Neuro Oncol. Anti-angiogenesis agents evaluated imaging Anti-angoogenesis that commonly used to detect Anti-angiogenesis agents changes in tumor tissue. Paez-Ribes M et al Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.

Anti-angiogenesis agents -

Further studies established that a vascular endothelial growth factor-A VEGF is a key driver of sprouting angiogenesis, b VEGF is overexpressed in most solid cancers, and c inhibition of VEGF can suppress tumour growth in animal models [ 2 — 4 ]. Based on these observations, numerous therapies have been developed that target angiogenesis by blocking the VEGF signalling pathway Fig.

The biology of VEGF signalling, angiogenesis and the principles upon which anti-angiogenic therapy is based have been extensively reviewed [ 2 , 5 — 8 ]. Here we review the progress of VEGF-targeted therapies in the clinic see also Table 1 , discuss the current questions and controversies that exist in the field and propose routes to more effective and personalised anti-angiogenic therapy.

The role of sprouting angiogenesis in tumour growth. Early observations on the growth of tumours supported the following model for how tumours obtain a vascular supply. a When a tumour mass is small, it can obtain oxygen and nutrients from existing local blood vessels.

b As the tumour grows beyond the capacity of local blood vessels, soluble pro-angiogenic factors are released which promote the sprouting of new vessels from local existing blood vessels sprouting angiogenesis. c These vessels provide a blood supply for the tumour and this is required in order for the tumour to grow beyond 2—3 mm in size.

VEGF-targeted agents. The VEGF signalling system in mammals is complex and consists of five related ligands, VEGF-A, VEGF-B, VEGF-C, VEGF-D and PLGF that bind with different specificities to three receptor tyrosine kinases, VEGFR1, VEGFR2 and VEGFR3.

The biology of these interactions has been extensively reviewed [ , ]. Shown is a highly simplified diagram designed to illustrate the three major classes of agent that target this signalling system: a ligand binding agents that block the binding of VEGF ligands to receptors e.

bevacizumab which binds to VEGF-A alone and aflibercept which binds to VEGF-A, VEGF-B and PLGF , b antibodies that block signalling through VEGF receptors e. ramucirumab which binds to VEGFR2 and c tyrosine kinase inhibitors which block the kinase activity of VEGFR1, VEGFR2 and VEGFR3 e.

sorafenib, sunitinib, pazopanib. Note that these tyrosine kinase inhibitors can also can inhibit the kinase activity of some other receptor tyrosine kinases, including platelet derived growth factor receptors PDGFRs , c-Kit and fms-related tyrosine kinase FLT3 [ ]. Since angiogenesis is deemed necessary for the growth of metastases in all sites of the body, it is assumed that anti-angiogenic therapy should be of benefit for patients with metastatic disease.

However, variable results have been obtained across different cancer types, suggesting that whilst the metastases of certain cancers are sensitive to this form of therapy, the metastases of others are not. Tyrosine kinase inhibitors TKIs , designed to inhibit VEGF receptor signalling Fig.

In metastatic renal cell carcinoma mRCC these agents have proven highly successful, with four drugs now FDA approved in this setting, namely sorafenib, sunitinib, pazopanib and axitinib.

Sorafenib was the first TKI to demonstrate activity in mRCC, in a placebo-controlled phase III randomised trial of patients who had progressed on previous cytokine therapy [ 9 ]. Progression free survival PFS was almost doubled 5. A subsequent study comparing single agent sunitinib with interferon-α in mRCC patients that were naïve to treatment demonstrated a significant improvement in PFS in the sunitinib arm 11 vs.

Improvement in OS was observed in the sunitinib arm Single agent pazopanib compared with placebo was subsequently shown to extend PFS in mRCC in the first-line setting A recent phase III trial comparing sunitinib with pazopanib has demonstrated that both drugs have similar efficacy [ 15 ] and single agent therapy with either drug is now recommended as standard of care in the first-line in mRCC.

Axitinib, a more recently developed TKI, has shown efficacy in the second-line setting in patients that progressed on first-line TKI therapy [ 16 ] and is now recommended for mRCC in this setting.

TKIs have also shown single agent activity in advanced hepatocellular carcinoma and advanced pancreatic neuroendocrine tumours PNET. In hepatocellular carcinoma, sorafenib improved OS from 7.

Sunitinib is FDA-approved for the treatment of PNET based on the results of a randomised placebo-controlled study that demonstrated doubling of PFS from 5. Bevacizumab, a humanised monoclonal antibody that binds specifically to VEGF-A alone, has shown efficacy in several indications in the metastatic setting.

