Whacking the Hedgehogs in Basal Cell Carcinoma with Vismodegib

If the year 2011 was the year for the 5% of skin cancers, this is the year for the 95% majority.  Last year saw approvals of two new melanoma cancer drugs, vemurafenib and  ipilimumab.  But, this year may be dubbed as the year when the other skin cancer called basal cell carcinoma finally gets a new Erivedge loaded Webley.

Skin cancer is the most common type of cancer in the western world—40% of all cancers are skin cancers with 80% of skin cancers being nonmelanoma, and primarily basal cell carcinoma.

Over one million new cases of basal cell carcinoma are diagnosed every year in the United States.  The incidence in the United States is 0.5-1%, but Australia with a 2% rate has the highest rate of basal cell carcinoma in the world. Ultraviolet rays from sunlight, sunbathing and tanning beds are among the major modifiable risk factors. Individuals with light-colored skin, blue or green eyes, and blond or red hair are particularly susceptible.

Basal cell carcinoma looks like pink pearly pimples.  If left untreated they can spread to the surrounding areas, into eyes, nasal cartilage, or deeper into muscle and bone.  The cancer originates in the basal cell layer of the epidermis, the outermost layer of the skin.

 The painless, slow and outward growing tumors of basal cell carcinoma are commonly managed with surgical excision, and it rarely spread to the deeper tissues or metastasizes.  The common treatments are Mohs surgery (named after a Wisconsin surgeon, Frederick Mohs), local radiation and imiquimod topical cream.

In some patients cancer progresses to advanced or metastatic stage. The advanced disease is defined by the spread of lesion to surrounding areas and also includes patients where surgery is not a viable option due to risk of substantial deformity.

The patients with advanced or metastatic disease have poor prognosis with the median survival time of 8 months. Genentech's new drug vismodegib (vis-mo-DE-jib), approved by the FDA this January, is a very effective option for patients with recurrent basal cell carcinoma who cannot be treated with surgery or radiation. Vismodegib (aka GDC-0449, RG3616, HhAntag691; Trade name: Erivedge) is a potent and specific small molecule inhibitor of hedgehog signaling pathway.

Phase I Studies

Vismodejib was tested in an open-label, multicenter, two-stage phase I trial in 68 patients with various solid tumors.  Of these 68 patients, 33 had advanced basal cell carcinoma. Out of 33 patients, 18 had a positive response (2 had complete and 16 had partial responses) to the drug, 11 had stable disease for up to 10.8 months, and only 4 patients had progressive disease.

Out of 33 basal cell carcinoma patients in the study, 18 had metastatic disease and 15 patients had advanced cancer. Among the 18 patients with metastatic disease, the overall response rate was 50% (95% CI, 29 to 71) and it was 60% (95% CI, 33 to 83) in 15 patients with advanced disease. The median duration of response was 8.8 months.

In this study, the investigators tested three doses, 150, 270 or 540 mg per day. The patients received a single oral dose on day 1 and then every day starting day 8. There was no dose-limiting toxic effects or Grade 5 adverse events during continuous and daily administration for up to 19 months. There was a single Grade 4 event, an asymptomatic hyponatremia, deemed unrelated to the study drug.

The results pointed to high potency and negligible toxicity. The investigators chose 150 mg per day for the pivotal Phase II trial because doses greater than 150 mg did not increase plasma drug levels.

Phase II pivotal trial  (ERIVANCE BCC/SHH4476g trial)

The multicenter, two-cohort, single-arm, open-label phase II trial was conducted across 31 sites in US, EU and Australia.  There were 71 advanced basal cell carcinoma and 33 metastatic basal cell carcinoma patients in this study. All patients received 150 mg vismodegib per day until disease progressed or intolerable toxicity was observed. The results were announced in a press release on June 20, 2011, by Roche, Basal, and were presented at the Seventh European Association of Dermato-Oncology (EADO) Congress, Nantes, France (Abstract C014,14:50. CET).

The overall response rate, ORR, (visible shrinkage or healing of lesions or tumors) was observed in 43% of the patients with advanced cancer and in 30% of patients with metastatic disease when judged by the independent review board (primary endpoint); the study investigators determined the ORR to be 60% and 46% for advanced and metastatic disease, respectively (secondary endpoint.)

