Drugs that inhibit tumor angiogenesis have dramatically altered the treatment landscape for some of the most common and lethal cancer types, including cancers of the colon, lungs, and kidneys. Instead of killing cancer cells directly, antiangiogenic agents disrupt the blood supply to the tumor, depriving it of oxygen and nutrients. This approach represents a revolutionary shift in treatment built upon decades of research. Administering antiangiogenic drugs with standard therapies can also make those treatments more effective.

For the treatment of skin cancer, a number of antiangiogenic therapies are either already being used in the clinic or are under study in clinical trials. These therapies target specific growth factors or their receptors on cells that are known to stimulate angiogenesis during skin cancer development. By attacking these growth factors, angiogenesis inhibitors can slow or stop tumor growth, often without the unpleasant side effects from conventional skin cancer treatments, such as surgery and radiation.

In the following sections, we look at some of the antiangiogenic therapies being used for skin cancer treatment, and a number of promising therapies in development.

The enzyme cyclooxygenase-2 (COX-2) plays an important role in skin cancer angiogenesis by increasing production of VEGF and other angiogenesis-stimulating proteins following UV exposure. COX-2 inhibitors, in addition to being potent suppressors of pain and inflammation, also suppress angiogenesis. The oral COX-2 inhibitor celecoxib (20 mg/kg per day) has been shown to suppress SCC and melanoma tumors in mice. A topical COX-2 inhibitor, diclofenac 3% gel (Solaraze), is approved for the treatment of AK lesions, which are now generally recognized as an early form of SCC.²

Diclofenac 3.0% gel (twice daily for 3 months) was compared to placebo in a randomized, double blind, placebo controlled study involving 96 patients with at least 5 AK lesions each.³ At follow up, 79% of patients treated with diclofenac had complete or significant lesion improvement, and 50% had complete clearance of their AKs.  Among patients who got placebo, only 45% showed improvement. In another study, diclofenac 3.0% gel was as effective as topical chemotherapy (5-FU) for the treatment of AKs of the face and scalp, but with much less inflammation.⁴

Another therapy target in skin cancer are the Toll-like receptors (TLRs). Stimulating the production of TLRs inhibits tumor growth by enhancing the immune response and inhibiting angiogenesis. Since TLRs are ubiquitous in different types of skin cells, therapies that stimulate TLRs are particularly promising as skin cancer treatments.

Imiquimod (imidazoquinoline 5% cream; Aldara), a Toll-like receptor-7 (TLR-7) agonist (stimulator), has been approved since 1997 treat genital warts, and since 2004 to treat AK and BCC. Imiquimod stimulates the production of interferons (IFN) and interleukins (IL)—powerful chemicals called cytokines that stimulate the immune response. Many cytokines also inhibit angiogenesis by decreasing the production of angiogenic growth factors.

Typically, topical agents like imiquimod are applied with increasing frequency until a severe skin reaction occurs, which has traditionally been viewed as a sign the medication is working. While effective, many patients experience painful skin irritation accompanied by unsightly redness, crusting and peeling.

More recent clinical experience suggests, however, that using lower doses of imiquimod to induce an antiangiogenic response is just as effective and better tolerated. Using a flexible, patient-specific, dose-response protocol designed by clinicians—the Individualized Maximal Tolerated Dose (iMTDSM)—patients apply imiquimod to their lesions at slowly increasing doses until the first signs of redness and irritation appear.⁵

Because each patient responds differently, iMTD allows for the most effective dosing frequency while avoiding undesirable skin inflammation. In data recently presented involving 56 non-melanoma skin lesions (AK, BCC, SCC in situ), iMTD with imiquimod completely resolved all of the treated lesions without any gross inflammation.⁶ Maximum dose frequency ranged from as infrequently as 3 times per week to as much as twice daily, which shows that a single dosing schedule is not appropriate for all patients.

Inhibitors of VEGF and other angiogenesis-promoting growth factors have produced remarkable results in treating certain solid tumors. One such agent, bevacizumab (Avastin), a monoclonal antibody for VEGF, is now approved to treat advanced cancers of the breast, colon, lung, brain, and kidneys. A challenge for developing topical VEGF inhibitors is formulating agents of sufficiently low molecular weight to penetrate the upper layers of the skin.

One agent, dobesilate, an inhibitor of bFGF and acidic fibroblast growth factor (aFGF), has shown promising results for the treatment of rosacea, one of many skin conditions that have excessive angiogenesis as a contributing factor.⁷ In one study, calcium dobesilate (2.5% suspension, twice daily for four weeks) produced complete resolution of a BCC, with no evidence of tumor recurrence at five months.⁸ No irritation or adverse effects were observed during treatment.  

Natural plant extracts, such as polyphenolic antioxidants found in green tea and grape seed, have been shown to inhibit angiogenesis through a number of mechanisms. Epigallocatechin-3-gallate (EGCG), the major catechin (flavonol) in green tea, has been shown to inhibit angiogenesis both in animal and human studies.⁹ Green tea or purified EGCG administered to mice has been shown to prevent angiogiogenesis of the corneas and inhibit the growth of highly angiogenic tumors. Topical EGCG reduced angiogenesis in UV-induced skin cancer in laboratory mice.¹⁰

EGCG is the active component of sinecatechins ointment 15% (Veregen), which was approved by the FDA in 2007 to treat genital warts. A related compound, kunecatechins ointment (Polyphenon E topical ointment) is being tested for AK in clinical studies.