The first phase III trial published demonstrating the efficacy of an anti-angiogenic agent in the clinic was in metastatic colorectal cancer mCRC , where the combination of chemotherapy with bevacizumab was shown to result in superior PFS Based on these data, bevacizumab was approved for the treatment of mCRC when given in combination with chemotherapy.

Subsequent phase III studies have also demonstrated a beneficial effect of adding bevacizumab to chemotherapy in mCRC [ 20 — 22 ]. Additional evidence for the efficacy of anti-angiogenic therapy in colorectal cancer comes from a study of aflibercept, a novel fusion protein that binds to three VEGF family ligands: VEGF-A, VEGF-B and placental growth factor PLGF.

Adding aflibercept to chemotherapy was shown to extend PFS and OS compared to chemotherapy alone in metastatic colorectal cancer [ 27 ]. Moreover, a striking separation of the survival curves was observed in this study, with 2-year survival significantly increased in the aflibercept arm compared to the control arm Based on these data, aflibercept was recently approved for the treatment of mCRC when given in combination with chemotherapy.

Curiously, despite the benefit observed when bevacizumab or aflibercept are combined with chemotherapy in mCRC, efforts to combine anti-angiogenic TKIs with chemotherapy in mCRC have so far proven disappointing in terms of improving OS [ 28 — 30 ]. However, single agent treatment with the TKI regorafenib was recently reported to extend OS compared to placebo in mCRC patients who had previously progressed on standard therapies [ 31 ].

Regorafenib is now approved for the treatment of mCRC in this setting. In non-squamous non-small cell lung cancer NSCLC , two phase III trials have shown an improvement in PFS for the addition of bevacizumab to chemotherapy [ 32 — 34 ] although only one study reported an improvement in OS [ 32 ].

In the first-line treatment of ovarian cancer, two pivotal studies ICON-7 and GOG have been reported examining the addition of bevacizumab to chemotherapy [ 36 , 37 ].

Both studies reported a significant improvement in PFS of between 2. OS data were not significant in the GOG study but were confounded due to cross-over and OS data are still awaited for the ICON7 study. However, in ICON7, an improvement in overall survival with bevacizumab was observed in the high-risk group compared to chemotherapy alone In relapsed ovarian cancer, the addition of bevacizumab to chemotherapy has demonstrated a significant improvement in PFS, although this has not translated into an OS benefit [ 38 ].

In contrast to these promising data, there are several notable examples of metastatic cancers where anti-angiogenic agents have consistently failed to make a significant impact on overall survival, including breast, melanoma, pancreatic and prostate.

The history of anti-angiogenic therapy in the treatment of metastatic breast cancer is of significant interest. In , the AVF phase III study demonstrated that the addition of bevacizumab to capecitabine did not result in extension of either PFS or OS in metastatic breast cancer [ 39 ].

However, in , the E phase III study demonstrated that the addition of bevacizumab to paclitaxel resulted in extension of PFS On the basis of these data, the FDA granted the accelerated approval of bevacizumab in combination with paclitaxel for the treatment of HER2-negative metastatic breast cancer.

Three further phase III trials of bevacizumab in combination with chemotherapy in HER2-negative metastatic breast cancer AVADO, RIBBON-1 and RIBBON-2 demonstrated an extension of PFS, but no effect on OS, when compared to chemotherapy alone [ 41 — 43 ]. In , the FDA concluded that the results of these studies failed to provide evidence that bevacizumab could prolong survival in metastatic breast cancer.

As a consequence of this, in the FDA withdrew its approval for bevacizumab in this indication. In addition to this, disappointing results have also been observed with TKIs in breast cancer. Three phase III studies examining the addition of sunitinib to chemotherapy [ 44 — 46 ], and one comparing single agent sunitinib versus chemotherapy [ 47 ], all failed to demonstrate improvement in PFS or OS.

In adenocarcinoma of the pancreas, the addition of bevacizumab to chemotherapy in a phase III randomised trial failed to improve PFS [ 51 ]. In men with castrate-resistant prostate cancer, the addition of bevacizumab [ 52 ], or aflibercept [ 53 ], to chemotherapy have failed to improve OS in comparison to chemotherapy alone.

The precise explanation as to why conventional anti-angiogenic agents show efficacy in some metastatic cancers, and not others, is currently unknown [ 54 ]. Conceivably, important differences in the biology of these cancers may underlie the contrasting results seen with this therapeutic approach across different cancers.

The use of anti-angiogenic agents in the adjuvant setting is based on the principle that, after surgical removal of the primary tumour, inhibition of angiogenesis may prevent local relapse or the growth of micrometastatic tumours.

Two phase III trials in the adjuvant setting NSABP C and AVANT were designed to compare overall survival in colorectal cancer patients treated with chemotherapy alone for 6 months in one arm and chemotherapy plus bevacizumab for 6 months followed by 6 months bevacizumab maintenance therapy in the second arm.

