Evolving angiogenesis therapies

National report - As the development of angiogenesis therapies continues to unfold, Vincent Li, M.D., M.B.A., of the Brigham and Woman's Hospital dermatology department, Boston, and the Angiogenesis Foundation (Cambridge, Mass.) emphasizes that more than any other medical or surgical specialty, dermatologists have access to an armamentarium of treatment modalities to control blood vessels.

"Angiogenesis therapies represents an under-appreciated area in dermatology. We have a tremendous number of diseases that we can impact with drugs that turn on or off blood vessels, and clinicians are beginning to use an arsenal of treatments that are available. What is clear is that we need to think about these drugs from a molecular point of view and the disease from a molecular point of view to better help our patients," Dr. Li says.

Inhibitors and stimulators

"There are two faces of skin diseases if you look at it from the angiogenesis perspective. One is where diseases have excessive blood vessels such as skin cancer, actinic keratoses, psoriasis, benign skin tumors, as well as warts.

"On the other side of the equation, there are diseases characterized by neovascularization, vessels that prohibit wounds from healing properly, so that would include almost every single type of diabetic wounds, venous leg ulcers and pressure sores.

"One face you treat with angiogenesis inhibitors as therapy, the other you treat with angiogenesis stimulators," Dr. Li tells Dermatology Times.

"What we have done is take ascience-based approach to identify or develop drugs that can affect the endothelial cells lining blood vessels. Dermatology is unique in that it is one of the only fields of medicine with such ready access, especially topically, to agents with proven angiogenesis activity and proven efficacy for managing or curing," Dr. Li says.

Anti-angiogenesis agents Research has demonstrated that skin cancers depend on angiogenesis for their growth and proliferation. Dr. Li and colleagues have found that even the earliest form of skin cancer, actinic keratoses (AK), depends on a lifeline of blood vessels for growth.

Because initiation of angiogenesis has already started in the AK state and because chronic sun exposure induces a high frequency of such mutational clones, there is likely a "field" of evolving subclinical malignant changes that can lead to invasive squamous cell carcinoma.

Dr. Li emphasizes the importance of treating actinic keratoses early on, as well as understanding that anti-angiogenic therapy may help prevent the ultimate development of cancer.

"Normal skin actually has a relatively low normal density of blood vessels - just enough to keep the skin healthy. But with skin cancers, the number of blood vessels skyrockets in order to support the supply side of tumor growth. The interesting thing is that the angiogenic 'switch' has already been triggered, so this may be the best time to intervene.

"We happen to know from our work and others that all skin cancers (AKs, SCCs, BCCs) and certainly the melanomas are associated with an overproduction of angiogenic growth factors by abnormal cells. As a consequence, drug developers are now focusing on anti-angiogenic therapy for skin cancer as a new avenue for dermatology," Dr. Li says.

In fact, at least one drug approved by the Food and Drug Administration for skin cancer has been shown to have potent anti-angiogenic affects.

Aldara (imiquimod, 3M) is a topical drug that inhibits angiogenesis on a molecular basis (interferons, interleukins), in cells (vascular cells) and on treated tissue (animals, humans), and clinically there is now proof of principle that Aldara effectively treats vascular diseases and skin cancers.

"We know that this drug actually induces the cells near treated tissue to produce natural angiogenesis inhibitors including interferons (alpha, beta, gamma) and interleukins (IL-12, IL-18). These are molecules that help keep angiogenesis in check under physiological conditions, but dermatologists using Aldara have a way of increasing their levels right at the site of a skin cancer on a topical basis," Dr. Li says.

Aldara was originally developed as an immune response modifier, to boost immune-mediated killing of cancer cells. This anti-angiogenic mechanism is now being appreciated by dermatologists and researchers.