TEM8 May Be a Better Anti-Angiogenesis Target

Graphic shows a solid tumor signaling for formation of new blood vessels. This process is called angiogenesis. New blood vessels are spreading into tumor because TEM8 is signaling for them to do so.

A solid tumor signals for the formation of new blood vessels. This process is called angiogenesis. The light blue dashed line represents the selective expression of TEM8 on tumor vasculature.

Anti-angiogenesis agents have improved the efficacy of many treatment strategies for solid tumors, but their ability to inhibit tumor vasculature is often incomplete and comes at a price, namely, side effects that can harm normal tissues including blood vessels. As a result, tumor angiogenesis is seldom completely halted, and both angiogenesis and tumor growth inevitably progress.

One reason for this situation is that the angiogenesis-triggering signaling system most often chosen for targeting is VEGF/VEGFR2, a duo which happens to be widely expressed and active in nonangiogenic normal adult tissues as well. The VEGF/VEGFR2 system also plays critical roles in normal adult physiology. What is needed, then, is a vascular target that can discriminate tumor-induced blood vessels from normal blood vessels.

In a recent paper published in Cancer Cell, Brad St. Croix, Ph.D., working with his team within CCR’s Mouse Cancer Genetics Program, has demonstrated a new anti-angiogenesis agent that may indeed have the desired tumor-vascular specificity. Using xenografts of diverse origin—including melanoma, breast, colon, and lung cancer—St. Croix and his colleagues demonstrated that a host-derived vascular signaling molecule called TEM8 is a new and improved target for blocking tumor angiogenesis. The St. Croix team developed antibodies against TEM8’s functional extracellular domain and showed that it can effectively inhibit tumor angiogenesis in the xenograft models they studied. Their anti-TEM8 antibody achieved broad antitumor activity and boosted the activity of clinically approved anticancer agents used in combination therapies without adding toxicity to their model systems. It also did not interfere with wound healing, and augmented the ability of natural killer cells to mount an immune response against TEM8 in an in vitro assay.

So TEM8 may provide a more discriminating target than VEGF for achieving selective inhibition of tumor angiogenesis. The evidence for this lies in data from St. Croix’s xenograft systems, where TEM8 is functionally required for optimal tumor angiogenesis and growth, but it is not essential for normal development and physiological angiogenesis.

Summary Posted: 02/2012

Reference

A Chaudhary, et al. TEM8/ANTXR1 Blockade Inhibits Pathological Angiogenesis and Potentiates Tumoricidal Responses against Multiple Cancer Types. Cancer Cell, Feb. 14, 2012 PubMed Link