturnal leg cramps. Curr Neurol Neurosci Rep. 2010;10(1):53–9. https://doi.org/10.1007/s11910-009-0079-5.CrossRefPubMed

67.

Girard E, Lacour A, Abi Rached H, Ramdane N, Templier C, Dziwniel V, et al. Occurrence of vismodegib-induced cramps in the treatment of basal cell carcinoma: a prospective study in 30 patients. J Am Acad Dermatol. 2018;78(6):1213-6.e2. https://doi.org/10.1016/j.jaad.2017.11.045.CrossRef

68.

Dinehart MS, McMurray S, Dinehart SM, Lebwohl M. L-Carnitine reduces muscle cramps in patients taking vismodegib. SKIN. 2018;2(2):90–5. https://doi.org/10.25251/skin.2.2.1.CrossRef

69.

Ally MS, Tang JY, Lindgren J, et al. Effect of calcium channel blockade on vismodegib-induced muscle cramps. JAMA Dermatol. 2015;151(10):1132–4. https://doi.org/10.1001/jamadermatol.2015.1937.CrossRefPubMed

70.

Cannon JGD, Tran DC, Li S, Chang S. Levocarnitine for vismodegib-associated muscle spasms: a pilot randomized, double-blind, placebo-controlled, investigator initiated trial. J Eur Acad Dermatol Venereol. 2018;32(7):e298–9. https://doi.org/10.1111/jdv.14844.CrossRefPubMed

71.

Dessinioti C, Antoniou C, Stratigos AJ. From basal cell carcinoma morphogenesis to the alopecia induced by hedgehog inhibitors: connecting the dots. Br J Dermatol. 2017;177(6):1485–94. https://doi.org/10.1111/bjd.15738.CrossRefPubMed

72.

Soura E, Plaka M, Dessinioti C, Syrigos K, Stratigos AJ. Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma? A report of two cases. J Eur Acad Dermatol Venereol. 2016;30(10):1726–9. https://doi.org/10.1111/jdv.13754.CrossRefPubMed

73.

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. https://doi.org/10.1634/theoncologist.2016-0186.CrossRefPubMedPubMedCentral

74.

Solomon J, Chever D, Iarrobino A, Caldwell C. 1088. Successful control of adverse events associated with vismodegib treatment of advanced basal cell carcinoma by recognition of hedgehog pathway activity in normal adult tissue. International Investigative Dermatology Meeting; 7 May, 2013; Edinburgh.

75.

Kumari A, Ermilov AN, Allen BL, Bradley RM, Dlugosz AA, Mistretta CM. Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation. J Neurophysiol. 2015;113(3):1034–40. https://doi.org/10.1152/jn.00822.2014.CrossRefPubMed

76.

Yang H, Cong W-N, Yoon JS, Egan JM. Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds. Cancer Med. 2015;4(2):245–52. https://doi.org/10.1002/cam4.350.CrossRefPubMed

77.

Le Moigne M, Saint-Jean M, Jirka A, Quéreux G, Peuvrel L, Brocard A, et al. Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management. Support Care Cancer. 2016;24(4):1689–95. https://doi.org/10.1007/s00520-015-2932-1.CrossRefPubMed

78.

Edwards BJ, Raisch DW, Saraykar SS, Sun M, Hammel JA, Tran HT, et al. Hepatotoxicity with vismodegib: an MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project. Drugs R D. 2017;17(1):211–8. https://doi.org/10.1007/s40268-016-0168-2.CrossRefPubMedPubMedCentral

79.

Thomas CL, Arasaratnam M, Carlos G, Parasyn A, Baumgart KW, Fernandez-Penas P, et al. Drug reaction with eosinophilia and systemic symptoms in metastatic basal cell carcinoma treated with vismodegib. Australas J Dermatol. 2017;58(1):69–70. https://doi.org/10.1111/ajd.12472.CrossRefPubMed

80.

Lam T, Wolverton SE, Davis CL. Drug hypersensitivity syndrome in a patient receiving vismodegib. J Am Acad Dermatol. 2014;70(3):e65–6. https://doi.org/10.1016/j.jaad.2013.11.018.CrossRefPubMed

81.

Hosiriluck N, Jones C. Emergence of squamous cell carcinoma during treatment of basal cell carcinoma with vismodegib. J Integr Oncol. 2016;5(2):1–4. https://doi.org/10.4172/2329-6771.1000169.CrossRef

82.

Mohan SV, Chang J, Li S, Henry A, Wood DJ, Chang AS. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol. 2016;152(5):527–32. https://doi.org/10.1001/jamadermatol.2015.4330.CrossRefPubMed

83.

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. https://doi.org/10.1016/j.jaad.2017.03.038.CrossRefPubMed

84.

Saintes C, Saint-Jean M, Brocard A, Peuvrel L, Renaut JJ, Khammari A, et al. Development of squamous cell carcinoma into basal cell carcinoma under treatment with vismodegib. J Eur Acad Dermatol Venereol. 2015;29(5):1006–9. https://doi.org/10.1111/jdv.12526.CrossRefPubMed

85.

Danial C, Sarin KY, Oro AE, Chang ALS. An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib. Clin Cancer Res. 2016;22(6):1325–9. https://doi.org/10.1158/1078-0432.ccr-15-1588.CrossRefPubMed

86.

Atwood SX, Sarin KY, Whitson RJ, Li JR, Kim G, Rezaee M, et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell. 2015;27(3):342–53. https://doi.org/10.1016/j.ccell.2015.02.002.CrossRefPubMedPubMedCentral

87.

Tu J, Li JJ, Song LT, Zhai HL, Wang J, Zhang XY. Molecular modeling study on resistance of WT/D473H SMO to antagonists LDE-225 and LEQ-506. Pharmacol Res. 2018;129:491–9. https://doi.org/10.1016/j.phrs.2017.11.025.CrossRefPubMed

88.