In both trials, an analysis performed after 1 year demonstrated improved PFS in the bevacizumab arm. However, no significant difference in OS was observed between treatment arms when assessed at 3 or 5 years [ 55 — 57 ].

In addition to these data, recently disclosed findings from the BEATRICE trial show that adjuvant bevacizumab failed to improve disease free survival in triple negative breast cancer patients at 3 years [ 58 ].

Given the efficacy demonstrated for bevacizumab in metastatic colorectal cancer, the poor results achieved in the adjuvant setting are clearly disappointing. The results suggest that, even in a disease where anti-angiogenic therapy is shown to be effective in the metastatic setting, the same may not be true when used in the adjuvant setting.

However, this situation is not unique to bevacizumab, because it has been reported for other agents in colorectal cancer. In colorectal cancer, for many years the quest for successful adjuvant therapies has followed a simple and reliable path. Drugs such as 5-FU, oxaliplatin and capecitabine were first shown to be effective in the metastatic setting, which was followed by successful trials in the adjuvant setting [ 59 — 61 ].

However, there are now three notable exceptions that have not followed this path: irinotecan, cetuximab and bevacizumab have all shown efficacy in the metastatic setting, but failed in the adjuvant setting in colorectal cancer [ 56 , 57 , 59 , 62 ].

The reasons that underlie these discrepant results are currently unknown. However, it seems most likely that the biology of micrometastases can be very different to the biology of established metastatic disease and that this has important consequences for therapy response.

Theoretically, there may be several advantages to using anti-angiogenic therapy in the neoadjuvant setting. Firstly, it might be used to downsize a tumour in order to convert a non-resectable lesion to one that is potentially resectable.

Secondly, it might be used to downstage the disease to reduce the chance of local relapse or metastasis. Two large randomised trials recently reported on the efficacy of bevacizumab plus chemotherapy as a neoadjuvant therapy for primary breast cancer compared to neoadjuvant chemotherapy alone [ 63 , 64 ].

Both used pathological complete response pCR as the endpoint. Although a significant increase in the rate of pCR was observed, the absolute increase in response rate was small 3. Moreover, subgroup analysis revealed contradictory findings, with one study reporting greater benefit in women with hormone receptor negative triple negative disease [ 64 ] and the other study suggesting that women with hormone receptor positive cancer were more likely to benefit [ 63 ].

It is as yet unclear whether any survival benefit will be associated with the use of bevacizumab in this setting because there is currently no mature data. In CRC, surgical resection of liver metastases is potentially curative and has significantly improved overall survival in this setting [ 65 ].

Although only a fraction of patients are resectable at presentation the use of neoadjuvant chemotherapy to convert unresectable metastases to potentially resectable metastases has lead to improvements in resection rates and is a recommended practice [ 66 ].

Interestingly, there is evidence to suggest that combination of bevacizumab with chemotherapy may also be an effective conversion therapy for CRC liver metastasis [ 67 — 69 ]. However, a randomised trial directly comparing the efficacy of chemotherapy versus chemotherapy combined with an anti-angiogenic agent has not been undertaken in this setting.

In most settings, with the exception of ovarian cancer where single agent activity for bevacizumab has been observed [ 70 ], anti-angiogenic agents such as bevacizumab and aflibercept have only shown significant activity when they are combined with cytotoxic chemotherapy [ 19 , 27 ].

How can this be explained? Preclinical studies showed that suppression of VEGF signalling can lead to improvements in tumour vessel function vascular normalisation , and in turn, this was proposed to mediate increased delivery of chemotherapy to tumours [ 71 , 72 ].

However, the clinical relevance of this phenomenon for chemotherapy delivery in patients is still unclear. For example, the addition of bevacizumab to chemotherapy would be expected to lead to improvements across the board in all settings, but this is not the case.

Moreover, a recent study reported the opposite relationship i. bevacizumab led to a sustained decrease in the delivery of chemotherapy in NSCLC patients [ 73 ].

At this point it should be noted that pharmacological induction of vessel normalisation may have additional therapeutic effects in cancer beyond control of chemotherapy delivery.

For example, in glioblastoma patients, vessel normalisation induced by VEGF-targeted therapy may prolong survival due to alternative mechanisms involving oedema control or improved tumour oxygenation [ 74 , 75 ].

Despite these facts, it is still not clear why agents like bevacizumab and aflibercept show greater activity when they are combined with chemotherapy. Any number of alternative mechanisms could underlie this activity. For example, an alternative explanation is that anti-angiogenic drugs prevent the rebound in tumour growth that may occur during breaks in chemotherapy [ 76 ] or counteract the ability of chemotherapy to promote tumour invasion [ 77 ].

