Blocking resistance to antiangiogenic cancer therapy

Tumor resistance to anti-angiogenic therapy
Increasing studies, both in mouse models and patients, show that many tumor types are either poorly responsive or develop resistance to anti-angiogenic therapy, a form of anti-cancer treatment aimed to inhibit tumor angiogenesis (the growth and function of tumor-associated blood vessels, which are required for tumor progression). The failure of anti-angiogenic drugs–also when combined with other anti-cancer treatments–to achieve important and durable anti-tumor responses in cancer patients mirrors that of other targeted drugs and can be attributed to either pre-existing or induced mechanisms of tumor resistance. For example, when one pro-angiogenic factor is effectively neutralized (e.g. VEGFA, the target of the broadly used anti-angiogenic drug Avastin), others can compensate for its absence and restore tumor angiogenesis. Such mechanism of tumor resistance limits the clinical success of anti-angiogenic therapy and suggests that multiple pro-angiogenic factors should be concomitantly targeted to increase its efficacy in cancer patients.

Role of angiopoietin-2 in tumor resistance to VEGFA-targeted therapy
Angiopoietin-2 (ANG2) is a pro-angiogenic factor that promotes tumor angiogenesis in concert with VEGFA. Previous studies have shown that blocking ANG2 in mouse models of cancer inhibits tumor angiogenesis and metastasis. However, it was unclear whether blocking ANG2 could induce long-lasting anti-tumor responses, and/or overcome tumor resistance to VEGFA-targeted drugs. With the financial support of the Leenaards Foundation and the Swiss Cancer League (Oncosuisse), Michele De Palma and colleagues have now found that ANG2 plays an important role in driving tumor resistance to anti-VEGFA therapy, but only in selected cancer types. Specifically in these tumors, targeting VEGFA induced a compensatory response involving increased ANG2 levels, which promoted tumor resistance to anti-VEGFA therapy. Co-targeting VEGFA and ANG2 signaling in the “resistant” tumors could effectively block angiogenesis, halt cancer progression, and hence reverse tumor resistance to anti-angiogenic therapy.

Therapeutic implications
It is currently unclear why some tumors are relatively sensitive, while others are ostensibly refractory, to anti-VEGFA therapy (e.g., by Avastin). The authors’ findings suggest that high ANG2 levels in tumors treated with Avastin might predict a poor response to this form of anti-angiogenic therapy. These considerations may motivate the selection of patients who are more likely to respond to Avastin based on the low levels of ANG2 in their tumors. Furthermore, tumors with high ANG2 levels – either before or during Avastin – might specifically benefit from the combined (anti-VEGF/ANG2) therapy.

The study is reported this week in Cell Reports. First authors of the study are Dr. Nicolò Rigamonti, post-doc, and Ece Kadioglu, Ph.D. student of the EPFL Doctoral Program in Biotechnology and Bioengineering (EDBB).

Reference: Nicolò Rigamonti, Ece Kadioglu, Ioanna Keklikoglou, Céline Wyser Rmili, Ching Ching Leow, and Michele De Palma. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signalling blockade. Cell Reports. July 2014 (online publication ahead of print).

Complete funding: Leenaards Foundation; Swiss Cancer League (Oncosuisse); European Research Council (ERC); MedImmune.