Latest updates on advanced BCC treatment research

Advanced basal cell carcinoma (aBCC) is a term used to describe a subset of basal
cell carcinomas (BCCs) that have extensive, invasive or metastatic involvement; 
are located near vital and sensitive areas; or are recurrent despite multiple treatments.
 The diagnosis of aBCC is dependent on many patient specific factors, some of which are subjective and may be open to interpretation by both the patient and provider.

Standard BCC treatments including topical therapy, photodynamic therapy, cryotherapy, electrodessication and curettage, and simple excision are usually inappropriate for aBCC.

Although curative treatments such as Mohs surgery or wide local excision are the standard of care for aBCC, radiation should also be considered for some patients as adjunctive or primary therapy. More aggressive treatments including chemotherapy, extensive Mohs with reconstruction or radical dissection may not be practical for every patient, such as the elderly, immunocompromised or medically ill. Recently, a new treatment (vismodegib) has become available and there are several other treatments in phase 1 and 2 studies.

Hedgehog pathway’s role

Since many of the drugs under evaluation in current research studies also target the same pathway as vismodegib, it is important to understand the Hedgehog signaling pathway that is defective in almost 90 percent of BCCs. The Hedgehog signaling pathway is critical for embryonic development and plays a role in cell maintenance for stem cells, hair follicles and some skin cells¹. This pathway is silenced in most adult tissues but abnormal activation through various mutations has been documented in BCC, medulloblastoma, hematologic malignancies and many other cancers.

The Hedgehog signaling pathway was named for an intracellular signaling protein, Hedgehog (Hh), found to be important for body segment development in the Drosophila fruit fly. Drosophila larvae with mutated hedgehog genes were found to be stubby and spiky, which suggested the name for the gene and gene product.

The signaling pathway starts with the Hh ligand binding to Patched (PTCH), a transmembrane receptor. PTCH usually acts a tumor suppressor preventing the pathway from continuing. With the binding of Hh, however, the signaling cascade is activated. PTCH releases smoothened (Smo), a G-protein-coupled receptor, which then releases suppressor of fused molecule’s (Sufu) inhibition of glioma-associated protein (Gli). Gli proteins are transcription factors that enter the nucleus causing upregulation of growth and oncogenic signals². The hedgehog pathway is also known to interact with several other molecular pathways important for cancer development and resistance, including PI3K, p53, mTOR, retinoic acid and Wnt^2,3. More than 90 percent of sporadic BCCs have a mutation in PTCH1 while up to 10 percent
have an activating mutation in SMO causing constitutive activation of the Hh pathway.

Next: Benefits and drawbacks of vismodegib

Vismodegib benefits, drawbacks

Vismodegib is an oral smoothened inhibitor and was the first medication approved for aBCC. It is an appropriate treatment choice for patients who have failed or are ineligible for surgery or radiation. Vismodegib has proven useful and effective, but adverse effects and resistance limits its use. Almost all patients experience some adverse effects, with the most common being grade 1 and 2 reactions such as muscle spasms, dysgeusia and alopecia⁴.

Most of the adverse reactions are reversible and improve in three to four weeks after discontinuation. Many practitioners advocate drug holidays to better tolerate the side effects. A recent study revealed that up to 20 percent of patients that do respond to vismodegib may eventually develop resistance⁵.

Resistance to vismodegib has been found from a number of mechanisms including missense mutations in SMO hindering binding of the drug⁶. In addition, upregulation of GLI2 and the PI3/AKT pathway has also demonstrated resistance³. An important point is that a repeat biopsy may be warranted if the tumor regrows or a particular area of an aBCC does not seem to be responding to a SMO inhibitor. Several case reports have demonstrated that collision tumors between aBCC and squamous cell carcinoma or other malignancies are possible and these are not expected to respond to a SMO inhibitor⁷.

Current clinical trials

Several SMO inhibitors are currently in clinical trials and may have a broader inhibitory profile compared to vismodegib. An investigational oral compound LDE225 (Sonidegib, Novartis) recently completed phase 2 trials⁸. The trial tested the efficacy and safety of two doses in patients with aBCC and mBCC.