Importantly, in contrast to bevacizumab, TKIs generally show single agent activity and so any mechanistic explanation for the synergy between VEGF-targeted agents and chemotherapy must account for this unexplained dichotomy. A recent study, which examined data from both clinical samples and preclinical models, provided intriguing evidence that this dichotomy may stem from intrinsic differences in the stromal component of different cancers [ 78 ].

They provided evidence that, in cancers that are more responsive to bevacizumab when it is combined with chemotherapy e. mCRC, NSCLC , the vasculature has a stromal-vessel phenotype, where the vessels are surrounded by a well-developed stroma.

In contrast, cancers that are responsive to single agent TKIs e. mRCC, PNET have a tumour-vessel phenotype, where the vessels sit closer to the tumour cells without a well-developed intervening stromal component. Although the molecular mechanisms were not uncovered, these data do suggest that an interaction between multiple stromal components influences the response to anti-angiogenic therapy.

Therefore, our understanding of why TKIs work as single agents and why VEGF-targeted agents synergise with chemotherapy in patients is still incomplete.

A further unresolved question is whether certain types of chemotherapy may work better with bevacizumab than others. Several on-going phase III studies in advanced breast cancer will address the efficacy of bevacizumab when combined with different chemotherapies or with other targeted agents [ 79 , 80 ].

However, further studies that elaborate on the mechanistic basis for the interaction of chemotherapy with VEGF-targeted therapies are urgently needed. It was assumed that because angiogenesis is a relatively rare process in the adult, VEGF-targeted therapies would be toxicity free.

However, clinical experience reveals a number of adverse events associated with these agents, including hypertension, proteinuria, impaired wound healing, gastrointestinal perforation, haemorrhage, thrombosis, reversible posterior leukoencephalopathy, cardiac toxicity and endocrine dysfunction, which have been extensively reviewed [ 81 , 82 ].

Although some of these side effects can be managed in a routine fashion, excessive toxicity may necessitate the use of treatment breaks, dose reductions or even treatment cessation, which may limit therapeutic efficacy.

However, it has also been proposed that certain side effects could be used as a predictive biomarker for efficacy. It has been suggested that, if this association can be validated prospectively, then assessment of hypertension early in treatment might be used to stratify patients likely to benefit from anti-angiogenic therapy versus those that might be transferred to an alternative therapy.

Preclinical and clinical work shows that when VEGF-targeted therapy is discontinued, the tumour vasculature can become rapidly re-established [ 87 , 88 ].

Conceivably, this could lead to tumour re-growth when therapy is withdrawn. Indeed, there are reports of tumour re-growth during planned treatment breaks in anti-angiogenic therapy [ 89 , 90 ].

These data suggest that prolonged use of VEGF-targeted therapy may be necessary to achieve maximal therapeutic benefit. In support of this, an observational study, which analysed data from 1, patients treated with bevacizumab, showed that continuation of bevacizumab treatment beyond progression was indeed associated with greater benefit in terms of overall survival [ 91 ].

This observation was recently validated prospectively in mCRC in the ML18 trial [ 92 ]. Another interesting observation is that acquired resistance to anti-angiogenic therapy may in some cases be a transient phenomenon.

Following the development of resistance to one VEGF-targeted agent, mRCC patients have been transferred to a second course of VEGF-targeted therapy.

Surprisingly, a proportion of these re-challenged patients respond again to therapy [ 93 — 95 ]. Moreover, the benefit that is achieved upon re-challenge can be proportional to the length of time that elapses between therapy [ 96 ]. These data suggest that resistance to VEGF-targeted therapy can sometimes be a reversible phenomenon [ 97 ].

There are some interesting parallels between these data and preclinical studies also showing that resistance to VEGF-targeted therapy can be reversible [ 98 , 99 ]. However, this idea has yet to be formally proved in the clinic.

Given the variable results obtained with anti-angiogenic agents in the clinic, there is a need to distinguish which patients are likely to benefit from this form of therapy from those patients that will not.

This entails the development of predictive biomarkers that are capable of predicting response or outcome [ — ]. However, despite intensive efforts, there are currently no validated biomarkers for selecting these patients.

Many types of predictive biomarkers have been investigated, including hypertension, circulating markers, germline single nucleotide polymorphisms SNPs , in situ markers in tumour material and functional imaging.

This area has been extensively reviewed [ , ] and we will cover here only some recent developments in circulating markers, SNPs and imaging. Historically speaking, studies examining baseline-circulating levels of angiogenesis-related factors, such as VEGF, have yielded disappointing and contradictory findings, often providing prognostic rather than predictive information [ 10 , — ].