Chen L, Aria AB, Silapunt S, Lee H-H, Migden MR. Treatment of advanced basal cell carcinoma with sonidegib: perspective from the 30-month update of the BOLT trial. Future Oncol. 2018;14(6):515–25. https://doi.org/10.2217/fon-2017-0457.CrossRefPubMed

89.

Wang C, Wu H, Evron T, Vardy E, Han GW, Huang X-P, et al. Structural basis for Smoothened receptor modulation and chemoresistance to anti-cancer drugs. Nat Commun. 2014;5:4355. https://doi.org/10.1038/ncomms5355.CrossRefPubMed

90.

Zhao X, Pak E, Ornell KJ, Pazyra-Murphy MF, MacKenzie EL, Chadwick EJ, et al. A transposon screen identifies loss of primary cilia as a mechanism of resistance to SMO inhibitors. Cancer Discov. 2017;7(12):1436–49. https://doi.org/10.1158/2159-8290.cd-17-0281.CrossRefPubMed

91.

Sharpe HJ, Pau G, Dijkgraaf GJ, Basset-Seguin N, Modrusan Z, Januario T, et al. Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell. 2015;27(3):327–41. https://doi.org/10.1016/j.ccell.2015.02.001.CrossRefPubMedPubMedCentral

92.

Brinkhuizen T, Reinders MG, van Geel M, Hendriksen AJL, Paulussen ADC, Winnepenninckx VJ, et al. Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J Am Acad Dermatol. 2014;71(5):1005–8. https://doi.org/10.1016/j.jaad.2014.08.001.CrossRefPubMed

93.

Banvolgyi A, Lorincz K, Kiss N, Gyongyosi N, Marton D. Experiences with SMO antagonist vismodegib for the treatment of locally advanced basal cell carcinoma. J Invest Dermatol. 2017;137(Suppl. 2):abstract no. 035.

94.

Yoon J, Apicelli AJ 3rd, Pavlopoulos TV. Intracranial regression of an advanced basal cell carcinoma using sonidegib and itraconazole after failure with vismodegib. JAAD Case Rep. 2018;4(1):10–2. https://doi.org/10.1016/j.jdcr.2017.11.001.CrossRefPubMed

95.

Pounds R, Leonard S, Dawson C, Kehoe S. Repurposing itraconazole for the treatment of cancer. Oncol Lett. 2017;14(3):2587–97. https://doi.org/10.3892/ol.2017.6569.CrossRefPubMedPubMedCentral

96.

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. https://doi.org/10.1200/JCO.2013.49.9525.CrossRefPubMed

97.

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. https://doi.org/10.1001/jamadermatol.2015.5473.CrossRefPubMedPubMedCentral

98.

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. https://doi.org/10.1126/scitranslmed.3001599.CrossRefPubMedPubMedCentral

99.

Tran DC, Moffat A, Brotherton R, Pague A, Zhu GA, Chang ALS. An exploratory open-label, investigator-initiated study to evaluate the efficacy and safety of combination sonidegib and buparlisib for advanced basal cell carcinomas. J Am Acad Dermatol. 2018;78(5):1011–3. https://doi.org/10.1016/j.jaad.2017.11.031.CrossRefPubMed

100.

Shou Y, Robinson DM, Amakye DD, Rose KL, Cho Y-J, Ligon KL, et al. A five-gene Hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma. Clin Cancer Res. 2015;21(3):585–93. https://doi.org/10.1158/1078-0432.ccr-13-1711.CrossRefPubMed

101.

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. https://doi.org/10.1016/j.jaad.2014.05.020.CrossRef

102.

Kunstfeld R, Zloty D, Tang JY, Basset-Seguin N, Bissonette R, Grob JJ, et al. Analysis of patients with and without Gorlin syndrome in MIKIE, a randomized phase 2 study to assess the efficacy and safety of two intermittent vismodegib regimens in patients with multiple basal cell carcinomas. European Association of Dermato-Oncology; 3 September, 2016; Vienna.

103.

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. https://doi.org/10.1016/S1470-2045(16)30566-6.CrossRefPubMed

104.

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. https://doi.org/10.1038/jid.2011.48.CrossRefPubMed

105.

Dong X, Wang C, Chen Z, Zhao W. Overcoming the resistance mechanisms of Smoothened inhibitors. Drug Discov Today. 2018;23(3):704–10. https://doi.org/10.1016/j.drudis.2018.01.012.CrossRefPubMed

Title: Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma
Authors: Ralf Gutzmer
James A. Solomon
Publication date: 01-06-2019
Publisher: Springer International Publishing
Keywords: Itraconazole
Basalioma
Basalioma
Basalioma
Basalioma
Published in: Targeted Oncology / Issue 3/2019
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-019-00648-2

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2019

Current Systemic Treatment Landscape of Advanced Gynecologic Malignancies

Real-Life Efficacy of Osimertinib in Pretreated Octogenarian Patients with T790M-Mutated Advanced Non-small Cell Lung Cancer

Comparison of Standard Initial Dose and Reduced Initial Dose Regorafenib for Colorectal Cancer Patients: A Retrospective Cohort Study

Clinical Modality of Resistance and Subsequent Management of Patients with Advanced Non-small Cell Lung Cancer Failing Treatment with Osimertinib

The Urinary Microbiome and Anticancer Immunotherapy: The Potentially Hidden Role of Unculturable Microbes

Venetoclax Synergistically Enhances the Anti-leukemic Activity of Vosaroxin Against Acute Myeloid Leukemia Cells Ex Vivo

Keynote webinar | Spotlight on antibody–drug conjugates in cancer