INTRODUCTION — This topic reviews the process of angiogenesis and discusses therapies that target angiogenesis therapeutically.
Separate topics review endothelial biology and toxicities of angiogenesis inhibitors:
●Endothelial biology – (See "The endothelium: A primer".)
●Cardiovascular toxicities – (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
●Noncardiovascular toxicities – (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
DEVELOPMENT AND REMODELING OF THE VASCULATURE — As the embryo develops, mesodermal precursors differentiate into endothelial cells and assemble into primitive vascular networks in a process called vasculogenesis. These networks undergo extensive budding and branching and associate themselves with vascular smooth muscle elements in a process termed angiogenesis, thus yielding an extensive vasculature capable of responding to systemic as well as local tissue needs. The end result is that each cell is supported by a capillary network that enables it to receive necessary nutrients and oxygen, and export its cellular products (eg, hormones, vasoactive materials, metabolic waste products).
Following embryogenesis, angiogenesis is repeated during tissue repair (eg, wound healing) and overall growth of the organism. Angiogenesis also occurs during certain specialized situations such as during the menstrual cycle and implantation of the embryo during pregnancy and can be highly coordinated with hemostasis [1]. Alterations in normal or newly formed vascular networks can also be associated with disease, as illustrated by the following situations:
●Occlusion of blood vessels can result in tissue hypoxia and damage (eg, peripheral vascular disease, myocardial infarction, stroke, vaso-occlusion in sickle cell disease).
●Interference with the action of vascular endothelial growth factor and placental growth factor may play a central role in the placental hypoperfusion seen in preeclampsia. (See "Preeclampsia: Pathogenesis", section on 'Role of systemic endothelial dysfunction in clinical findings'.)
●Inappropriate and excessive growth of blood vessels plays a causative role in ocular disorders such as diabetic retinopathy and macular degeneration.
●The induction of angiogenesis (neovascularization) is an important mechanism by which tumors promote their own continued growth and metastasis [2].
Because of the central role of angiogenesis in tumor growth, it represents an attractive therapeutic target for patients with cancer. The general approaches for inhibiting angiogenesis in the treatment of malignancy will be discussed here [3,4]. The toxicity of antiangiogenic drugs is discussed separately. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
The clinical uses of angiogenesis inhibitors are discussed in the relevant disease topics.
REGULATION OF ANGIOGENESIS — Angiogenesis is a complex process under both positive and negative control by naturally-occurring growth factors [5-7]. Many, but not all of the growth factors that stimulate angiogenesis bind heparin. The biologic counterpart of this property is the ability to bind to structurally similar glycosaminoglycans known as heparan sulfates on cell surfaces and the extracellular matrix (ECM). Binding of a growth factor to heparan sulfate typically stabilizes the growth factor, prolongs its tissue half-life, and may facilitate its binding to specific high affinity receptors.
Growth factors are a broad category of endogenous molecules that promote cell proliferation and/or differentiation. All growth factors that induce neovascularization are presumed to do so by stimulation of endothelial cell proliferation and migration. Other contributory factors include stimulation of ECM breakdown, attraction of pericytes and macrophages, stimulation of smooth muscle cell proliferation and migration, formation and "sealing" of new vascular structures, and deposition of new matrix [8,9].
The ability of growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF) system, and transcription factors such as hypoxia inducible factor (HIF-1) to increase the rate of endothelial cell proliferation has been demonstrated in several animal models; proliferation is largely limited to ischemic zones, even following systemic administration or activation of these factors [10-14]. The mechanism that limits their action to ischemic areas is not clear, but it may involve spatially limited expression of high affinity growth factor receptors, a local interplay of growth factors and ECM-derived angiogenic inhibitors, and the presence or absence of other regulatory molecules [15].