However, recent studies, based on prospective, robust sample sets collected within clinical trials are now starting to show more consistent results. For example, a correlation between high circulating levels of VEGF-A and survival benefit in metastatic breast and gastric cancer patients treated with bevacizumab has been reported [ — ].

A large phase III trial MERiDIAN will prospectively test the utility of high circulating VEGF-A levels as a potential biomarker of response to bevacizumab in HER2-negative metastatic breast cancer [ ]. Biomarker signatures, composed of multiple circulating factors, may also have potential value as predictive biomarkers.

In pazopanib-treated mRCC patients for example, circulating levels of six serum cytokines and angiogenesis factors CAF HGF, interleukin 6, interleukin 8, osteopontin, VEGF, and TIMP1 were able to identify a sub-set of patients that derived significantly greater overall survival benefit from treatment [ ].

Moreover, a serum-based protein signature composed of mesothelin, FLT4, AGP and CA has recently been shown to identify patients with ovarian cancer more likely to benefit from bevacizumab [ ]. However, there are several challenges associated with taking circulating factors forward as a prospective marker.

Firstly, measurement of circulating markers can be difficult to standardise across centres, due to technical issues associated with sample handling [ ]. Secondly, deciding on a predefined cut-off for high versus low levels of circulating factors is challenging because it may vary with geography and disease setting [ ].

Baseline predictive markers that are binary in nature i. a mutation or gene amplification are attractive because they may be easier to measure and apply prospectively than biomarkers based on the measurement of circulating factors.

A large study that examined data from two phase III trials of bevacizumab in metastatic pancreatic adenocarcinoma AViTA and mRCC AVOREN recently reported that a SNP in VEGFR1 was significantly associated with poor outcome in patients treated with bevacizumab [ ].

The same SNP has subsequently been associated with poor outcome in mRCC patients treated with sunitinib [ ]. Fine mapping of this SNP to tyrosine 1, of VEGFR1 shows that mutation at this site leads to increased expression and signalling of VEGFR1, providing a plausible explanation as to why VEGF-targeted therapy is less effective in patients bearing this SNP [ ].

Therefore, this work identifies a negative biomarker that might be used prospectively to exclude patients who are less likely to benefit from VEGF-targeted therapy. Functional imaging of the tumour vasculature, using CT, MRI or PET, is a potentially attractive approach for predicting response and outcome, as reviewed in [ ].

Imaging permits inspection of various parameters, such as tumour morphology and blood flow, which may provide important predictive information.

There are studies showing that baseline features of tumours, such as the level of vascular perfusion, can predict response or outcome in patients treated with anti-angiogenic agents. For example, at least 4 published studies demonstrate that a high level of vascular perfusion predicts for response or outcome in mRCC patients treated with TKIs [ — ].

Early changes in vascular characteristics detected on imaging after the initiation of therapy have also been shown to correlate with response or outcome.

For example, many studies performed in mRCC patients treated with TKIs show that a reduction in vascular perfusion on therapy provides extra predictive information regarding response or outcome than using criteria based on change in lesion size alone [ , — ]. Moreover, in patients with colorectal liver metastases treated with bevacizumab and chemotherapy, changes in tumour morphology on CT were shown to associate more significantly with overall survival than the use of RECIST criteria [ ].

Although these studies suggest a promising role for imaging as a predictive marker in certain settings, many challenges remain.

For example, we have an incomplete understanding of how features detected on imaging correlate with the underlying tumour biology [ ]. Also, methodologies used to assess imaging biomarkers vary considerably between studies and require standardisation for their prospective application across multiple study centres [ ].

Therefore, biomarkers that predict response or outcome for VEGF-targeted therapy are emerging, but they require further standardisation and validation before they are incorporated into clinical practice. Resistance to anti-angiogenic therapy is a prominent issue that likely explains the variable results obtained in the clinic with this approach.

Resistance can broadly be classified into intrinsic resistance where tumours fail to respond from the outset of treatment and acquired resistance where tumours initially respond and then progress whilst still on treatment [ ].

Since anti-angiogenic therapy targets tumour cells indirectly by acting on tumour blood vessels, mechanisms that determine response and resistance are likely to stem from a complex interaction between tumour cells and stroma. Insight into this tumour-stromal relationship in the setting of intrinsic resistance can be gained from studies in mRCC patients, which examined both change in tumour blood flow and change in lesion size in clinically detectable tumours upon treatment with single agent anti-angiogenic therapy [ — ].

In some cases, a strong vascular response may be observed, which is accompanied by significant tumour shrinkage Fig. Tumours undergoing this type of response probably fulfil two important conditions: a the growth and survival of the vasculature is very sensitive to the agent, and b tumour cell survival is highly dependent on the vascular supply.

