After bevacizumab was approved by FDA, anti-angiogenic therapy has quickly inte- grated into traditional anti-cancer treatments. In contrast to the fact that angiogenesis is an ef- fective and low toxicity target for a broad range of solid tumors and non-malignant diseases, three decades of numerous pre- and clinical studies only provide us with a handful of anti- angiogenesis reagents that approved by FDA for clinical usage. Among them, as introduced above, most are monoclonal antibodies or small molecular TKIs that specifically or selectively block VEGF/VEGFR and other pro-angiogenic signaling pathways. As suggested by clinical data compiled within past several years of experience with this novel anti-cancer strategy, several drawbacks of currently available anti-angiogenic reagents have clearly emerged.
First, no matter VEGF/VEGFR, EGF/EGFR or other growth factors that promote an- giogenesis, all are widely expressed in various normal tissues with diverse physiological roles.
Inhibition of those signaling pathways yields adverse effects. Inhibition of VEGF/VEGFR was in- itially assumed to only block developmental and pathological angiogenesis sparing ECs in nor- mal tissues (reviewed in [170]). Interference with wound healing is a common risk related to angiogenesis inhibition; however, other systematic adverse events have become evident with VEGF/VEGFR inhibitors treatment. Since profound cardiovascular side effects were associated with administration of VEGF/VEGFR inhibitors, more and more studies have demonstrated that VEGF is essential in maintaining normal cardiovascular function (reviewed in [171]). VEGF in- duces endothelial type nitric oxide (NO) and prostacyclin (PGI2) in endothelium, which are es- sential for endothelial-dependent vasodilation in coronary arteries [172-174]. Lee and col- leagues also show that autocrine of VEGF is required for EC survival and blockage of this signal- ing pathway by small molecule kinase inhibitors results in increased ECs apoptosis in normal tissues, and subsequent rarefaction in small arteries and arterioles [175]. VEGF/VEGFR inhibi- tors also increase arterial stiffness possibly by interaction with endothelin, a vasoconstrictor [176, 177]. Therefore, hypertension is the most common side effects associate with VEGF/VEGFR inhibitors due to defects in vessel vasodilation, rarefaction and increase in vessel stiffness (reviewed in [171]). From 11 to 32% of patients under bevacizumab treatment have been reported to experience elevated blood pressure (reviewed in [178]). Around half of those who develop to hypertension require pharmacologic interventions. The incidence of hyperten- sion with VEGF TKIs treatment is about 15% to 60% (reviewed in [171]). Data have also shown a tendency of increasing in incidents of hypertension when patients are treated with higher po- tency TKIs (reviewed in [171]). More serious cardiac side effects, such as myocardial infarction (MI) and congestive heart failure, and bevacizumab treatment-related deaths during clinical
trials have been reported (reviewed in [178]). Those events may be related to microvascular rarefaction upon VEGF inhibition. Outside the cardiovascular system, VEGF is also plays impor- tant roles in maintaining mucosal homeostasis, platelet function, and neuron protection, so that bleeding, gastrointestinal perforation, thromboembolism, voice change, upper and lower digestive tract mucositis, and neurological complications are also reported with inhibition of VEGF/VEGFR (reviewed in [179]). VEGF is expressed in normal renal cortex and mediates glo- merular inflammation and repair, which is possible reason that bevacizumab and VEGFR TKIs treatments are associated with proteinuria and oedema [170, 180]. Small molecular TKIs inhi- bits many other receptors other than VEGFR, and therefore are accompanied by more compli- cations other just inhibition of VEGF signaling pathway alone.
Resistance to VEGF/VEGFR inhibitors has been observed in preclinical and clinical studies. Bergers and coworkers developed a two-mode theory to explain the phenomena (re- viewed in [181]). In general, there are two outcomes after treatment with VEGF/VEGFR inhibi- tors, either initial disease regression followed by restoration of tumor growth (referred as “eva- sive resistance”), or no beneficial effects in tumor inhibition (referred as “intrinsic resistance”). Among many possible mechanisms responsible for these two types of drug resistance, up- regulation of alternative pro-angiogenic signaling pathways play essential roles. Ferrara pointed out that other signaling pathways mediating VEGF-independent tumor angiogenesis exist in var- ious types of preclinical and clinical tumor models (reviewed in [182]). Treatments with VEGFR inhibitors in cancer patients are reportedly increase circulating pro-angiogenic growth factors such as FGF and PIGF. In some cases, FGF leads to a new wave of revascularization that enables tumor to escape treatment with VEGFR inhibitors. Tumors that intrinsically resist treatment
with VEGF/VEGFR inhibitors may due to pre-existing redundant pro-angiogenic signals. For ex- ample, in early stage of human breast cancer biopsies VEGF is the major pro-angiogenic signal, but in late stage FGF and other growth factors become dominant. Recently, FDA is considering withdrawal of bevacizumab from breast cancer treatment due to adverse effects and contro- versial benefits in patient survival rates.
At last, large efforts have been made to overcome the resistance to VEGF/VEGFR inhibi- tors, such as developing multi-targeting TKIs and combinatory therapy with reagents that target parallel pro-angiogenic signaling pathways. Selective TKIs usually cause more side effects due to off-target inhibitory effects. In addition, they may not necessarily increase clinical efficacy as expected. For example, a phase 3 clinical trial showed that axitinib (AG013736; Pfizer), a potent selective inhibitor of VEGFR-1, 2, and 3, cKIT and PDGFR does not improve overall survival in advanced pancreatic cancer when it is combined with gemcitabine [183]. Both VEGF and EGFR are over-expressed in advanced NSCLC, colorectal carcinoma, RCC and many other solid can- cers. Although VEGF and VEGFR are considered valuable therapeutic targets for NSCLC treat- ment, the introduction of monoclonal antibodies (mAbs) that target either of these two signal- ing pathways have marginally increased survival rates in certain types of cancer, for example in advanced NSCLC patients eligible for these agents (reviewed in [184]). Several clinical trials demonstrated that even the combination of bevacizumab with anti-EGFR inhibitors produces controversial benefits (reviewed in [185]). Many preclinical models showed promising effects when VEGF/VEGFR inhibitors are combined with other pro-angiogenic inhibitors targeting PDGF, mTOR and FGF, but their efficacies require further clinical investigation [102, 186, 187]. Hence, resistance to VEGR/VEGFR inhibitors may not be solved simply by blocking multiple pro-
angiogenic signaling pathways, which urges the development of agents with novel anti- angiogenic mechanisms that will further validate angiogenesis as a therapeutic target.