The median progression-free survival (PFS) was 9.5 months. Seventy-five percent of the treated patients had prolonged stable disease for more than 24 months (ie, clinical benefit rate of 75%.)

The most common adverse events included muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea.  While 25% pf the patients had one or more serious adverse event (SAE), it was related to treatment only in 4% of the patients (SAEs in 21% patients were due to other per-existing conditions). Also, there were seven deaths (7% of cohort) but none of the deaths was related to vismodegib treatment.

Genentech/Roche filed for FDA approval in September and received approval on January 30th, 2012. The estimated cost of a 10-month course is $7500 per month is in line with other targeted therapies in the market today. Vismodegib is also undergoing trials for operable forms of basal cell carcinoma.

Hedgehog pathway and vismodegib

The word “hedgehog,” Hh in short, comes from the spiky appearance of fruit flies carrying mutations in this gene.

Hedgehog signaling, along with other morphogenic pathways, such as Wnt and Notch, controls proliferation and differentiation in developing embryo.  Few roles of Hh pathway have been described in the adults, including proliferation of hematopoietic stem cells in the bone marrow, neuronal stem cells and stem cells in the mammary glands.

There are three secreted forms of hedgehog proteins (hedgehog ligands) in vertebrates: Sonic hedgehog (SHH), Indian hedgehog IHH) and Desert hedgehog (DHH); the first was named after a video game and the other two after species of hedgehog, the animal.

The cell membrane receptor of Hh protein called Patched1 (PTCH1) is active in the absence of Hh ligands. Active PTCH1 inhibits a protein called Smoothened (SMO) which is located in the intracellular endosomal membrane: active PTCH1 inhibits the migration of SMO to a cilia (called primary or nonmotile cilia which is present in all mammalian cells) where the targets of SMO called Gli proteins (GLI1, GLI2 and GLI3) reside. Without SMO migration the activation pathway hits a dead end.

The Hh ligands bind and block PTCH1 activity and thus, relieves SMO from inhibition which can now translocate to the primary cilia and lead to the activation of Gli to their activator forms (GliA). The activator GliA enters nucleus and transactivates Hh target genes. Hh target genes involved in cell proliferation include cyclins and cyclin-dependent kinases; the those involved in differentiation, including angiogenic and neurotropic factors.

Similar outcome occurs if the cells carry activating mutations in the SMO gene. Activating mutations in SMO gene are fairly common in basal cell carcinoma and meduloblastoma.

Nearly 100% of basal cell carcinomas are driven by dysregulated hedgehog signaling pathway: approximately 90% of the spontaneous basal cell carcinomas have loss-of-function mutations in PTCH1 gene, and the other 10% have activating mutations in SMO gene.

Vismodegib is a specific inhibitor of SMO.

Picture Credit: Huangfu and Anderson. Development 2006.  http://dev.biologists.org/content/133/1/3.short ; 

Fig. 1.The Hedgehog pathway in Drosophila and vertebrates. The Hedgehog (Hh) pathway in Drosophila (A,B) and in vertebrates (C,D) in the absence (A,C) or presence (B,D) of the Hh ligand. [...]. (C) In the absence of Hh, Ptch1 prevents the accumulation of Smo in cilia, possibly through the action of a small molecule. Gli3 is processed into a repressor form (Gli3^R) in a cilia-dependent manner. The activation of all Gli proteins is inhibited by Sufu, Iguana (for zebrafish) and probably Cos2. (D) In the presence of high levels of Hh ligand, Ptch1 inhibition is relieved; Smo is targeted to cilia and activates Gli proteins in a cilia-dependent manner. Gli3 processing is also inhibited. p, phosphorylation; PKA, protein kinase A.

Grolin's Syndrome

Grolin's syndrome, also called basal cell nevus syndrome (BCNA), is a rare autosomal genetic disorder.  It is characterized by a loss-of-function mutation in PTCH1 gene which maps to chromosome 9q22 and results in constitutive activation of the hedgehog signaling pathway.

Grolin's syndrome patients have many spontaneously occurring basal cell carcinoma tumors, and often have facies, calcifications and bony abnormalities, such as, bifid ribs and spina bifida occulta. 