In the second instance, despite a strong vascular response, tumour growth is only stabilised Fig. In this scenario, tumour cells may be adapted to survive, despite a reduction in vascular supply. In the third instance, the targeted agent results in minimal or insignificant suppression of the tumour vascular supply, resulting in stabilisation of disease or tumour progression Fig.

In this scenario, the growth and survival of the vasculature is apparently poorly sensitive to the agent. Response and resistance to anti-angiogenic therapy. Tumours may respond initially to anti-angiogenic therapy in different ways. a Therapy results in a strong vascular response a significant reduction in the amount of perfused tumour vessels and significant tumour shrinkage.

b Therapy results in a strong vascular response, but only stabilisation of disease is achieved. c Therapy results in a poor vascular response minimal reduction in the amount of perfused tumour vessels and tumour stabilises or progresses.

d , e After a period of response, acquired resistance can occur. This may be due to the activation of alternative angiogenic pathways d or because tumour cells adapt to the lack of a vascular supply via various potential mechanisms e.

Longitudinal assessment of mRCC patients treated with these agents demonstrates that acquired resistance to therapy can also arise following a period of initial disease control [ — ]. Acquired resistance may conceivably occur because the tumour finds alternative means to drive tumour vascularisation which are insensitive to the therapy Fig 3 d or because tumour cells become adapted so that they can grow despite the reduced vascular supply Fig 3 e [ ].

Evidence for specific cellular and molecular mechanisms that may underlie intrinsic or acquired resistance to anti-angiogenic therapy are discussed below. The tumour vasculature is heterogeneous with respect to its response to anti-angiogenic therapy, with some vessels being sensitive whilst others are resistant Fig.

In preclinical studies, VEGF-targeted therapy suppresses the growth of newly formed tumour vessels, but is less effective against more established tumour vasculature [ — ]. One aspect of vessel maturation is the recruitment of pericytes to tumour vessels, mediated by platelet-derived growth factors PDGFs.

It has been demonstrated that inhibition of PDGF-mediated pericyte recruitment improves the efficacy of VEGF-targeted therapy [ , ]. Of interest, many clinically approved anti-angiogenic TKIs are potent inhibitors of both VEGF and PDGF receptors e.

sunitinib, sorafenib, pazopanib and may therefore target pericyte recruitment. However, paradoxically, in xenograft models TKIs have been shown to result in either decreased or increased pericyte coverage, dependent on the study [ — ].

Therefore, whilst mature tumour vessels may be resistant to VEGF-targeted therapy, it is not currently clear how these tumour vessels can be effectively targeted. Potential mechanisms involved in resistance to VEGF-targeted therapy. a Tumours present with a mixture of therapy-sensitive and therapy-insensitive vessels.

The top vessel is destroyed by the therapy depicted in grey , whilst the bottom one remains depicted in red. b Alternative signalling pathways can regulate the sensitivity of vessels to therapy. In the panel, the tumour cells in blue have up-regulated an alternative pro-angiogenic growth factor in order to drive blood vessel growth and survival.

c Stromal cells, such as immature myeloid cells black or fibroblasts green infiltrate the tumour and mediate resistance either by releasing pro-angiogenic growth factors or by physically incorporating into vessels.

d Tumour cells can survive conditions of stress. Some tumour cells depicted in blue have survived the loss of a vascular supply, because they are adapted to survive conditions of hypoxia or nutrient shortage. e Tumours may use alternative mechanisms of vascularisation besides sprouting angiogenesis.

In intussusceptive microvascular growth new vessels are generated by the fission of existing vessels. Glomeruloid angiogenesis is characterised by tight nests of vessels that resmemble the renal glomerulus. In vasculogenic mimicry, tumour cells directly form vascular channels blue cells that are perfused via connection to the host vasculature red cells.

In looping angiogenesis, contractile myofibroblasts green pull host vessels out of the normal surrounding tissue pink region. In vessel co-option tumour cells engulf host vessels in the normal surrounding tissue pink region as the tumour invades.

f Increased tumour aggressiveness i. Other pro-angiogenic signalling pathways can stimulate blood vessel growth and blood vessel survival even when the VEGF-pathway is blocked Fig.

Pre-clinical studies have identified numerous candidates including angiopoietins [ ], Bv8; Bombina variagata peptide 8 [ ], EGF; epidermal growth factor [ ], the Delta-Notch pathway [ ], FGF1 and FGF2; fibroblast growth factors 1 and 2 [ , ], HGF; hepatocyte growth factor [ ], IL-8; interleukin 8, [ ], PDGF-C; platelet derived growth factor-C [ , ] and PLGF; placental growth factor [ 26 ].

