Angiogenesis inhibitors have seen a long and rather chequered history since Judah Folkman first propounded the concept that tumours grow by adding new blood vessels. Many of these inhibitors have ended up in the dog heaven scrap heap, so to speak, while others (some monoclonals, some small molecule inhibitors) have made it to market in some indications, but failed miserably in others. All in all, it’s been a bit of a crapshoot at best for manufacturers trying to crack this particularly difficult nut.
Perhaps the most famous (some would say infamous) drug is bevacizumab (Avastin), a monoclonal antibody to VEGF-A, which has been approved for colon, lung, glioblastoma, renal cancers but just had its approval revoked in advanced breast cancer by the FDA due to a poor risk-benefit and efficacy profile.
Although Vascular Endothelial Growth Factor (VEGF) has been the target most associated with angiogenesis, there are quite a few other pathways involved in the process, including Platelet Derived Growth Factor (PDGF), Placental Growth Factor (PIGF), Fibroblast Growth Factor, Notch, angiopoeitins (eg Ang1-3 and Tie2) and many others.
Recently, at the European Multidisciplinary Cancer Conference (formerly ECCO and ESMO) in September, new data emerged on two new angiogenesis compounds in colorectal cancer, namely aflibercept (VEGF-Trap) from Regeneron and BIBF1120 (Vargatef) from Boehringer. Both drugs showed promising efficacy and tolerability data in a phase III (VELOUR) and a phase II trial, respectively.
I’m not going to go into details of those trials here, but to expand on the idea of angiogenesis further, because it makes logical scientific sense to target several aspects of the process to see if improved outcomes result. Closely related to this is lymphangiogenesis, which is the formation of new lymphatic vessels from pre-existing lymphatic vessels, in a similar way to blood vessel development or angiogenesis.
According to Tobler and Detmar (2006), a simplified angiogenic and lymphangiogenic mechanism is thought to look something like this:
It was therefore with great interest that I came across Regeneron’s latest poster at the AACR-EORTC-NCI Molecular Targets meeting last week. They looked at the idea of combining aflibercept (VEGF) and (Ang2) to determine whether there was a synergistic effect. The angiogenesis process is described below (courtesy of Regeneron):
The answer, in short, was yes.
They found that combined blockade of both VEGF (aflibercept) and Ang2 (REGN910) promoted noticeable tumour necrosis and growth inhibition in colorectal cancer xenografts over either agent alone.
Of course, we don’t know which biomarkers will be useful predictors of response, but that’s a discussion in itself for another post.
Now, while these results are encouraging, it does not mean they will automatically translate to patients in the clinic, but I do think it looks like a promising dual targeting approach that is well worth exploring further. In the research there appeared to be no obvious signs of additional toxicities with the combination. This is one specific multi-targeted approach that we may see more of in the clinic going forward. What this space for progress!
Tobler, N. (2006). Tumor and lymph node lymphangiogenesis–impact on cancer metastasis Journal of Leukocyte Biology, 80 (4), 691-696 DOI: 10.1189/jlb.1105653