Angiopoietins are a subset of growth factors identified for their role in angiogenesis. Specific angiopoietins (eg, angiopoietin-1) appear to regulate endothelial cell survival as well as interactions with supporting pericytes [16]. In addition, the capacity of tissues to respond to angiogenic signaling may be regulated by changes in the composition of the ECM, including expression of matrix-digesting enzymes such as matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) [17]. Changes in endothelial cell expression of integral matrix proteins (eg, avb3 and avb5 integrins) and heparan sulfate-carrying proteoglycans (such as syndecans) may also be important. (See "Therapeutic angiogenesis for management of refractory angina".)
The existence of both positive and negative angiogenesis regulators has led to two separate strategies for inhibiting pathologic angiogenesis:
●Inhibition of positively-acting agents (eg, small molecule VEGF receptor [VEGFR] inhibitors; antibodies; soluble receptor extracellular domains directed against VEGF, VEGFR, or endothelial cell surface proteins; inhibitors of angiopoietin pathways [18-20]). (See 'Anti-VEGF antibodies' below.)
●Administration of negatively-acting agents or functionally-related analogs (eg, angiostatin, endostatin, fumagillin) [21]. This strategy remains experimental. (See 'Other antiangiogenesis approaches' below.)
Angiopoietin 1 and the angiopoietin receptor Tie2 are potential targets for antiangiogenic therapies, as discussed below. (See 'Bispecific antibodies' below and 'Angiopoietin-Tie2 blockade or activation' below.)
VASCULAR ENDOTHELIAL GROWTH FACTOR — The dominant growth factor controlling angiogenesis is vascular endothelial growth factor (VEGF-A, previously called vascular permeability factor [VPF]) [22-24]. VEGF-A is one member of the VEGF family, which also contains VEGF-B, VEGF-C, VEGF-D, orf virus VEGF (VEGF-E), and placental growth factor (PLGF).
VEGF-A is the most studied and pharmacologically targeted VEGF family member for pathologic angiogenesis. VEGF-A is produced by a number of different cell types (eg, diverse epithelial lineages, inflammatory and hematopoietic cells, endothelial cells themselves), acts selectively on vascular endothelial cells, and is capable of stimulating angiogenesis in vitro and in vivo. As such, it appears to play an active role in the induction, maintenance, and growth of vascular endothelial cells. Because of its association with both normal and abnormal angiogenesis, VEGF-A has become an attractive target for both proangiogenic and antiangiogenic therapy. Direct actions of VEGF-A include:
●Stimulation of endothelial mitogenesis.
●Promotion of endothelial survival by an Akt-dependent pathway.
●Control of vascular permeability; VEGF-A is 50,000 times more potent in inducing vascular leakage than histamine [25]. The mechanism of this effect appears to be fenestration of the endothelium of small venules and capillaries through a Src kinase-dependent mechanism [26].
●Increased expression of tissue plasminogen activator, urokinase plasminogen activator, collagenases, and matrix metalloproteinases. All are involved in the degradation of the ECM, needed for endothelial cell migration [27-31].
●In embryos lacking one of the two VEGF alleles, the mutation is lethal by early gestation. Angiogenesis and blood-island formation are impaired, resulting in several developmental anomalies [32].
While a full discussion of functions of VEGF family members is beyond the scope of this review, VEGF-A as well as VEGF-B, -C, -D, and PLGF have well recognized effects on diverse processes including but not limited to lymphangiogenesis, metabolism, bone formation, hematopoiesis, and pathologic angiogenesis [33-36].
Effect of hypoxia and cytokines — Expression of VEGF-A is highly regulated by hypoxia, providing a feedback mechanism to accommodate reduced tissue oxygenation via the promotion of new blood vessel formation. The regulation of VEGF-A expression by hypoxia is mediated by a family of hypoxia-inducible transcription factors (HIFs), which increase transcription of the VEGF gene [37-40]. In addition, hypoxia also upregulates VEGF levels by stabilizing VEGF messenger RNA [41], as well as through multiple mechanisms not involving HIF [42]. (See "Regulation of erythropoiesis", section on 'Hypoxia-inducible factor and the response to hypoxia'.)
