Angiogenesis inhibition and metastasis: The saga continues

If you were a cancer patient receiving anti-angiogenic therapy, and you heard media reports that this treatment might make you worse and not better, what would you do? Recent peer-reviewed studies have indicated that inhibitors of vascular endothelial growth factor (VEGF), the central factor controlling formation of new blood vessels, actually promote tumor invasiveness and increase metastasis in animal models – far from their intended effect of forcing the cancer into remission. Vector covered this surprising twist last fall. Understandably, as these findings got out, some patients called their physicians and asked to be taken off the drugs.

Knowing all this, I was eager to attend this week’s World Anti-Angiogenesis Summit, which promised a panel discussion addressing the controversy. It’s one that interests me, as I am the licensing manager for the Vascular Biology Program at Children’s Hospital Boston. In that role, I work to translate innovations into products by finding industry partners to license and further develop new anti-angiogenic agents discovered by the program.

Representatives of major companies working on the next generation of anti-angiogenesis agents were at the Summit, and the panel discussion did not disappoint. Addressing the contentious findings, Hans-Peter Gerber from Pfizer, Gavin Thurston from Regeneron, Michael Bass from Amgen, Nicholas Marsh from Adnexus, and Randolph Watnick from the Vascular Biology Program at Children’s, made several interesting points:

1) Mice are not people. As one panelist said, “if mice models were predictive of the human response, we would have cured cancer already.” Many cancer agents have shown activity in rodent models of disease, but have gone on to disappointing results in clinical trials. So it might be that these adverse effects on invasion, shown only in mice, may not prove be reproduced in humans. In fact, Genentech indicated that postmarketing studies with Avastin, the blockbuster VEGF antagonist, have not shown an increase in metastasis. Efforts are ongoing to develop new systems to better translate preclinical results into clinical efficacy, as well as to predict potential side effects – both major themes at the Summit.

2) Dosage regimen matters. In the controversial preclinical studies, increased metastasis occurred when the anti-angiogenic agent was given at high doses over a short period of time followed by a period where the treatment was stopped. But in studies where the dosage and regimen were deemed to be more representative of clinical usage, anti-VEGF-treated mice lived longer compared to controls.

3) Recent findings may be specific to glioblastoma. Panelists and audience members pointed out that they have not been able to replicate the contended results in lung, breast and colon cancer models. However, it does appear that additional labs have observed increased invasion with VEGF antagonists in glioblastoma models. It was suggested that this type of cancer may be more susceptible to metastasis perhaps due to a higher stress response in the brain and to the inherent special nature of nerve cells compared to cells from other organs.

Not surprisingly, this 30-minute discussion, led by Murray Robinson from Aveo Pharmaceuticals, didn’t get to the bottom of this controversy. Although panelists presented some constructive criticism, the recent early findings on the connection between angiogenesis inhibition and metastasis couldn’t be dismissed entirely. But I think there are positive outcomes. We’re getting a greater appreciation for the complexity of the angiogenic process, and there’s a commitment to mitigating the risk of metastasis by developing novel combination drug regimens — along with biomarkers to closely monitor their effects.