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Antiangiogenesis agents: Therapy shows promise in treating port wine stains and cutaneous disease


Physicians historically have used antiangiogenic agents in oncologic and ophthalmologic indications, but dermatologic applications for these medications are under investigation, an expert says.

Key Points

San Francisco - Antiangiogenic agents show early promise in treating port wine stains and a host of cutaneous diseases, an expert says.

However, she says that when using PDLs for this purpose, "We have occasionally been frustrated, because, while we often are able to help patients, some don't respond. Or they respond, then their lesion recurs."

Accordingly, she says she and her colleagues are interested in using antiangiogenic agents to remove unwanted cutaneous vascular lesions, such as hemangiomas, vascular malignancies and angiofibromas, as well as to prevent recurrence of port wine stains, vascular malignancies and telangiectasias.

Although many therapies approved by the Food and Drug Administration (FDA) possess recognized antiangiogenic properties, she says, "Their use in dermatology has been somewhat limited, but that is changing as people do more research in this area."

Currently available antiangiogenic agents include monoclonal antibodies, such as Avastin and Lucentis (bevacizumab and ranibizumab, respectively, both made by Genentech), Macugen (pegaptanib, Pfizer) and Erbitux (cetuximab, Bristol-Myers Squibb), all of which target angiogenesis growth factors and/or their receptors, Dr. Kelly says.

Additional antiangiogenic agents include tyrosine kinase inhibitors, such as Sutent (sunitinib, Pfizer), Nexavar (sorafenib, Bayer/Onyx) and Tarceva (erlotinib, Genentech/OSI). Rapamune (sirolimus/rapamycin, Wyeth/Ayerst) and Toricel (temsirolimus, Wyeth), on the other hand, represent mammalian target of rapamycin (mTOR) inhibitors, Dr. Kelly says.

Other mechanisms of action among current antiangiogenic drugs include matrix metalloproteinase inhibition (batimastat, British Biotech) and protease inhibition (Velcade, bortezomib; Millennium), she says.

As for skin diseases researchers are targeting with antiangiogenic agents, Dr. Kelly says that because existing treatments for melanoma - particularly advanced and metastatic disease - have limited efficacy, melanoma garners perhaps the most attention. For example, she says ABT-510 (thrombospondin-1 analog, Abbott) is currently in phase 2 testing for metastatic melanoma.

Testing bevacizumab

Dr. Kelly says researchers are prospectively testing bevacizumab in patients with metastatic melanoma who have failed multiple other therapies. Using paclitaxel 70 mg/m2 weekly and bevacizumab 10 mg/kg biweekly for five consecutive weeks followed by one week off, two patients in this study achieved partial response; eight experienced disease stabilization (median: four months); and two experienced disease progression (Gonzalez-Cao M et al. Oncology. 2008;74(1-2):12-16).

"These agents aren't perfect. Some studies show some improvement, but the trials are all relatively small," she says.

However, Dr. Kelly says antiangiogenic drugs are perhaps promising for treating metastatic melanoma, especially if used in combination with cytotoxic agents.

In Kaposi's sarcoma, she says, researchers have had a fair amount of success using various agents. For instance, sirolimus has proven effective in treating Kaposi's sarcoma in renal transplant patients while maintaining sufficient immunosuppression to prevent rejection (Campistol JM et al. J Am Soc Nephrol. 2006 Feb;17(2):581-589). Moreover, sirolimus enabled one immunocompetent patient to achieve complete clinical, histological and immunohistochemical remission in 16 of 17 Mediterranean KS lesions (Guenova E at al. Arch Dermatol. 2008 May;144(5):692-693).

Similarly, Dr. Kelly says, "Hemangiomas are definitely an area that could be very responsive. For example, Aldara (imiquimod, Graceway) can have antiangiogenic effects, as well as other mechanisms of action, and has been used to treat hemangiomas (Welsh O et al. J Am Acad Dermatol. 2004 Oct;51(4):639-642).

Additionally, she says researchers have begun using propranolol for hemangiomas. In one study involving 11 children, all patients showed a change from intense red to purple, with lesion softening, within 24 hours of beginning propranolol therapy (Leaute-Labreze C et al. N Engl J Med. 2008 Jun 12;358(24):2649-2651).

This study suggests that further research in this area is warranted, she says. "We don't really know the mechanism of propranolol, but some people think it might have an antiangiogenic effect."

Regarding port wine stains, she says, "We've done some research in an animal model looking at bevacizumab in combination with laser therapy. We're also halfway through a randomized clinical trial comparing PDL plus imiquimod to PDL plus placebo and have seen improved response with the PDL plus imiquimod (Kelly KM et al. J Biomed Optics. (submitted 2008)."

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