Unlike general population, where basal cell carcinoma occurs during the midlife years, Grolin's syndrome patients have many tumors starting from a relatively young age.  Vismodegib offers hope to these patients as was profiled in the story about Orit Rindner, 46, a Grolin's syndrome patient from Tel Aviv, who participated in the phase II clinical trial.  The story was profiled in the Chicago Magazine last May.

Other Hedgehog pathway inhibitors in development

Cyclopamine, a natural product from corn lilies, a steroidal alkaloid, is a potent SMO antagonist, but it is not an ideal drug.  GDC-0449 (vismodegib) is the first synthetic SMO inhibitor is enter clinic and marketed.  Other SMO antagonists in development include,

• BMS-833923 (Bristol-Myers Squibb)
• IPI-926 (Infinity)
• LDE-225 (Pfizer)
• PF-04449913 (Pfizer)

READING ROOM

1. Caro I, Low JA. The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment. Clin Cancer Res. July 1, 2010;16(13):3335-3339 | PubMed| 
2. Huangfu D, Anderson KV. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development. 2006 Jan;133(1):3-14. | PubMed |
3. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005 Nov 24;353(21):2262-2269. | PubMed | Scholar |
4. Rubin LL, de Sauvage FJ. Targeting the hedgehog pathway in cancer. Nat Rev Drug Discov. 2006 Dec;5(12):1026-1033. | PubMed| Scholar |
5. Skin Cancer Module: Practice Exercises [online.] EXCITE: Centers for Disease Control and Prevention.  Available at http://www.cdc.gov/excite/skincancer/mod10.htm. Accessed March 5, 2012.  ... EXCITE! (Excellence in Curriculum Innovation through Teaching Epidemiology and the Science of Public Health) is a program of CDC and Science Olympiad.  This webpage has general information about skin cancers.
6. Pivotal study showed vismodegib helped shrink tumours or heal lesions in people with rare form of advanced skin cancer [online press release]. Basal, Switzerland:Roche; June 20, 2011.  Available at http://www.roche.com/media/media_releases/med-cor-2011-06-20.htm. Accessed March 4, 2012. ... describes vismodegib phase II trial data
7. Pollack A. Drugs show promise slowing advanced melanoma [online]. New york Times. June 5, 2011. Available at http://www.nytimes.com/2011/06/06/health/research/06melanoma.html. Accessed March 5, 2012 ... about vemurafenib and ipilimumab successes in clinic
8. Springen K. New pill offers alternative for skin cancer care [online]. Chicago Magazine. May 2011. Available at http://www.chicagomag.com/Chicago-Magazine/May-2011/New-Pill-Offers-Alternative-for-Skin-Cancer-Care/.  Accessed March 4, 2012  ... profiles a Grolin's syndrome patient who participated in vismodegib trial
9. Stenger M. Gathering data point to potential advantages of vismodegib in basal cell carcinoma and other advanced cancers [online]. ASCO Post. 2011 Dec 15. Vol. 2, No. 18. Available at http://www.ascopost.com/articles/december-15-2011/gathering-data-point-to-potential-advantages-of-vismodegib-in-basal-cell-carcinoma-and-other-advanced-cancers/. Accessed March 4, 2012 ... describes vismodegib  phase I and II trial data
10. Von Hoff DD, LoRusso LM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.  N Engl J Med. 2009 sep 17;361(12):1164-1172. | PubMed | Scholar | ... describes vismodegib phase I trial data

Pronunciation key:

Vismodegib (vis-mo-DE-jib) 

vemurafenib (vem-yoo-RAF-en-ib) 

ipilimumab (ip-ee-LIM-yoo-mab)

RELATED POSTS

Deploying Immunotherapeutic Drones for Cancer. December 20, 2011.
Vemurafenib Seeks Wider Audience. January 30, 2012.

 




Von Hoff, D., LoRusso, P., Rudin, C., Reddy, J., Yauch, R., Tibes, R., Weiss, G., Borad, M., Hann, C., Brahmer, J., Mackey, H., Lum, B., Darbonne, W., Marsters, J., de Sauvage, F., & Low, J. (2009). Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma New England Journal of Medicine, 361 (12), 1164-1172 DOI: 10.1056/NEJMoa0905360