Most of these studies also show that co-targeting of VEGF and the candidate factor improves therapeutic response. Therefore, therapies that target signalling by multiple pro-angiogenic growth factors may be necessary to achieve efficient and durable suppression of tumour angiogenesis and tumour growth.

There is also clinical evidence showing that circulating levels of certain pro-angiogenic factors, including FGF2, HGF, PLGF and SDF-1α can become elevated in patients just prior to progression on anti-angiogenic therapy, providing potential evidence that these factors are indeed related to the development of acquired resistance [ , ].

However, the concept that these alternative growth factor and cytokine signalling pathways mediate resistance to anti-angiogenic therapy has yet to be truly validated clinically. The majority of TKIs used to treat patients including brivanib, cediranib, dovitinib, sunitinib, sorafenib, vatalanib and many others are multitargeted in nature and can suppress the signalling of multiple pro-angiogenic signalling pathways, including VEGF, FGF and PDGF.

And yet, despite this, tumours have been shown to progress through treatment with these agents in many indications, including metastatic breast cancer [ 44 — 47 ], glioblastoma [ 75 ], hepatocellular carcinoma [ , ] and mRCC [ ].

This is in contrast to preclinical studies demonstrating a role for alternative growth factor signalling pathways and questions the relevance of alternative pro-angiogenic growth factors in mediating resistance to anti-angiogenic therapy in patients.

It is now well established that tumours are a community composed of both transformed tumour cells and distinct stromal cell types. These stromal cells include fibroblasts and many different kinds of immune cell such as lymphocytes, granulocytes and macrophages as well as the cells that make up the vasculature endothelial cells and pericytes.

The roles played by these different stromal cell types in tumour progression have been extensively reviewed [ — ]. Importantly, the tumour stroma can promote tumour progression and therapy resistance, including resistance to anti-angiogenic therapies [ — ].

Preclinical studies have demonstrated that infiltration of tumours by various stromal cell types, including immature myeloid cells [ , ], endothelial progenitor cells [ ] or fibroblasts [ ] can all mediate resistance to VEGF-targeted agents in preclinical models Fig.

Alternatively, there is evidence that immature myeloid cells and endothelial progenitor cells may promote resistance to therapy by physically incorporating into tumour vessels [ — ]. Inhibition of tumour vascularisation should reduce the supply of oxygen and nutrients to tumours and slow tumour growth.

However, preclinical work shows that tumour cells can be adapted to survive, even when the vascular supply is significantly reduced. These survival mechanisms include a reduced propensity for certain tumour cells to die under conditions of stress and may be driven by genetic aberrations such as loss of p53 function [ , ].

Tumours treated with anti-angiogenic agents may also adapt to survive under conditions of nutrient withdrawal and hypoxia, by adapting their metabolism or through autophagy [ , — ].

Pre-adaptation or reactive adaptation to stress may therefore play a key role in determining whether tumours respond to VEGF-targeted therapies Fig.

Despite a prevailing dogma that tumours utilise mainly VEGF-dependent sprouting angiogenesis Fig. IMG is a process that generates two new vessels via the fission of an existing vessel Fig. It has been observed in human primary melanoma and glioblastoma [ , ].

Glomeruloid angiogenesis results in tight nests of tumour vessels known as a glomeruloid bodies Fig. Glomeruloid bodies have been reported in a wide range of malignancies, including glioblastoma, melanoma, breast, endometrial and prostate cancer [ ].

In vasculogenic mimicry, tumour cells organise into vessel-like structures that are perfused via connection to the host vasculature Fig.

It has been reported in many human cancers, including melanoma, breast, ovarian, prostate and sarcoma [ ]. Recent pre-clinical studies suggest that tumour stem cells can directly differentiate into endothelial cells or pericytes, which may be a mechanism for vasculogenic mimicry [ — ].

In looping angiogenesis, vessels are extracted from normal surrounding tissue by the action of contractile myofibroblasts [ ] Fig. Although only well-characterised in wound healing, tumours might conceivably also utilise looping angiogenesis [ ].

In vessel co-option, tumours recruit existing local blood vessels as they invade into surrounding host tissue Fig. Analysis of human cancers reveals vessel co-option in glioblastoma [ , ], adenocarcinoma of the lung [ , ] cutaneous melanoma [ ], lung metastases of breast and renal cancer [ — ], liver metastases of colorectal and breast cancer [ , ] and brain metastases of lung and breast cancer [ ].

Importantly, these alternative mechanisms of angiogenesis may be VEGF-independent and therefore capable of mediating tumour vascularisation despite VEGF-inhibition.

