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Research Updates

Basal Cell Carcinoma, Hedgehog and Vismodegib

Rita Patel, Gary Goldenberg

Tuesday, March 20, 2012

Basal cell carcinoma (BCC) of the skin, which is the most common malignancy in individuals of mixed European descent, is increasing in incidence owing to the aging population and sun exposure habits. Yearly, BCC accounts for 25% of all diagnosed cancers in the United States.1 The pathogenesis usually involves damage to DNA caused by ultraviolet light, and currently available treatment options have high success rates when chosen appropriately and applied skillfully. For example, the range of treatments for superficial BCCs includes chemical destruction (curettage, electrodessication, or cryosurgery), topical treatment (imiquimod, 5-fluorouracil, or photodynamic therapy with aminolevulinic acid), and surgical excision. Nodular or infiltrative BCCs have a higher risk of progression and can be treated with either surgical excision or Mohs micrographic surgery, with or without adjunctive modalities.2

In less than 1% of the American population, BCCs metastasize or advance locally to a depth, size, or extent that makes them completely unresectable. Moreover, those with the rare genetic disorder basal cell nevus syndrome (also known as Gorlin syndrome) have a high propensity for the development of multiple, even hundreds, of BCCs in addition to ondontogenic cysts and medulloblastomas.3 Currently, there is no standard therapy for locally advanced or metastatic BCC.4 The reported survival time for metastatic BCC varies widely, but the median is 8 months.5,6

Sonic Hedgehog Signaling Pathway

First discovered in the 1970s in the Drosophila melanogaster fruit fly, hedgehogs are secreted signaling proteins that have sparked widespread investigations into how embryonic cells are "directed" to differentiate into specific structures at specific locations. This research has led not only to the understanding of normal pathways of development but also to the recognition of how mutations affect these pathways.2 

The hedgehog signaling pathway was first implicated as being abnormal in those with Gorlin syndrome when an excessive or inappropriate expression of a hedgehog ligand homolog, known as sonic hedgehog (Shh), was linked to BCC development. Additionally, Shh expression has been implicated in the pathogenesis of a number of sporadic cancers, such as colon, pancreas, prostate, and B-cell malignancies.7-9 Therefore, disruption of Shh signaling may be beneficial for a broad array of tumor types. 

Shh is known to play an important embryologic role in the development and maintenance of structures, including the nervous system, axial skeleton, lungs, skin, hair, and stem cells.10 In the adult, the role of this signaling pathway is much reduced and may be limited to sites of hair growth, spermatogenesis, and areas of tissue damage, where it mediates tissue repair.11,12

Cellular biology studies have revealed that extracellular Shh protein binds to patched-1 (PTCH1), a 12-transmembrane receptor, and prevents PTCH1-mediated inhibition of signaling through smoothened (SMO), a seven-transmembrane protein (Figure 1). Once the inhibition of SMO is relieved, SMO then activates GLI transcription factors in the nucleus to induce target genes that are responsible for cell growth.10   

Figure 1. Schematic of the Shh signaling pathway. Vismodegib (GDC-0449) inhibits the activity of SMO.

Ordinarily, in the absence of Shh, PTCH1 acts as a braking mechanism on the entire pathway; however, the vast majority of all BCCs contain mutations that activate PTCH1. Less frequently, constitutive activation of SMO stimulates the Shh pathway. Similar activating mutations have been noted in medulloblastoma, a malignancy also found in those with Gorlin syndrome.2 All of these mutations cause constitutive Shh signaling, which mediates the unrestrained proliferation of basal cells in the skin.4 

Vismodegib

The first evidence that SMO could be antagonized came with the isolation of compounds called cyclopamine and jervine from corn lilies, which both cause teratogenic effects and cyclopia in lambs.13,14 The novel SMO inhibitor vismodegib (GDC-0449) was discovered by high-throughput screening of a library of small-molecule compounds and subsequent optimization through medicinal chemistry.7,15

Early clinical trials have confirmed the effectiveness of the oral formulation of this selective hedgehog pathway inhibitor in treating metastatic or locally advanced BCC. Von Hoff et al. reported successful results in those patients who were no longer amenable to conventional treatment secondary to either locally advanced or metastatic BCC.4 Of the 33 subjects enrolled, 18 had an objective response to GDC-0449: two with a complete response and 16 with a partial response. The other 15 patients had either stable disease (11 subjects) or progressive disease (4 subjects).4 A Phase II study involving 40 subjects with Gorlin syndrome who were randomized in a 2:1 ratio to receive either GDC-0449 at 150 mg/day or placebo was prematurely ended by the Data and Safety Monitoring Board because of the significant differences that were seen between the active treatment and placebo groups in an interim analysis of data. The analysis showed that the 24 subjects treated with vismodegib developed 0.07 new BCCs/month compared with 1.74 BCCs/month in the placebo group (p<0.001). In the treatment arm, the aggregate size of existing BCCs decreased by 24 cm; the decrease in aggregate size of BCCs in the placebo arm was 3 cm (p=0.006). Near-complete remission was seen in several patients in the treatment arm. The most common adverse events included fatigue, weight loss, muscle spasms, hyponatremia, and dysgeusia.16