Cytokines such as epidermal growth factor (EGF) and transforming growth factor beta (TGF-beta) and other influences (eg, p53 expression) may also increase VEGF expression by a number of different mechanisms [43-47]. Conversely, the antiangiogenic (and antitumor) properties of interferon alfa may be mediated, at least in part, by inhibition of VEGF gene transcription [48-50].
VEGF receptors — VEGFs mediate angiogenic signals to the vascular endothelium via high affinity receptor tyrosine kinases, designated VEGFR-1 (Flt1), VEGFR-2 (Flk1/KDR), and VEGFR-3 (Flt4). These receptors, which are expressed almost exclusively on endothelial cells, are characterized by seven immunoglobulin-like domains in their extracellular region, a single transmembrane domain, and an intracellular tyrosine kinase domain [51].
Neuropilin-1, a cell surface glycoprotein originally implicated as a semaphorin receptor controlling developmental axon guidance, also functions as a nonclassical VEGF receptor [52]. It binds to exon 7 of the splice variant VEGF165 as opposed to the more N-terminal motifs of VEGF recognized by the classical VEGF receptors Flk1 and Flt1. Neuropilin-1 has been proposed to function as a co-receptor for VEGFR-2 capable of enhancing the biological effect of VEGF165 on endothelial cells; a related receptor, Neuropilin-2, has also been described [53].
VEGF in malignancy — The action of VEGF-A, as well as other related family members, likely underlies the highly permeable and haphazard architecture of tumor vasculature relative to normal capillaries. VEGF-A mRNA and protein are markedly upregulated in the vast majority of human tumors. VEGF-A in tumors can be produced by tumor cells, stroma, and endothelial cells, consistent with autocrine and paracrine modes of action [54,55]. In some tumors, VEGF-A overexpression is associated with poor prognosis and reduced survival. (See "Molecular pathogenesis of diffuse gliomas", section on 'Angiogenesis'.)
Receptors for VEGF (VEGFRs) are expressed on both tumor endothelium and tumor cells, and VEGFR-2 is upregulated in tumor versus normal endothelium. This pleiotropic expression may contribute to cross-talk of VEGF signaling in tumors.
VEGF in ocular disease — VEGF also plays a major role in the pathogenesis of several prevalent ocular disorders. In exudative ("wet") age-related macular degeneration (AMD), excessive VEGF-driven angiogenesis occurs in the subretinal space, where it can cause edema and/or hemorrhage. VEGF may also facilitate neovascularization in diabetic retinopathy. (See "Diabetic retinopathy: Pathogenesis", section on 'Growth factors' and "Age-related macular degeneration".)
ANTIANGIOGENIC THERAPY OF CANCER
The angiogenic switch — Angiogenesis is a rate-limiting step for numerous pathologic processes, including cancer growth [25]. The concept of an "angiogenic switch" has been proposed, whereby, as the tumor grows and cells in the center of the tumor become hypoxic, the tumor initiates recruitment of its own blood supply, by shifting the balance between angiogenesis inhibitors and stimulators towards the latter [56,57]. Thus, neovascularization both precedes and is necessary for tumor progression and metastasis [58,59].
Mechanistically, the development of tumor blood vasculature is complex, involving the growth of blood vessels into initially avascular tumor masses [27-30], early co-option of vasculature from neighboring tissue [60], as well as a contribution from circulating endothelial stem cells [61,62]. Given the therapeutic potential of angiogenesis blockade, significant efforts have been devoted towards understanding the molecular mechanisms underlying these events [63-66].
The hypothesis that cancer growth is angiogenesis-dependent has been repeatedly affirmed by experimental treatment of tumors with angiogenesis inhibitors [67,68]:
●Striking inhibition of tumor growth in experimental animals can be achieved by selective inhibition of VEGF via anti-VEGF monoclonal antibodies (MoAbs), VEGF receptor small molecule kinase inhibitors or MoAbs, or soluble VEGF receptors [69-73].
●An alternative but indirect approach is to inhibit one or more of the molecules that stimulate VEGF expression (eg, EGF and its receptor, platelet-derived growth factor [PDGF] and its receptor, HIFs, cyclooxygenase-2 [COX-2] inhibitors, and IL-1beta) [74-78].
