Novel and Emerging Therapies
Vismodegib (Erivedge®) is the first antitumor drug to target the hedgehog signaling pathway, which is a set of proteins that interact to regulate the growth of keratinocyte stem cells (Amin 2013; Erb 2008). Dysregulation of the hedgehog signaling pathway is associated with aggressive subtypes of cancers that are prone to metastasis (Carpenter 2012). Vismodegib was FDA-approved for treatment of advanced and metastatic basal cell carcinoma in 2012. In two phase II trials of patients with metastatic basal cell carcinoma or basal cell nevus syndrome (a genetic disorder that predisposes patients to basal cell carcinoma), vismodegib (150 mg/day) significantly decreased the appearance of new tumors and reduced the size of existing tumors (Amin 2013).
Tumor Treating Fields
Tumor treating fields (TTFields) represent a noninvasive antitumor technique that uses low-intensity alternating electrical fields to disrupt tumor cell division and induce cell death. Different cancer types can be specifically targeted by “tuning” the electrical field frequency delivered by the TTField generator. It has been approved for the treatment of recurrent glioblastoma in the United States. Ongoing preclinical studies have demonstrated efficacy in preventing proliferation of isolated human melanoma cells, intradermal melanoma in rats, and the spread of injected malignant melanoma cells in mice (Davies 2013).
Several case reports have detailed success in treating basal cell carcinoma and squamous cell carcinoma in situ using pulsed CO2 or pulsed dye laser light (Brightman 2011). Lasers ablate (vaporize) tumor tissue from the skin, offering better visualization for the surgeon and less tissue injury than some other current treatments, such as ED&C (Shimizu 2011). Tumor clearance may be a concern for deeper tumors treated by laser. In a large case report of 44 patients with a form of squamous cell carcinoma, CO2 laser treatment was associated with a tumor clearance rate of 97.6% overall, with a tumor recurrence of 6.8% over 8-52 months (Covadonga Martínez González 2008).
Vemurafenib and Trametinib. BRAF is a gene involved in the regulation of cell growth and proliferation; mutations of this gene leave it in a permanently (constitutively) active state and can result in uncontrolled cellular proliferation. Approximately 50% of melanomas contain BRAF mutations (Kudchadkar 2013). Therapies that inhibit the activity of BRAF and related regulatory factors represent a novel systemic approach to increase survival in patients with metastatic melanoma (melanoma that has spread to distant sites). Before either of these drugs is prescribed, presence of BRAF mutations must first be confirmed.
- Vemurafenib. Vemurafenib (Zelboraf®) is a BRAF inhibitor that has demonstrated significant antitumor activity in clinical trials and was shown to improve survival in patients with metastatic melanoma that carries the BRAF mutation (a median survival of 13.6 months in patients taking vemurafenib vs. 9.7 months in patients on standard chemotherapy). Side effects include fatigue, joint pain, edema, nausea, and heart rhythm changes (ie, a longer QT interval on electrocardiogram) (Johnson 2013). By altering cell-signaling pathways, vemurafenib has also been shown to paradoxically increase the risk of cutaneous squamous cell carcinoma, with lesions appearing in up to 20% of patients (Johnson 2013; Ma 2014).
- Trametinib. Trametinib (Mekinist®) was approved as a single therapy in 2013 and as a combination therapy in 2014 against malignant melanoma (NCI 2014c; Wright 2013). It targets cancer cells by indirectly inhibiting the activity of mutant BRAF genes (it actually inhibits cell cycle signaling proteins called MEK1 and MEK2) (Johnson 2013). As a single therapy, the most common side effects of trametinib include rash, diarrhea, hair loss, dermatitis, and edema (Liu 2013).
Interferon alpha. Interferon alpha (IFN-α) is an inflammatory signaling molecule produced by cells of the immune system in response to pathogens (primarily viruses) (Bekisz 2004); its antitumor effect comes from its ability to increase the activity of natural killer cells of the innate immune system (Quigley 2013). IFN-α has been used for the local treatment of cutaneous melanoma and as an adjuvant (additional) therapy to surgical resection (Quigley 2013; Tarhini 2012). As an adjuvant therapy, IFN-α has been shown to improve survival and reduce tumor recurrence in patients with high-risk melanoma (Tarhini 2012). Case reports also suggest IFN-α may be used to treat metastatic melanoma of the skin (Quigley 2013). IFN-α is given by injection. Side effects include depression, anxiety, and infection (Ma 2014).
Interleukin-2. Interleukin-2 is a cell-signaling molecule that helps orchestrate the development of specialized immune cells involved in anticancer immunity (Lotze 1985; van der Vliet 2007). Intravenous high-dose interleukin-2 therapy was approved by the US FDA in 1998 for the treatment of metastatic melanoma. As of 2013, it remained the only FDA-approved treatment regimen associated with continuous remission lasting longer than 5 years. Unfortunately, the overall response rate is only 16% and high-dose interleukin-2 therapy is associated with significant toxicity. Thus, its use has been restricted to patients who have advanced melanoma but are otherwise in good health (Guan 2012; Chu 2013; Weide 2010).
One of the major toxicities associated with high-dose interleukin-2 therapy is injury of the delicate endothelial cells that line the inside of blood vessels, leading to a potentially life-threatening condition called vascular leak syndrome (Guan 2012; Chu 2013). Interestingly, adding oral supplementation with resveratrol, a phytochemical found in Japanese knotweed and grapes (Chen 2013; Latruffe 2013), to high-dose interleukin-2 therapy significantly mitigated the development of vascular leak syndrome in a murine model of metastatic melanoma. Moreover, the combination of resveratrol and high-dose interleukin-2 was more effective in inhibiting tumor growth and metastasis than high-dose interleukin-2 alone. The dose of resveratrol given to the mice was equivalent to about 648 mg for an 80 kg adult human. The scientists who conducted the study remarked “Our results suggested the potential use of resveratrol in [high-dose interleukin-2] treatment against melanoma” (Guan 2012).