The study found an overall response rate of 41.8 percent for the 200 mg group and 35.2 percent for the 800 mg group in aBCC. Grade 3 or 4 adverse effects were less frequent in the 200 mg group (30.4 percent vs. 56 percent) with the most common being elevated levels of creatine phosphokinase, increased lipase, hypertension, weakness and muscle spasms. Muscle toxicity was the main dose limiting toxicity for sonidegib⁹.

A topical formulation of LDE225 was tested on BCCs in patients with nevoid basal cell carcinoma syndrome^10,11. Of 13 topical LDE225- treated BCCs, three showed a complete response, nine a partial, and only one with zero clinical response. On immunohistochemistry, however, there appeared to be persistent tumor nests despite looking clear clinically. There are a number of SMO inhibitors in development and under investigation in additional clinical trials including LDE225 (Novartis), LEQ506 (Novartis), and BMS-833923 (BMS/Exelixis)¹².

Next: Results with combination therapy

Combination therapy results

Combination treatments with smoothened inhibitors and downstream molecules such as Gli may prove effective in BCCs resistant to SMO inhibitors. Pyrvinium, a medication approved by the Food and Drug Administration for pinworms, was actually found to inhibit the Hh pathway in vivo by reducing the stability of the Gli family of transcription factors¹³.

Another molecule, ML340, was also found to be a non-cytotoxic potent antagonist of Gli function¹⁴. Targeting the PI3K pathway in tumors resistant to SMO inhibitors has proven beneficial in medulloblastoma. One study showed that co-administering a PI3K inhibitor, NVP- BKM120, with a SMO inhibitor, NVP-LDE225, may prevent resistance and was more effective than adding after resistance had already developed¹⁵.

Vismodegib may be useful as a neoadjuvant therapy to surgery in high risk BCCs in sensitive areas. One study showed that vismodegib reduced the surgical defect area by 27 percent from baseline if taken for three months or longer prior to surgery¹⁶. Currently, there is a phase 2 trial combining radiation and vismodegib therapy in patients with aBCC of the head and neck region¹⁷. The protocol consists of patients taking vismodegib daily for three weeks and then radiation is added for another seven weeks. This multimodality treatment may prove to be effective by shrinking the tumor thickness and size with vismodegib prior to irradiating the field.

Combining a systemic treatment such as a SMO inhibitor with a topical therapy such as imiquimod was described in an aBCC case that recurred after vismodegib therapy but only with histologically superficial BCC^18,19.

Antifungal approach

Several antifungals have also shown some benefit in the treatment of BCC. Itraconazole demonstrates anti-smoothened activity distinct from vismodegib and the other SMO inhibitors. There is some evidence that it may be effective against tumor variants that are resistant to other SMO inhibitors²⁰. In a small phase 2 trial, itraconazole reduced cellular proliferation by 45 percent and tumor area by 24 percent in 19 patients with BCC²¹.

Several chemotherapeutic agents have been tested in the treatment of aBCC including cisplatin, 5-FU, vincristine, etoposide, bleomycin, cyclophosphamide, methotrexate, doxorubicin and arsenic. Cisplatin based therapy seems to be the most effective, but trials are limited²².

Arsenic has been known to increase the risk of skin carcinomas but is currently being studied as a potential treatment of BCC. Arsenic has the ability to reduce Gli transcription and increase apoptosis^11,23. Intralesional treatment with interferon alpha-2b has been effective in several case reports. Patients were treated three times a week for four to eight weeks, but most experienced systemic flu-like side effects. The size of the tumor may limit this treatment given the systemic side effects²⁴.

In the next few years, several novel approaches to treating aBCC may become available. The incidence of BCC continues to rise with an estimated 3,000 deaths per year in the United States due to aBCC¹⁹. The advent of vismodegib oral therapy has been very promising for patients and dermatologists alike. It is probable that, like many advanced cancer regimens, a combination of treatments will be needed to overcome drug resistance and control aBCC.

References:

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[Internet] Dermatology Times. [cited 2014 Jul 20]. Available from: http:// dermatologytimes.modernmedicine.com/dermatology-times/news/vismodegib-life- changing-bcc-patient-populations
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