Smoothened Inhibitors and the Hedgehog Pathway: Applications in Basal Cell Carcinoma and Beyond

Publication
Article
The Journal of Targeted Therapies in CancerFebruary 2016
Volume 5
Issue 1

The purpose of this article is to discuss the efficacy, indications for use, and safety of oral Hh pathway inhibitors for locally advanced BCC (LABCC) and for metastatic BCC (MBCC) through a review of the literature.

Abstract

Basal cell carcinoma (BCC) is the most commonly diagnosed human cancer, with more than 2 million cases per year in the United States. While most of these cases are amenable to local excision, many progress to locally advanced or metastatic disease that precludes surgical intervention.

Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and other human tumors are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumor suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh)-secreted protein signal, and oncogenic mutations affecting these proteins cause excessive activity of the Hh response pathway.

Clinical trials have shown exceptional decrements in tumor burden as well as resolution of metastatic disease with Hh pathway inhibitors as the sole treatment, thus reducing the need for surgery and associated morbidity and mortality. Reported response rates to Hh inhibitors therapy vary from 43% to 86%. The most commonly reported side effects include dysgeusia, muscle spasms, alopecia, weight loss, and fatigue.

Introduction

Hedgehog pathway inhibitors are a promising group of drugs to be used in cancer chemotherapy and are an excellent example of disease modulation at the biochemical level. They are a new, target-specific treatment alternative associated with high tumor responses. Treatment patterns, clinical outcomes, health care resource use, and definitions of advanced and complex/difficult- to-treat disease are not uniformly adopted in the literature and clinical practice. Larger cohort studies are needed to confirm the long-term efficacy and safety of Hh pathway inhibitors and their role in neoadjuvant use for cytoreduction prior to planned surgical intervention. The purpose of this article is to discuss the efficacy, indications for use, and safety of oral Hh pathway inhibitors for locally advanced BCC (LABCC) and for metastatic BCC (MBCC) through a review of the literature.

Basal cell carcinoma (BCC) is the most commonly diagnosed human cancer, accounting for more than 2 million cases each year in the United States. While most of these cases can be treated by local excision, many progress to locally advanced BCC (LABCC) or metastatic BCC (mBCC) that rule out surgery.

Basal cell cancer comprises most non-melanoma skin cancers (NMSCs) and is more common than all other human malignancies combined. Evidence suggests that the worldwide incidence of BCCs is increasing. In the US, the diagnosis and treatment of NMSCs have increased dramatically, with a growth rate of 77% over the past 2 decades.1Overall, the reasons for this dramatic growth have been postulated to include the aging population, changes in sun exposure habits, environmental changes, migration patterns, and, to a lesser extent, increased prevalence of immunosuppressant use.2,3Besides environmental risk factors, host susceptibility factors have been described in several familial cancer syndromes, including nevoid basal cell carcinoma syndrome (Gorlin syndrome), which is an autosomal dominant familial cancer syndrome. This form of BCC predisposes patients to the early development of multiple BCCs with a higher likelihood of becoming locally advanced or even metastatic as surgery becomes less likely because of the multiplicity of lesions.

More than 2.8 million new cases of BCC are diag- nosed each year in the United States, alone and are estimated to result in more than 3,000 deaths.4Fortunately, BCCs are usually diagnosed and treated early.5Nevertheless, reported 5-year recurrence rates are estimated to be 2% to 3 %.6BCCs that are extensive and infiltrate structures below the skin or abut vital structures, such as the brain or eyes, may be difficult to surgically clear without significant morbidity. Many of these may become locally advanced or metastasize; those that metastasize to either local or distant lymph nodes or distant organs would best be addressed through systemic therapy.

