Antiangiogenic potency of FK866/K22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma.

As described in the “Focus on Apoptosis” section of this edition of TherapeuticAdvances, renal cell carcinoma (RCC) is a niche cancer that accounts for 2-3% of all solid tumors in the major pharmaceutical markets. Approximately 30,000 patients are diagnosed with the disease each year in the US and 12,000 patients die of the disease annually. The market is currently dominated by the cytokines, but there is significant interest among physicians in the potential of anti-angiogenics, particularly so since renal cell carcinomas are known to be well vascularized.

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 designed to destroy existing tumor vasculature or to prevent neovascularization.

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 endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). Activation of VEGF receptors promotes endothelial cell growth, mitogenesis, and tube formation.

Despite early enthusiasm for angiogenesis inhibitors as safe and effective anticancer drugs, several Phase III and Phase II trials have proved disappointing. Newer strategies have however been developed culminating in the approval of the first inhibitor of angiogenesis, Avastin. Despite recent warnings that this humanized monoclonal antibody to VEGF may increase the risk of thrombosis and hence stroke and myocardial infarction, analysts estimate that annual global sales will reach between $1.6 billion and $1.8 billion by 2008.

Fujisawa’s FK-866, is a novel antitumor agent in phase I trial, which inhibits intracellular NAD biosynthesis and induces apoptotic cell death without any DNA-damaging effect. Previous results imply that decreased NAD(+) concentration initiates the apoptotic cascade however it has also been suggested that FK-866 may inhibit the production of VEGF thereby offering a novel approach to the inhibition of angiogenesis. In their Anticancer Research paper Drevs et al investigate this possibility further in a well characterized model of RCC.

Using the RENCA model in which primary kidney tumors and subsequent lung, intestinal lymph nodes and spleen metastases are induced by subcapsular renal injection of murine renal carcinoma cells Drevs et al demonstrate the efficacy of FK-866. At its maximum tolerated dose, oral FK-866 reduced the primary tumor volume by 40% when dosing was initiated at a time when metastasis was first observed. Angiogenesis in the primary tumor was reduced at even lower doses. Furthermore the number of metastases was reduced by 57%.

This study demonstrates the potential of FK-866 in a model of RCC. The therapeutic window was particularly wide when inhibition of angiogenesis rather than tumor size per se was observed. This suggests that like Avastin, which has been approved as an adjuvant to 5-fluorouracil-based chemotherapy in the treatment of metastatic colorectal cancer, FK-866 may be of particular benefit when administered alongside current therapies. In this context inhibiting the vascular supply further compounds already compromised tumor viability. The results of clinical studies testing this concept are awaited.

Entry date Monday, September 13, 2004

Adapted from Drevs et al, Anticancer Res. 2003 Nov-Dec;23(6C):4853-8.