●The administration of endogenous inhibitors of angiogenesis (eg, endostatin, angiostatin) has also shown efficacy in xenograft models, but clinical validation remains elusive [79-81].
All of these strategies have resulted in inhibition of a wide variety of diverse tumor types, consistent with the concept that tumor growth may be angiogenesis-dependent, regardless of the tissue of origin.
Mechanisms for clinical effects of VEGF inhibition
Inhibition of tumor endothelial proliferation — Classically, the anti-tumor effects of VEGF inhibition have been ascribed to the observed reductions in tumor microvessel density and tumor blood flow. VEGF blockade as monotherapy has been clearly shown to have a direct and rapid antivascular effect in both animal and human tumors [82], presumably through deprivation of tumor vascular supply and inhibition of endothelial proliferation.
In an animal tumor model, inhibition of VEGF receptor signaling caused a loss of 50 to 60 percent of tumor vasculature, although empty sleeves of basement membrane and pericytes were left behind [83]. By seven days after drug withdrawal, the tumors were again fully vascularized. These results suggest that the empty sleeves of basement membrane and accompanying pericytes can provide a scaffold for rapid regrowth of tumor vasculature after removal of anti-VEGF therapy they also highlight the importance of pericytes and basement membrane components as potential additional targets. (See 'Vascular disrupting agents' below.)
However, in a retrospective analysis of five randomized, placebo-controlled phase III trials in patients receiving the VEGF-blocking monoclonal antibody bevacizumab for breast, colorectal, renal, or pancreatic cancer, similar patterns of disease progression and mortality rates were seen following discontinuation of bevacizumab or placebo [84].
Vascular normalization — An alternative hypothesis for the anti-tumor effects of VEGF-A has emerged with the observation that, with the notable exception of renal cell carcinoma, bevacizumab appears more efficacious in concert with chemotherapy than as monotherapy [85]. It has been proposed that VEGF blockade results in a temporary and paradoxical "normalization" of tumor vasculature, with selective pruning of poorly formed vessels and a resulting temporary improvement of blood flow and oxygen delivery to the tumor, which in turn enhances chemotherapy delivery [86,87].
Inhibition of VEGF-A and its activity as a vascular permeability factor is postulated to reduce vessel leakiness and thus tumor interstitial pressure. The net effect of improved tumor blood flow and reduced tumor interstitial pressure is enhanced delivery of chemotherapeutic agents to the tumor cells. It is possible that this mechanism predominates at intermediate levels of VEGF inhibition, while more classical antiangiogenic mechanisms may predominate at higher levels of VEGF inhibition.
Reduction of edema — In brain tumors such as glioblastoma, vessel leak with subsequent edema can elevate intracranial pressures to dangerous levels, causing damage to the brain by herniation and significantly increasing patient mortality. Treatment of brain tumors with bevacizumab clearly reduces vascular leak and edema in patients with glioblastoma, as indicated by strong reductions in the extravasated gadolinium signal on MRI, which can be accompanied by improved neurologic status. Such MRI findings actually overestimate the reduction in tumor vascularity from VEGF inhibitors, since comparatively smaller reductions in vascular content are measured when larger intravascular tracers such as iron-based nanoparticles are used for imaging.
Potential resistance to antiangiogenic agents — The addition of angiogenesis inhibitors to cytotoxic chemotherapy often does not prolong survival of cancer patients for more than a few months, possibly because the tumors elicit evasive resistance or adaptation to these agents. Preclinical data have raised the possibility that angiogenesis inhibitors might in fact reduce primary tumor growth while at the same time inducing tumor adaptation, invasiveness and metastatic behavior [88-91]. These findings may help to explain the development of resistance to these agents, but equivalent effects in humans have not been demonstrated, and thus their relevance to clinical use of angiogenesis inhibitors in patients with cancer is unknown [92]. Tumor production of alternative angiogenic factors, such as FGF and HGF, may help underlie clinical resistance to VEGF inhibition.