While accurate estimates of the incidence of LABCCs are difficult to obtain, in part because of the lack of widespread use of a staging system by dermatologists and the lack of uniform reporting requirements for NMSCs, LABCCs are thought to represent 1% to 10 % of all BCCs, with mBCC accounting for 0.0028% to 0.5%.7-9From our clinical experience, patients presenting with LABCC, appear to fall into 2 categories: those who present after a delay in accessing medical attention, or those who have BCCs that are intrinsically aggressive, are refractory, or recur after treatment. Included in this latter group are those patients with chronic immunosuppression after organ transplant and some patients with Gorlin syndrome. Therapeutic options for such patients are limited.10,11Research into the reactivation of embryonic molecular pathways in adult tissues has led to the discovery of novel antineoplastic agents capable of redefining systemic treatment for LABCC and mBCC.12

The Hedgehog Pathway

The Hh pathway was initially identified as a critical developmental regulator of embryonic segment polarity in Drosophila in 1980.13This, and related developmental work in fruit fly body patterning, was recognized by the Nobel Prize in Physiology and Medicine in 1995. Vertebrate homologs of the Drosophila Hedgehog ligand were first reported in 1993, and definition of central components of the mammalian signaling pathway followed in the late 1990s and early 2000s.14The first definitive linkage of mutation in this pathway to cancer, that is, to development of BCC, was made in 1996.15,16Hedgehog signaling regulates embryonic development, ensuring that tissues reach their correct location, size, and cellular content. The Hh pathway normally remains inactive in adult tissues, but reactivation of this pathway results in malignant transformation and tumorigenesis.17,18More than 90% of all BCCs have identified abnormal Hh pathway signaling. There are 2 classic mechanisms of Hh pathway reactivation: mutation-driven signaling (ligand independent) and abnormal signaling in the tumor microenvironment (ligand dependent).19In mutation-driven signaling, tumor cells harbor mutations in key components of the Hh pathway, allowing for independent activation of the biomolecular system and subsequent stimulation of unregulated proliferation.12In ligand-dependent activation, tumor cells overexpress Hh ligands that activate surrounding stromal cells, leading to uncontrolled growth.20Mutations in 2 major receptor proteins, Patched-1 (PTCH1), and Smoothened (SMO), may result in abnormal activation of the Hh pathway and are the focus of proposed interventions.

Hh pathway activation occurs via binding of an extracellular Hh ligand (Shh) to PTCH1, a transmembrane receptor. Once bound, PTCH1 is internalized and degraded, allowing for release of the transmembrane protein SMO from the inhibitory effect of PTCH1.21SMO can then move from the intracellular compartment to the cell membrane of the cilium and activate the Gli family of transcription factors. Activated Gli factors enter the nucleus and initiate the transcription of target genes.21Most sporadic BCCs contain mutations that result in inactivation of PTCH1, with subsequent constitutional activation of SMO.22Inhibition of SMO activation, either through appropriate PTCH hindrance or through new SMO inhibitors, prevents unregulated proliferation.

Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and other human tumors are associated with mutations that activate the proto-oncogene SMO or that inactivate the tumor suppressor PTCH. Smoothened and Patched mediate the cellular response to the Hh-secreted protein signal, and oncogenic mutations affecting these proteins cause excessive activity of the Hh response pathway.

The story of how cyclopamine, the first inhibitor of the Hh pathway, was discovered is one of the most fascinating stories in biomedicine. In the late 1950s, Idaho farmers noticed that a random batch of their lambs were being born with strange birth defects. The creatures had underdeveloped brains and a single eye, planted, Cyclops-like, in the middle of their foreheads. In 1957 they called in scientists, who worked for 11 years to solve the mystery: corn lilies. When the animals moved to higher ground during droughts, they snacked on the flowers. The lilies, it turned out, contained a poison, later labeled cyclopamine, that stunted developing lamb embryos. The adult mothers remained unharmed. The case of cyclopamine and the one-eyed Idaho lambs remained a freakish chemistry footnote for the next 3 decades.10,23

In the 1970s, the active agent inducing these changes, cyclopamine, was isolated and its structural formula identified. Subsequent studies in the 1990s in chick embryos demonstrated cyclopamine’s ability to induce holoprosencephaly and to bind the transmembrane protein, Smoothened.24Subsequently, a number of analogues were developed by modifications to cyclopamine to improve solubility and oral bioavailability. Collectively, these analogues are called Smoothened inhibitors (SIs) because of their targeting of the Smoothened protein.