In November of 2011, the New Drug Application for vismodegib was granted priority review by the Food and Drug Administration (FDA). This filing was based on the positive results from a pivotal Phase II clinical trial that was presented in June 2011 at the European Association of Dermato-Oncology. This study enrolled 104 subjects, comprising those with locally advanced BCC (71/104) and metastatic BCC (33/104), all of whom received 150 mg/day of the study drug. The primary endpoint of the trial showed an overall response rate of 43% in the locally advanced cohort and 30% in the metastatic cohort, as assessed by independent review. The median duration of progression-free survival for both metastatic and locally advanced BCC patients was 9.5 months. In addition, the clinical benefit rate (defined as patients who experienced response, as well as those who experienced prolonged stable disease for more than 24 weeks) showed that vismodegib shrank tumors, healed visible lesions, or prevented them from growing any further in 75% of patients.

Four serious adverse events were considered to be related to GDC-0448 and included syncope, cardiac failure, pulmonary embolism, and cholestasis. There were seven fatalities, but all were thought to be caused by pre-existing risk factors and comorbid conditions.17 Phase III studies utilizing vismodegib have already begun, and GDC-0449 is being tested in combination with chemotherapeutic agents and/or regimens.18 Early indications suggest that some tumors may develop resistance over time.15 Despite this uncertainty, vismodegib shows significant inhibitory activity in the treatment of advanced BCC.

Conclusions

The FDA-approved vismodegib for the treatment of advanced BCC on January 30th 2012.19 The indication is for BCC that has metastasized or relapsed after treatment with surgery, or for those who are not candidates for surgery or radiation. A boxed warning associated with this drug will state that use of this drug can result in embryo-fetal death or severe birth defects. Women need to be advised to use contraception and men need to be aware of the risk of vismodegib exposure through semen. In conclusion, vismodegib represents the first FDA-approved drug for use in advance forms of the most common skin cancer. Further clinical research will hopefully expand on the indications for this Shh inhibitor and future studies result in the addition of vismodegib to the treatment armamentarium for those with operable BCC.

Author disclosure

Dr Goldenberg is a consultant for Genetench. Dr Patel has no conflicts of interest to report.

References

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  2. Tang JY, Marghoob AA. Emerging treatments and signaling pathway inhibitors. Semin Cutan Med Surg 2011;30:S14-S18.
  3. Amin SH, Tibes R, Kim JE, Hybarger CP. Hedgehog antagonist GDC-0449 is effective in the treatment of advanced basal cell carcinoma. Laryngoscope 2010;120:2456-2459.
  4. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009;361:1164-1172.
  5. Wadhera A, Fazio M, Bricca G, Stanton O. Metastatic basal cell carcinoma: a case report and literature review. How accurate is our incidence data? Dermatol Online J 2006;12:7.
  6. Raszewski RL, Guyuron B. Long-term survival following nodal metastases from basal cell carcinoma. Ann Plast Surg 1990;24:170-175.
  7. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455:406-410.
  8. Fan L, Pepicelli CV, Dibble CC, et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 2004;145:3961-3970.
  9. Dierks C, Grbic J, Zirlik K, et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 2007;13:944-951.
  10. Low JA, de Sauvage FJ. Clinical experience with Hedgehog pathway inhibitors. J Clin Oncol 2010;28:5321-5326.
  11. McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 2003;53:1-114.
  12. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature 2004;432:324-331.
  13. Bryden MM, Evans HE, Keeler RF. Cyclopia in sheep caused by plant teratogens. J Anat 1971;110:507.
  14. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002;16:2743-2748.
  15. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009;361:1173-1178.
  16. Tang JY. An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients. 69th Annual Meeting of the American Academy of Dermatology; Feb 5 2011; New Orleans, LA. Available from: http://www.medscape.com/viewarticle/736975 [Accessed 8 February 2012].
  17. Roche Media Release. Pivotal study showed vismodegib helped shrink tumours or heal lesions in people with rare form of advanced skin cancer. 7th European Association of Dermato-Oncology; June 20 2011; Nantes, France. Available from: http://www.roche.com/media/media_releases/med-cor-2011-06-20.htm [Accessed 8 February 2012].
  18. NIH Hedgehog Inhibitor Clinical Trials Locator. Available from: http://clinicaltrials.gov/ct2/results?term=hedgehog+inhibitor [Accessed 8 February 2012].
  19. Nelson R. FDA approves vismodegib for adavanced basal cell carcinoma. Available from: http://www.medscape.com/viewarticle/757707 [Accessed 6 February 2012].
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