Biomarkers of angiogenesis — The search for biomarkers of angiogenesis and antiangiogenesis and their successful use in the development of angiogenesis inhibitor therapy is an ongoing challenge [93,94]. However, no validated biomarkers are currently available for routine clinical use to guide patient selection for antiangiogenic treatment [95].
APPROACHES TO BLOCKING VEGF FUNCTION
Anti-VEGF antibodies — Antibodies that bind to and neutralize VEGF have been employed to decrease VEGF signaling in patients with malignancy [96]. The most information is available on the anti-VEGF monoclonal antibody bevacizumab.
Bevacizumab is a humanized monoclonal antibody directed against VEGF that recognizes all isoforms of VEGF-A. A notable property is its extremely long circulating half-life of 17 to 21 days after IV infusion, which easily exceeds that of small molecule VEGF inhibitors. Bevacizumab is taken up by platelets in patients receiving this agent, resulting in virtually complete neutralization of platelet VEGF [97].
Based on its efficacy in advanced colorectal cancer, bevacizumab became the first angiogenesis inhibitor approved for treatment of cancer in the United States. Encouraging results have also emerged from clinical trials in other solid tumors. However, biomarkers that reliably predict for the clinical efficacy of this agent in cancer patients have not yet been identified [98].
The clinical efficacy of adding bevacizumab to chemotherapy for the treatment of various solid tumors (eg, cervical cancer, ovarian cancer, renal cell cancer, colorectal cancer, glioblastoma) is discussed separately. (See "Management of recurrent or metastatic cervical cancer", section on 'Initial treatment' and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Angiogenesis inhibition' and "Overview of the treatment of renal cell carcinoma", section on 'Antiangiogenic (VEGF pathway)' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Efficacy and toxicity of bevacizumab and biosimilars' and "Management of recurrent high-grade gliomas", section on 'Bevacizumab' and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Limited role of bevacizumab'.)
The clinical efficacy of Fab fragments of bevacizumab (ie, ranibizumab) for the treatment of wet age-related macular degeneration (wAMD), macular edema following retinal vein occlusion (RVO), and diabetic macular edema (DME) is discussed separately. (See "Retinal vein occlusion: Treatment", section on 'Vascular endothelial growth factor inhibitors' and "Diabetic retinopathy: Prevention and treatment", section on 'Anti-VEGF agents'.)
Bevacizumab is associated with several toxicities, some serious. Most of these are related to its effects on the systemic (ie, non-tumor) vasculature. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
Soluble VEGF 'decoy' receptors — Soluble "decoy" receptors consisting of native VEGFR sequences can bind to VEGF and prevent its interaction with VEGFRs on tumor or endothelial cells [99,100]. Aflibercept is an intravenously administered recombinant fusion protein that contains the VEGF-binding domains of VEGFR1 and VEGFR2 fused to the Fc domain of human IgG1, and functions as a soluble decoy receptor for VEGF. Aflibercept inactivates multiple members of the VEGF family including VEGF-A, VEGF-B, and PlGF by preventing binding to their receptors [60]. Aflibercept has potentially higher affinity for VEGF-A when compared with anti-VEGF monoclonal antibodies.
The clinical efficacy of adding aflibercept to chemotherapy for the treatment of colon cancer or as monotherapy for wet age-related macular edema is discussed separately. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Role of aflibercept'.)
Anti-VEGF receptor antibodies — Antibodies that target the cell surface receptor for VEGF (VEGFR) can also block VEGF signaling.
Ramucirumab is a promising monoclonal antibody directed against the VEGF receptor 2 (VEGFR2) that is being tested in a variety of malignancies [101]. Efficacy data and use of this agent in specific malignancies are discussed separately:
●Gastric – (See "Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer", section on 'Treatments targeting VEGF'.)
●Colorectal – (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Ramucirumab'.)
Prescribing information for ramucirumab includes a Boxed Warning regarding an increased risk of hemorrhage, which may be severe or fatal. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Bleeding'.)