In 2000, Taipale et al showed that cyclopamine inhibits the Hh response and is a potential ‘mechanism-based’ therapeutic agent for treatment of some tumors.25They showed that cyclopamine, or synthetic derivatives with improved potency, block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Their results also indicated that cyclopamine could act by influencing the balance between active and in- active forms of SMO.25

This discovery, together with rapidly accumulating evidence implicating the Hh pathway in oncogenesis, led to focused efforts by multiple biotechnology and pharmaceutical companies to develop cyclopamine derivatives with improved pharmacologic properties or to develop agents that effectively out-competed cyclopamine for binding to the critical cell-surface activator of Hh signaling, the 7-transmembrane G protein-coupled—like receptor, SMO. Vismodegib (Eri- vedge, Genentech) is a member of this class: structurally unrelated to cyclopamine but able to bind with high affinity and specificity to SMO, leading to potent suppression of Hh signaling in reporter systems and in a preclinical model of Hh-dependent disease.28An Investigational New Drug application for vismodegib was filed with the FDA in September 2006, leading to a first-in-human phase I clinical trial at 3 US sites in January 2007. A phase I trial with vismodegib included 68 patients with solid tumors, of whom 33 had advanced BCC, 8 had pancreatic cancer, and 1 had medulloblastoma, in addition to 17 other types.

The overall rate of complete or partial response was 58%, with specific response of 50% in patients with mBCC and 60% in patients with LABCC.29Despite vast heterogeneity with respect to tumor histology, patient characteristics, and dosing concentrations, vismodegib was generally well-tolerated, with 8.8% experiencing a grade 4 adverse effect (AE), including hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia, and 27.9% of patients experiencing a grade 3 AE, hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%).

The ERIVANCE trial was a multicenter, international, 2-cohort, nonrandomized study of 104 patients with mBCC or with LABCC who had inoperable disease or for whom surgery was inappropriate because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement. The patients were treated over 13 months and all received 150 mg of oral vismodegib daily. The primary endpoint was the independently assessed objective response rate (ORR); the primary hypotheses were that ORR would be greater than 20% for patients with LABCC and greater than 10% for those with mBCC.30In 33 patients with mBCC, the ORR was 30% (95% CI], 16 to 48;P= .001). In 63 patients with LABCC, the ORR was 43% (95% CI, 31 to 56;P<.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. The AEs occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious AEs were reported in 25% of patients, including 7 deaths. After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. The ORR increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with locally advanced disease. Median duration of response in patients with LABCC increased from 7.6 months to 9.5 months. No new safety signals emerged with extended treatment duration.30

An additional phase II trial was conducted in 41 patients with basal cell nevus syndrome.31Vismodegib was associated with a decrease in the number of new and existing surgically eligible BCCs, with surgically eligible BCCs occurring at a rate of 2 per year in the vismodegib group compared with 29 per year in the control group (P<.001). There was also a significantly greater decrease in the size of tumors in patients re- ceiving vismodegib (65% in the vismodegib group vs 11% in the control group;P= .003).32

The first FDA approved Smoothened inhibitor for treatment of LABCC and mBCC was vismodegib, which became commercially available in 2012. The second approved Smoothened inhibitor is sonidegib (Odomzo, Novartis), which received FDA approval in 2015. The approval of Odomzo was based on data from the phase II, randomized, double-blind, multicenter BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) study in patients with LABCC not amenable to local therapy or with mBCC at 2 doses (200 mg vs 800 mg).33In patients with LABCC treated with Odomzo 200 mg, the ORR was 56% per central review and 71% per investigator review. The median duration of response per central review has not been reached. The median progression-free survival was 22 months per central review and 19 months per investigator review. Virtually all patients in either cohort experienced some degree of AE (200 mg: 95%, 800 mg: 100%). These were identical AEs noted with the use of vismodegib. The most common AEs were muscle spasms, dysgeusia, alopecia, nausea, increased serum creatinine kinase, weight loss, and fatigue. Serious AEs noted were rhabdomyolysis, increased serum creatinine kinase, and secondary malignancies.33

