The long-standing proposition that induction of chronic angiogenesis is a hallmark of cancer is now solidly grounded in a substantial body of research involving genetic and pharmacological perturbation of elements in the vascular regulatory circuitry. The ‘angiogenic switch’1
is increasingly recognized as a rate-limiting secondary event in multistage carcinogenesis2
, as documented in animal models of cancer and correlated in advanced pre malignant stages, as well as their malignant derivatives, in a growing list of human cancer types. That this acquired capability is functionally important for manifestation of the disease has been further validated by the approval of angiogenesis inhibitors as cancer therapeutics, most notably ones targeting the vascular endothelial growth factor (VEGF) pro-angiogenic signalling pathways3
. The pioneers of the clinical proof-of-concept for angiogenesis inhibitors are bevacizumab
(Avastin, Genentech/Roche), a ligand-trapping monoclonal antibody, and two kinase inhibitors (sorafenib
(Nexavar, Bayer) and sunitinib
(Sutent, Pfizer)) targeting the VEGF receptor (VEGFR) tyrosine kinases, principally VEGFR2 (also known as KDR
). Since March 2008, bevacizumab has been approved for treating patients with late-stage colon cancer
, non-small-cell lung cancer
and breast cancer
, all in combination with chemotherapy. Sorafenib and sunitinib have both been approved for treating renal carcinoma, a highly vascularized (and angiogenic) tumour type. In addition, sunitinib has been approved for treating gastrointestinal stromal tumours, and sorafenib for hepatocel-lular carcinomas3–6
. Numerous ongoing clinical trials seek to expand the applications of each of these VEGF pathway inhibitors, and dozens of other angiogenesis inhibitors (many also targeting VEGF signalling) are being clinically evaluated (see Angiogenesis Inhibitors Therapy
URL and clinical trials URLs in Further information). Moreover, two VEGF pathway inhibitors (the RNA aptamer pegaptanib and a Fab derivative of bevacizumab) have been approved for treating the angiogenic (wet) form of macular degeneration7–9
Many of the demonstrable clinical benefits and side effects (such as hypertension) of the kinase inhibitors targeting the VEGF signalling pathway (sorafenib, sunitinib and dozens more in various stages of preclinical and clinical testing) can be attributed to inhibition of the activity of the VEGFRs, but it must be emphasized that all are intrinsically (owing to their chemistry) selective but not specific. Thus, virtually every VEGFR kinase inhibitor has an attendant variety of additional moderate-to-high affinity kinase targets in the ‘kinome’10
, of which some may convey added therapeutic benefit (such as inhibition of platelet-derived growth factor receptor (PDGFR), in the case of sunitinib), and others may evoke new toxicities. The components of the VEGF signalling pathway, the constellation of drugs developed to inhibit VEGF signalling, the specific mechanistic effects of VEGF signalling and VEGF inhibition, and the clinical trials evaluating their effects are described in depth and discussed in a Review by L. Ellis and D. J. Hicklin also in this Focus issue11
. Additional reviews, in this Focus on targeting angiogenesis12–14
, describe and discuss other targets and strategies for inhibiting tumour angiogenesis.
The clinical achievements with bevacizumab, sunitinib and sorafenib constitute a milestone event for the field of angiogenesis research, eliciting survival benefits in many aggressive tumours, but there is a sobering addendum: these VEGF pathway inhibitors are failing to produce enduring clinical responses in most patients5,22–24
. Rather, the introduction of anti-angiogenic therapy results in transitory improvements, in the form of tumour stasis or shrinkage and in some cases increased survival. Inevitably, however, the tumours begin to grow again and the disease progresses, after a fleeting period of clinical benefit that is typically measured in months25
. This seemingly preordained return to growth and progression in the face of ostensibly potent angiogenesis inhibitors conflicts with the widely accepted proposition that angiogenesis is an essential capability for the manifestation of lethal cancer2,26
. There is, therefore, a clear need to understand the mechanistic basis of this apparent conundrum for the therapeutic targeting of tumour angiogenesis.
In this Review, we elaborate a hypothesis for the transitory efficacy of the current generation of pathway-specific angiogenesis inhibitors, one we predict will prove general to potent angiogenesis inhibitors. our proposition is based both on emerging data from clinical and preclinical investigations, and on mechanistic insights from studying the biological regulatory mechanisms operative in the tumour microenvironment that govern tumour phenotypes, most notably angiogenesis and invasion. We envision two general modes of resistance to angiogenesis inhibitors, in particular those targeting the VEGF pathways: first, adaptive (evasive) resistance; and second, intrinsic (pre-existing) non-responsiveness (). Multiple mechanisms are suspected to underlie both modes of resistance, as outlined below.
Two modes of resistance in response to anti-angiogenic therapy imply adaptive evasion and intrinsic non-responsiveness of tumours