Targeting Established Tumor Vasculature: A Novel Approach to Cancer Treatment

Lloyd   R.   Kelland

Abstract

The selective targeting of established tumor vasculature represents an attractive new anticancer drug strategy, distinct from inhibiting angiogenesis. This is based on the concept that, in contrast to targeting individual tumor cells, the killing of relatively few vascular endothelial cells could result in the death of a large area of tumor (from lack of oxygen and nutrients), drug delivery to vasculature is less challenging than to large solid tumors (which may harbor regions of hypoxia) and, moreover, cells that comprise vasculature (such as endothelial cells) are more genetically stable than tumor cells and hence less likely to acquire changes causing drug resistance. There is accumulating evidence that there are inherent differences in the vasculature of tumors, both morphologic and biochemical, in comparison to normal organs, thus providing a rational basis for this approach. Vascular disrupting agents (VDAs) are now being tested clinically; several are also in late preclinical development. A major class of small molecule VDA is those targeting tubulin, e.g., combretastatin A4 phosphate (CA4P), ZD6126 and AVE8062A. Another distinct non-tubulin based compound, the flavonoid 5,6-dimethyl xanthenone 4-acetic acid (DMXAA, AS1404) induces direct apoptosis of endothelial cells and secondary induction of various vasoactive agents (such as serotonin and tumor necrosis factor a). These agents have all completed Phase I clinical evaluation; dose-limiting toxicities are generally non-overlapping with conventional cytotoxics; there has been evidence of efficacy. A common theme, now being pursued clinically, is that VDAs are expected to show maximum therapeutic benefit when used, intermittently rather than chronically and in combination with either conventional cytotoxics (such as platins or taxanes) or radiotherapy. Thereby, complementary kill of the central compartment of tumors (by VDAs) and the proliferating, well oxygenated, periphery (by cytotoxics or radiotherapy), is predicted. Non-invasive imaging techniques such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) have proven useful in the clinical monitoring of VDAs. A variety of additional small molecule anti-tubulin agents, N-cadherin inhibitors and antibody-based products (e.g., delivering effectors such as tissue factor to tumor blood vessels) are in earlier stages of development. The vascular targeting field is entering a particularly exciting phase; the next 1-2 years will be crucial in establishing clinical proof of principle for this approach.

Keywords: vascular, targeting, combretastatins, dmxaa, tumor blood flow