Bispecific antibodies — Bispecific (also called bifunctional) antibodies are monoclonal antibodies generated in such a way that their two valences (heavy-light chain complementarity-determining regions) bind to two different antigens. (See "Overview of therapeutic monoclonal antibodies", section on 'Bifunctional antibodies'.)
RG7716 is a bispecific antibody directed against VEGF and angiopoietin-2 (Ang-2) that is able to inactivate both VEGF and Ang-2 simultaneously. It is under evaluation for the treatment of diabetic macular edema (DME) and neovascular age-related macular degeneration (AMD) in preclinical models and early clinical trials [102,103].
SMALL MOLECULE TYROSINE KINASE INHIBITORS — In general, small molecule tyrosine kinase inhibitors (TKIs) have demonstrated promising antitumor activity in a variety of malignancies. Unlike monoclonal antibodies, TKIs have the advantage of oral bioavailability. They are also characterized by somewhat promiscuous activity (ie, not confined to VEGF receptors), inhibiting other tyrosine receptors and tyrosine kinases involved in tumor growth and angiogenesis. Examples of other tyrosine kinases inhibited by the antiangiogenic TKIs include the following:
●Platelet derived growth factor receptor (PDGFR); PDGF has been implicated in the regulation of endothelial-pericyte interactions
●c-kit receptor; c-kit signaling can influence cell survival, proliferation, and migration
●Epidermal growth factor receptor (EGFR); EGF has angiogenic and mitogenic activity
●Fibroblast growth factor receptor (FGFR); FGF has potent mitogenic activity
●Rearranged during transfection (RET); RET is a tyrosine kinase receptor protooncogene that has roles in cell growth and survival
The broader specificity of TKIs is attributable to the structural similarity of the catalytic ATP-binding site region amongst the tyrosine kinase superfamily. Given that target specificity is not limited to VEGF receptor tyrosine kinases, these are also referred to as multitargeted tyrosine kinase inhibitors or antiangiogenic TKIs.
Such broad-spectrum activity may in fact enhance the action of these compounds relative to monoclonal antibodies, allowing the simultaneous inhibition of multiple signaling pathways contributing to tumor angiogenesis and tumor growth, both within the tumor vasculature and the tumor mass itself. Research to determine these additional mechanisms of TKI effect on tumors is ongoing.
Examples of some of the antiangiogenic TKIs in clinical use and the receptor tyrosine kinases they target include the following:
●Sorafenib inhibits VEGFR2, fms-like tyrosine kinase 3 (FLT3), PDGFR, and fibroblast growth factor receptor (FGFR)-1.
●Sunitinib targets numerous receptors including c-kit, VEGFR1-3, PDGFR-alpha, PDGFR-beta, FLT3, CSF-1R, and REarranged during Transfection (RET).
●Pazopanib targets VEGFR1-3, PDGFR alpha and beta, FGFR1 and 3, c-kit, and other tyrosine kinases.
●Axitinib is a selective VEGFR inhibitor that targets VEGFR1-3.
●Vandetanib targets VEGFR, RET, and EGFR.
●Regorafenib targets VEGFR1-3 in addition to RET, c-kit, PDGFRa and b, FGFR1 and 2, and other membrane-bound and intracellular kinases.
●Lenvatinib targets VEGFRs, RET, and FGFR.
Additional antiangiogenic TKIs are in development. As an example, cediranib targets VEGFR1-3, PDGFR-alpha, PDGFR-beta, FGFR-1, and c-kit.
Relative disadvantages of the small molecule TKIs include somewhat short circulating half-lives requiring daily dosing, relatively low target affinity compared with monoclonal antibodies, and side effect profiles that may reflect the promiscuity of action amongst multiple kinases.
The clinical efficacy of small molecule TKIs is discussed in the sections on treatment for specific tumors:
●Advanced renal cell carcinoma – (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)
●Hepatocellular carcinoma – (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'First-line therapy'.)
●Differentiated thyroid carcinoma (DTC) – (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy", section on 'Initial systemic therapy'.)
