Combined radiation/SU11248 therapy for the treatment of cancer

Angiogenesis, the formation of new blood vessels, is crucial to a number of physiological processes such as reproduction, development and tissue repair, as well as in disease states including cancer, rheumatoid arthritis (see the “Focus on Immunology & Inflammatory Disease” section of this edition of TherapeuticAdvances) and other inflammatory diseases. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion.

Tumor vascularization is key to the development of solid tumors and the vast majority of pharmaceutical activity surrounding angiogenesis relates to the development of therapeutic strategies to destroy existing tumor vasculature or to prevent neovascularization. Despite early enthusiasm for angiogenesis inhibitors as safe and effective anticancer drugs, several Phase III and Phase II trials have proved disappointing. Newer strategies are however being developed which will hopefully confer greater efficacy to this field.

Although there are multiple opportunities for the development of anti-angiogenic molecules, the most advanced targets are the growth factors. The principal growth factors driving angiogenesis include VEGF, a homodimeric 45kDa glycoprotein that specifically acts on endothelial cells binding to a growing number of endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2).

Prior to their acquisition by Pfizer earlier this year, one of the leaders in the field of angiogenesis therapeutics was the San Francisco biotech, SUGEN. SU11248 is one inhibitor of angiogenesis that emerged from SUGEN’s pipeline. This orally active small molecule antagonizes Flk-1/KDR, as well as PDGFR, a further growth factor receptor involved in tumor angiogenesis. SU11248 has previously been shown to have broad and potent antitumor activity in mice, decreasing tumor microvessel density and tumor cell proliferation and increasing tumor cell apoptosis, culminating in tumor regression. SU11248 is currently in Phase I clinical trials in patients with advanced cancer.

Radiotherapy represents a focus of cancer therapeutics however radiation is known to increase the expression of pro-angiogenic factors such as VEGF, FGF, and PDGF and this may limit the efficacy of this approach. Receptor tyrosine kinase antagonists have been shown to enhance the cytotoxic effects of cancer therapy through the inhibition of the phosphatidylinositol 3-kinase/Akt pathway in tumor vascular endothelium and it is therefore possible that SU11248 may be able to enhance the efficacy of radiotherapy. In their recent Cancer Research paper, Schueneman et al investigate this possibility. Impressively, SU11248 increased the apoptotic cell death of endothelial cells exposed to radiation by over 10-fold. A similar enhancement of the therapeutic effect of radiation was observed in mice with lung cancer xenografts. In these animals the combination of SU11248 and radiation both reduced vascularization and increased tumor doubling time. Of particular interest continued treatment with SU11248 after an initial combined treatment with radiation and SU11248 resulted in a prolonged and dramatic reduction in tumor growth. This study suggests that patients receiving an initial combination of radiotherapy and SU11248 followed by a prolonged maintenance therapy with SU11248 may exhibit a particularly favorable response.
Entry date Monday, November 10, 2003

Adapted from Schueneman et al, Cancer Res. 2003 Jul 15;63(14):4009-16.