Other avenues are being pursued in hopes of optimizing the efficacy and safety profile of interleukin-2 therapy for melanoma. One promising approach involves administering interleukin-2 directly into tumors as opposed to systemic administration. In one study on 48 subjects with metastatic melanoma, intratumoral injection of interleukin-2 three times weekly led to a complete local response that lasted for at least 6 months in 70% of patients. Only mild to moderate toxicity was observed. The initial dose of interleukin-2 used in this study was 3 million IU. The dose was escalated as the study progressed depending on how well each subject tolerated the treatment (Weide 2010). Other researchers have investigated the possibility of administering interleukin-2 complexed with nanoparticles. In mice bearing engrafted melanoma, injection of interleukin-2-containing nanoparticles into the tissue surrounding the tumors suppressed tumor growth and improved the animals’ survival (Yao 2011).
Ipilimumab. Ipilimumab (Yervoy®) is a targeted immunotherapy that was approved in 2011 for the treatment of metastatic melanoma that is refractory to other treatments. Ipilimumab is a monoclonal antibody that binds to CTLA-4, a protein involved in regulating the activity of immune cells (T-lymphocytes or T-cells). By binding and inactivating CTLA-4, ipilimumab causes the continuous activation of T-cells, which is thought to stimulate the immune response against melanoma (Kudchadkar 2013). In a phase III clinical trial, ipilimumab improved median survival in patients with an unresectable stage III or IV melanoma compared to patients given only a cancer vaccine (10 months vs. 6.5 months, respectively). Side effects are autoimmune in nature and include pruritus (itchy skin), diarrhea, rash, colitis, and vitiligo (skin depigmentation) (Liu 2013). Although only a fairly low number of patients (10%) respond to ipilimumab, it produces significant results in those that do respond and may be useful in difficult-to-treat melanomas or as an adjuvant to other treatments (Davar 2013).
Ingenol mebutate (Picato®) is a topical antitumor therapy extracted from the sap of Euphorbia peplus, a plant traditionally used as a treatment for skin diseases (Bahner 2013). It is an FDA-approved treatment for actinic keratosis, a type of UV-induced precancerous lesion that has the potential of progressing to squamous cell carcinoma (Firnhaber 2012). Ingenol is being investigated as a potential topical treatment for non-melanoma skin cancers. It is thought to work by rapidly disrupting mitochondrial membrane integrity in tumor cells, leading to cell death, and by inducing antibody-mediated eradication of residual diseased cells (Ogbourne 2004; Siller 2010). A pilot trial of high-dose (0.05%) ingenol gel in patients with superficial basal cell carcinoma demonstrated tumor clearance in 63% of patients (Siller 2010). Application of Euphorbia sap containing ingenol to squamous or basal cell carcinoma lesions showed a complete clinical response (no evidence of tumor by visual inspection) in 75-82% of patients at one month following treatment in an uncontrolled trial, with 50-57% of patients with no visual evidence of tumor at an average of 15 months post-treatment (Ramsay 2011).
Metformin, an oral hypoglycemic agent and a first-line drug treatment for type 2 diabetes, possesses a tumor-suppressing effect that may be useful in treating skin cancer (Badr 2013). In mice injected with human squamous cell carcinoma cells, metformin reduced tumor growth rate and biomarkers of cancer cell proliferation (Chaudhary 2012). A similar study demonstrated metformin’s ability to inhibit the formation of chemically-induced skin tumors and reduce the size of existing tumors; this effect was more pronounced in obese mice than overweight control mice (Checkley 2013). Part of the antitumor activity in these studies was attributed to metformin’s ability to reduce activity of pro-inflammatory metabolic pathways. Metformin also inhibited growth of human melanoma cells in cell culture experiments (Badr 2013).
Aspirin and Non-Steroidal Anti-Inflammatory Drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin inhibit the cyclooxygenase (COX) enzymes, which are involved in several aspects of cancer biology (Zhan 2007). Use of NSAIDs or aspirin has been associated with reduced risk of several cancers, including skin cancers (Johannesdottir 2012). In a study on nearly 200 000 individuals in Denmark, ever having taken aspirin or NSAIDs was associated with a 15% reduced risk of squamous cell carcinoma and a 13% reduced risk of malignant melanoma. The risk reduction became more pronounced with higher intensity and longer duration of aspirin and NSAID use (Johannesdottir 2012).
In cell culture experiments, aspirin appears to be selectively toxic toward melanoma cancer cells (Vad 2008). Two large observational studies have demonstrated a significant reduction in the risk of cutaneous melanoma with frequent aspirin usage. In a large Dutch population-based study of 8104 subjects, daily low-dose aspirin usage (30-100 mg/day) for at least 3 years reduced melanoma risk by 46% among women (Joosse 2009). In the Women’s Health Initiative observational study of over 59 000 post-menopausal women, aspirin usage reduced cutaneous melanoma risk by 21% (Gamba 2013).
A topical preparation of the NSAID diclofenac sodium at 3% concentration (Solaraze®) is FDA-approved to treat actinic keratosis, a premalignant skin condition, which may lead to skin cancer. Topical diclofenac sodium is thought to treat actinic keratosis by inhibiting the COX-2 enzyme, inducing apoptosis (programmed cell death), and inhibiting the formation of new blood vessels (angiogenesis). It has demonstrated good efficacy, with one study reporting 58% of subjects treated with Solaraze achieved complete clearance at 30-days post-treatment (Martin 2012).