In the pivotal ERIVANCE trial, there was an increase in the incidence of serious AEs, and grade 3 and above AEs from 25% (collectively) in the primary analysis to 31.7%, and to 51.9% in the additional 12-month follow-up. The overall safety profile remained consistent, with the most common AEs being muscle spasm (71.2%), alopecia (65.4%), dysgeusia (53.8%), weight loss (50%), fatigue (40.4%), and nausea (32.7%). Treatment discontinuations in the LABCC cohort were predominantly because of patient choice (28.2%) and AEs (19.7%), with a smaller number dropping out because of disease progression (11.3%). This is in contrast to the mBCC cohort, where disease progression was the predominant reason for treatment termination (42.4%).30

Current research and clinical trials focusing on the administration of synthetic SMO inhibitors or Hh pathway inhibitors for patients with LABCC and mBCC are ongoing.28,29,34Clinical trials have shown exceptional decrements in tumor burden as well as resolution of metastatic disease with these drugs as monotherapy, thus reducing the need for surgical excision and associated morbidity and mortality.32Furthermore, recent case reports have documented the use of vismodegib as a potential neoadjuvant therapy prior to surgical or radiotherapeutic intervention.35-37While the mechanism is poorly understood at this time, several reports have documented a declining efficacy in tumor reduction in patients treated for an extended period, and who appear to develop some resistance over time.35Initial experience with itraconazole added to the treatment regimen appears to limit this resistance, but further investigation and protocol standardization are pending.35As Hh pathway inhibitors are more commonly used for BCC and for longer durations, it will become increasingly clear whether BCC will demonstrate the capacity to develop drug resistance, and the effect of altered dosage regimens.38Although clinical trials for topical and systemic therapies are in progress, vismodegib and sonedigib remain the only Hh pathway inhibitors approved by the FDA for the treatment of mBCC and LABCC.39

As an example algorithm and approach, we present 2 illustrative and successful cases from the initial 20-patient cohort treated in our institution. They are adult patients with LABCC and/or recurring mBCC who were not candidates for surgery or radiation therapy (because of clinical morbidities or patient&rsquo;s refusal of surgery/radiation therapy). The patients received vismodegib 150 mg once a day until disease progression, unacceptable side effects, or discontinuation of treatment at patient request. The peak plasma concentration of vismodegib was reached 48 hours after oral administration and maintained for 72 hours, in line with the recommended schedule of 150 mg PO daily.40Locally advanced BCC was defined as at least 1 lesion 20 mm or more in areas of limited tissue availability (eyelid, ear, nasal ala, etc); patients had to have recurrence after 2 or more surgical procedures, curative resection was unlikely, and surgery was expected to result in substantial morbidity and/ or deformity. Response was defined as a decrease of &ge;30% in the externally visible or radiographic dimension or complete resolution of ulceration if present at baseline. Radiographic imaging was obtained for all patients with mBCC and for patients with LABCC who had radiographically measurable disease.

The ORR of vismodegib on tumor regression and prevention of disease progression was visually and clinically appreciable in almost all treated patients. At the data cut-off point, 13/20 (65%) patients had complete response (defined as the absence of residual BCC on assessment of a biopsy specimen) and 7/20 (35%) patients had partial response. At the data cut-off point, all 13 patients who had a complete response did not have disease progression. One patient was excluded from treatment on his request because of unacceptable AEs (dysgeusia and muscle cramps). Most common AEs were dysgeusia (100%), muscle spasms (80%), hair loss (50%), weight loss (30%) and fatigue (10%). These AEs were mitigated with oral fluid and electrolyte replacement regimens, with many patients claiming improvement of muscle spasms with increased sports drink or pickle juice intake. While tolerable for all participants, the AEs subsided in up to 12 weeks on treatment completion. Surgery was performed in the 7 patients who had partial response; minimal residual tumor was identified in 5 of them and no residual tumor was found in 2 of the patients.