●Pancreatic neuroendocrine tumors (PNET) – (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Molecularly targeted therapy'.)
●Gastrointestinal stromal tumor (GIST) – (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)
●Small cell lung cancer – (See "Extensive-stage small cell lung cancer: Initial management".)
OTHER ANTIANGIOGENESIS APPROACHES
Inhibition of hypoxia-inducible factors — The hypoxia-inducible factors (HIFs) are hypoxia-regulated transcription factors that under normoxic conditions undergo rapid degradation via prolyl hydroxylase-dependent hydroxylation, followed by ubiquitination and degradation. However, in hypoxic tissues such as tumors, this hydroxylation does not occur, allowing HIF stabilization and expression of target genes such as VEGF and erythropoietin (EPO). HIF inhibition has thus been proposed as a novel strategy for antiangiogenic therapy by which expression of VEGF and other angiogenic signals could be interrupted [104].
Although HIF stabilization (ie, HIF stimulation) is achievable with small molecule prolyl hydroxylase inhibitors, the opposing process of HIF inhibition has proven relatively intractable to manipulation by conventional pharmacologic means. Promising data have been obtained with small molecule HIF2 inhibitors in renal cell carcinoma preclinical models [105]. Other approaches including EZN-2968, a locked nucleic acid antisense oligonucleotide targeting the HIF-1a transcript, appear intriguing [106-108].
Conversely, animal models predict that specific inhibition of a prolyl hydroxylase could induce HIF stabilization, which could paradoxically normalize the endothelial lining and induce vessel maturation, resulting in improved tumor perfusion and oxygenation with inhibition of tumor cell invasion, intravasation (ie, tumor cell invasion into blood vessels or lymphatics), and metastasis [109].
Delta-like 4/Jagged/Notch — Notch proteins are large transmembrane receptors that interact with Jagged and Delta-like ligands that are themselves transmembrane proteins. Intriguingly, the action of the transmembrane receptor Delta-like 4 (DLL4) via its interaction with ligands of the Notch family appears to regulate angiogenesis. Embryonic deletion of one copy of the Delta-like 4 locus results in embryonic lethality in the heterozygous state from vascular defects.
Pharmacologic inhibition of DLL4 during postnatal retinal angiogenesis or tumor angiogenesis is accompanied by marked vascular hyperproliferation. Paradoxically, these excessive blood vessels are not patent, producing a decrease in perfusion overall and a net antiangiogenic effect [110,111]. Vascular hyperproliferation has been noted upon DLL4 inhibition in normal mice as well [112]. The anti-DLL4 antibodies demcizumab and enoticumab have been evaluated in limited clinical trials. Inhibition of Notch and Jagged has also been proposed as a potential intervention for antiangiogenic therapy [113].
Immunomodulatory drugs (IMiDs) — Originally marketed as a sedative, thalidomide was found to have severe teratogenicity. However, thalidomide was subsequently shown to have clinical activity in several malignant disorders with abnormal angiogenesis. Thalidomide inhibits FGF-dependent angiogenesis in vivo, but its primary effects appear to be through potent immunomodulation. Analogs of thalidomide (eg, lenalidomide and pomalidomide), also called immunomodulatory drugs (IMiDs), were synthesized by modifying the original thalidomide structure. The activity of the IMiDs appears to depend on cerebron, a protein component of the ubiquitin proteasome pathway [114].
Angiopoietin-Tie2 blockade or activation — Angiopoietins are secreted by perivascular cells to regulate vascular permeability and endothelial cell junction integrity in response to environmental signals such as hypoxia [115]. There are four members of the angiopoietin family (encoded by the ANGPT1-4 genes).
The angiopoietin receptor (known as TEK or Tie2) is a receptor tyrosine kinase expressed primarily on endothelial cells. Angiopoietin-1 (Ang-1, encoded by ANGPT1) is a Tie2 agonist. Angiopoietin-2 (Ang-2, encoded by ANGPT2) typically antagonizes Ang-1 and can have agonistic functions during inflammation. Tie2 is negatively regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP). A related tyrosine kinase, Tie1, heterodimerizes with Tie2 to mediate signaling.