Marked resolution of the tumor with reduction in vertical height and surrounding erythema was evident by day 30 of treatment. By day 120, there were no palpable lesions and the surrounding erythema and induration associated with the metastatic lesion had been greatly diminished. Radiographically, the patient had exceptional regression of tumor burden matching the clinical picture. By 120 days, the patient had radiographic evidence of complete resolution of pulmonary metastases.

Conclusion

Hedgehog pathway inhibitors are a promising group of drugs for cancer therapy and are an excellent example of disease modulation at biochemical level. They are a new, target-specific treatment alternative associated with high tumor responses in patients with LABCC or mBCC. Initial experience with patients treated with vismodegib showed encouraging results, with high ORR and substantial clinical benefit. However, treatment patterns, clinical outcomes, and definitions of advanced and complex/difficult-to-treat disease are not uniformly adopted in the literature and clinical practice. Larger cohort studies, such as the STEVIE trial, a large multicenter, open-label trial on the safety and efficacy of vismodegib, are needed to confirm its long-term efficacy, its safety, and its role in neoadjuvant use for cytoreduction before planned surgical intervention.41

References

  1. Wu TP, Stein JA. Nonmelanoma skin cancer in young women.J Drugs Dermatol. 2013;12(5):568-572.
  2. Nan H, Kraft P, Hunter DJ, Han J. Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians.Int J Cancer. 2009;125(4):909-917. doi: 10.1002/ijc.24327.
  3. Weinstock MA, Fisher DE. Indoor ultraviolet tanning: what the data do and do not show regarding risk of melanoma and keratinocyte malignancies.J Natl Compr Canc Netw. 2010;8(8):867-872; quiz 873.
  4. Gould A, Missailidis S. Targeting the hedgehog pathway: the development of cyclopamine and the development of anti-cancer drugs targeting the hedgehog pathway.Mini Rev Med Chem. 2011;11(3):200-213.
  5. Alam M, Goldberg LH, Silapunt S, et al. Delayed treatment and continued growth of nonmelanoma skin cancer.J Am Acad Dermatol. 2011;64(5):839-848. doi: 10.1016/j.jaad.2010.06.028.
  6. Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ. Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma.J Invest Dermatol. 2013;133(5):1188-1196. doi: 10.1038/ jid.2012.403.
  7. Danial C, Lingala B, Balise R, et al. Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma.Br J Dermatol. 2013;169(3):673-676. doi: 10.1111/bjd.12333.
  8. Moser S, Borm J, Mihic-Probst D, et al. Metastatic basal cell carcinoma: report of a case and review of the literature.Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(2):e79-e82. doi: 10.1016/j.oooo.2012.04.030.
  9. Soleymani AD, Scheinfeld N, Vasil K, Bechtel MA. Metastatic basal cell carcinoma presenting with unilateral upper extremity edema and lymphatic spread.J Am Acad Dermatol. 2008;59(2 suppl 1):S1-S3. doi: 10.1016/j.jaad.2007.08.041.
  10. Mohan SV,Chang AL. Advanced basal cell carcinoma: epidemiology and therapeutic innovations.Curr Dermatol Rep. 2014;3:40-45.
  11. Mohan SV, Chang AL. Precision medicine and precision therapeutics: hedgehog signaling pathway, basal cell carcinoma and beyond.Semin Cutan Med Surg. 2014;33(2):68-71.
  12. Xie J,Bartels CM,Barton SW, GuD. Targeting hedgehog signaling in cancer: research and clinical developments.Onco Targets Ther. 2013;6:1425-1435. doi: 10.2147/OTT.S34678.
  13. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila.Nature. 1980;287(5785):795-801.
  14. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles.Genes Dev. 2001;15(23):3059-3087.
  15. 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):841-851.
  16. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, acandidate gene for the basal cell nevus syndrome.Science. 1996;272(5268):1668-1671.
  17. Atwood SX, Whitson RJ, Oro AE. &ldquo;Patch&rdquo;ing up our tumor signaling knowledge.J Invest Dermatol. 2013;133(5):1131-1133. doi: 10.1038/jid.2012.506.
  18. Dreier J, Dummer R, Felderer L, Nageli M, Gobbi S, Kunstfeld R. Emerging drugs and combination strategies for basal cell carcinoma.Expert Opin Emerg Drugs. 2014;3:353-365. doi: 10.1517/14728214.2014.914171.
  19. Agren M, Kogerman P, Kleman MI, Wessling M, Toftgard R. Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site.Gene. 2004;330:101-114.
  20. Lipinski RJ, Gipp JJ, Zhang J, Doles JD, Bushman W. Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling.Exp Cell Res. 2006;312(11):1925-1938.
  21. Villavicencio EH, Walterhouse DO, Iannaccone PM. The sonic hedgehog-patched-gli pathway in human development and disease.Am J Hum Genet. 2000;67(5):1047- 1054.
  22. Reifenberger J, Wolter M, Knobbe CB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas.Br J Dermatol. 2005;152(1):43-51.
  23. Keeler RF, Binns W. Teratogenic compounds of Veratrumcalifornicum (Durand). V. Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources.Teratology. 1968;1(1):5-10.
  24. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.Genes Dev. 2002;16(21):2743-2748.
  25. Taipale J, Chen JK, Cooper MK, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.Nature. 2000;406(6799):1005-1009.
  26. Cooper MK, Porter JA, Young KE, Beachy PA. Teratogen-mediated inhibition of target tissue response to Shh signaling.Science. 1998;280(5369):1603-1607.
  27. Incardona JP, Gaffield W, Kapur RP, Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction.Development. 1998;125(18):3553-3562.
  28. Robarge KD, Brunton SA, Castanedo GM, et al. GDC-0449-a potent inhibitor of the hedgehog pathway.Bioorg Med Chem Lett. 2009;19(19):5576-5581. doi: 10.1016/j.bmcl.2009.08.049.
  29. 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. 2011;17(8):2502-2511. doi: 10.1158/1078-0432. CCR-10-2745.
  30. 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):2171-2179. doi: 10.1056/ NEJMoa1113713.
  31. 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- 2188. doi: 10.1056/NEJMoa1113538.
  32. Rudin CM. Vismodegib.Clin Cancer Res. 2012;18(12):3218-3222.doi: 10.1158/1078-0432.CCR-12-0568.
  33. Migden MR, Guminski A, Gutzmer R, 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):716-728. doi: 10.1016/S1470-2045(15)70100-2.
  34. Ruiz Salas V, Alegre M, Garces JR, Puig L. Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies.Expert Rev Anticancer Ther. 2014;14(6):741-749. doi: 10.1586/14737140.2014.895326.
  35. 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. 2013;149(5):639-641. doi: 10.1001/jamadermatol.2013.30.
  36. Kahana A, Worden FP, Elner VM. Vismodegib aseye-sparing adjuvanttreatment for orbital basal cell carcinoma.JAMA Ophthalmol. 2013;131(10):1364-1366. doi: 10.1001/jamaophthalmol.2013.4430.
  37. Ally MS, Tang JY, Joseph T, et al. The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome.JAMA Dermatol. 2014;150(5):542-545. doi: 10.1001/jamadermatol.2013.7444.
  38. Khoo AB, Ali FR, Lear JT. Defining locally advanced basal cell carcinoma and integrating smoothened inhibitors into clinical practice [published online ahead of print January 15, 2016].Curr Opin Oncol.
  39. Tang T, Tang JY, Li D, et al. Targeting superficial or nodular Basal cell carcinoma with topically formulated small molecule inhibitor of smoothened.Clin Cancer Res. 2011;17(10):3378-3387. doi: 10.1158/1078-0432.CCR-10-3370.
  40. Lorusso PM, Jimeno A, DyG, et al. Pharmaco kinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors.Clin Cancer Res. 2011;17(17):5774-5782. doi: 10.1158/1078-0432.CCR-11-0972.
  41. Basset-Seguin N, Hauschild A, Grob JJ, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.Lancet Oncol. 2015;16(6):729-736. doi: 10.1016/S1470- 2045(15)70198-1.
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