In addition to regulating angiogenesis and vascular permeability, the angiopoietin-Tie2 system regulates lymphatic functions during embryogenesis. Ang-2 is also upregulated in numerous malignancies. Blockade of Ang-2 appears much more effective than blockade of Ang-1 in decreasing tumor angiogenesis and growth in preclinical cancer models [116]. (See 'Regulation of angiogenesis' above.)
A number of therapeutics that target the angiopoietin-Tie2 interaction are under investigation in clinical trials in cancer and ophthalmologic (macular) disorders. Examples include the following [115-118]:
●The peptibody AMG386
●The anti-Ang-2 monoclonal antibody REGN910
●The Anti-VEGF/Ang-2 bispecific antibody RG7716
Vascular disrupting agents — An alternative or complementary method for attacking tumor growth and integrity is via agents that directly disrupt existing tumor vessels. Vascular disrupting agents (VDAs) selectively damage the endothelial linings of tumor blood vessels, shutting off blood flow to the tumor, while leaving blood flow to normal tissues relatively intact [3,119-124]. Finding genes that are overexpressed during malignant, but not physiologic, angiogenesis will be critical in this regard [125,126].
TOXICITIES — Antiangiogenic agents have a variety of cardiovascular and noncardiovascular toxicities. Most of the cardiovascular toxicities appear to be related to the effects of these agents on non-tumor vasculature. Some of the toxicities of the tyrosine kinase inhibitors (TKIs) may be related to effects on non-VEGFR tyrosine kinases versus off-target effects.
Toxicities are reviewed in detail in separate topic reviews:
●Cardiovascular – (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
●Noncardiovascular – (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
CLINICAL TRIALS — The National Cancer Institute maintains a website at which updated information on clinical trials of angiogenesis inhibitors can be obtained: www.cancer.gov/clinicaltrials/search.
SUMMARY
●Angiogenesis as a target in cancer – The dependence of tumor growth on new blood vessel formation makes angiogenesis inhibition an attractive approach for treating malignant disease. (See 'Regulation of angiogenesis' above and 'Antiangiogenic therapy of cancer' above.)
●VEGF – Vascular endothelial growth factor (VEGF-A) is the dominant growth factor controlling angiogenesis; neutralizing antibodies against VEGF can be used to decrease VEGF signaling as an antiangiogenic strategy. (See 'Vascular endothelial growth factor' above and 'Anti-VEGF antibodies' above.)
●VEGF receptors – VEGF receptors (VEGFRs) are receptor tyrosine kinases expressed predominantly on endothelial cells that mediate angiogenesis; their pro-angiogenic roles can be inhibited by anti-VEGF and anti-VEGF receptor antibodies, soluble VEGF "decoy" receptors, and small molecule tyrosine kinase inhibitors (TKIs). (See 'Anti-VEGF antibodies' above and 'Soluble VEGF 'decoy' receptors' above and 'Small molecule tyrosine kinase inhibitors' above.)
●VEGF inhibition – Inhibition of VEGF signaling may inhibit tumor growth by preventing endothelial cell proliferation, improving chemotherapy delivery by normalizing tumor vasculature, and reducing tumor edema. (See 'Mechanisms for clinical effects of VEGF inhibition' above.)
●Other approaches – Additional approaches to inhibiting tumor angiogenesis in clinical use (or clinical development) include HIF inhibitors; DLL4 and Tie2/angiopoietin inhibition; vascular-targeting agents; and immunomodulatory drugs (IMiDs). (See 'Other antiangiogenesis approaches' above.)
●Toxicities – Antiangiogenic agents have a variety of cardiovascular and noncardiovascular toxicities. Most of the cardiovascular toxicities appear to be related to the effects of these agents on non-tumor vasculature. Some of the toxicities of the tyrosine kinase inhibitors (TKIs) may be related to off-target effects. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