For example, intussusceptive microvascular growth was demonstrated as a mechanism via which tumours can escape the effects of TKIs in a preclinical model of mammary carcinoma [ ].

Moreover, preclinical and clinical data show that tumours in the brain can become more infiltrative when the VEGF pathway is inhibited, which may facilitate vessel co-option [ 54 , , , — ].

However, despite these data, we have very little understanding of the molecular mechanisms that control these alternative mechanisms of tumour vascularisation. Some pre-clinical studies report that VEGF-targeted therapy can promote increased tumour invasion and metastasis Fig.

Paez-ribes et al. However, the treated tumours became more invasive and showed an increased incidence of liver and lung metastasis, compared to vehicle controls. Ebos et al.

mammary fat pad or skin, respectively. However, administration of sunitinib either prior to, or after, resection of the primary tumour increased the incidence of metastasis and led to a shortening of overall survival, compared to vehicle controls [ ].

In the same study, treatment of mice with sunitinib prior to, or after, intravenous injection of tumour cells also promoted the growth of metastases and shortened overall survival, compared to vehicle controls [ ]. These data imply that VEGF-targeted therapies could accelerate tumour progression when used in the metastatic, adjuvant or neoadjuvant setting.

Although these results are alarming, follow-up pre-clinical studies from other laboratories challenge some of these findings [ , , ]. Chung et al. However, they did observe increased invasion and metastasis in a GEMM of PNET treated with sunitinib [ ].

Two further studies examined more closely the ability of sunitinib to accelerate metastasis in mice. Both Welti et al. In addition, Welti et al. Is there evidence that anti-angiogenic therapy can promote tumour aggressiveness in patients? A retrospective analysis of mRCC patients treated with sunitinib found no evidence of accelerated tumour growth, suggesting that sunitinib does not accelerate tumour growth in advanced renal cancer [ ].

It has been shown that, upon withdrawal of anti-angiogenic therapy, the tumour vasculature can rapidly re-grow [ 87 , 88 ]. Moreover, a recent neoadjuvant study of sunitinib and pazopanib in mRCC demonstrated a paradoxical increase in Ki67 and tumour grade in the primary tumour after treatment [ ].

These findings might provide some clues to the source of the flare-up phenomenon, but the precise mechanisms are as yet unclear. The influence of bevacizumab treatment withdrawal has also been assessed in patients. A retrospective analysis of five large studies which included patients with mRCC, metastatic pancreatic cancer, metastatic breast cancer and metastatic colorectal cancer found no evidence that discontinuation of bevacizumab treatment lead to accelerated disease progression compared to placebo controls [ ].

Some data examining this question in the adjuvant setting are also available. Analysis of the NSABP-C08 trial of adjuvant bevacizumab in colorectal cancer failed to provide evidence for a detrimental effect of exposure to bevacizumab [ 56 ].

However, data from the AVANT trial of adjuvant bevacizumab in colorectal cancer did find evidence that treatment with bevacizumab was associated with a detrimental effect: a higher incidence of relapses and deaths due to disease progression was observed in the bevacizumab treated patients [ 57 ].

It has been proposed that the disappointing results obtained in the adjuvant setting with bevacizumab could be explained by an adverse effect of bevacizumab on tumour biology: increased aggressiveness of the cancer [ 54 ].

There is one setting in which the induction of a more invasive tumour phenotype upon treatment with anti-angiogenic therapy is relatively undisputed. Glioblastomas have been observed to adopt a more infiltrative tumour growth pattern upon treatment with VEGF-targeted therapy [ , , ].

Interestingly, it seems plausible that this invasive process can contribute to resistance to anti-angiogenic therapy by allowing vessel co-option to occur [ ].

In conclusion, there is conflicting evidence for the relevance of increased tumour aggressiveness in response to anti-angiogenic therapy and this persists as a controversial area [ 54 , , ].

However, taken together, the available data suggest that the ability of VEGF-pathway targeted agents to promote tumour aggressiveness is influenced by several factors, including cancer type, the stage of disease being treated neoadjuvant, adjuvant or metastatic the nature of the anti-angiogenic agent administered, the dose of agent that the recipient is exposed to and the physiology of the individual patient.

The mechanisms that underlie the increased invasiveness and increased metastasis observed in some studies of VEGF-targeted therapy are the subject of ongoing investigation.

Several studies have demonstrated that VEGF-targeted therapy can cause tumour cells to undergo an epithelial-to-mesenchymal transition, which could promote increased invasion and metastasis [ , , , ].

Activation of the MET receptor has been implicated in the process of increased invasion and metastasis observed upon VEGF-targeted therapy in preclinical models, and simultaneous inhibition of VEGF and MET signalling was shown to suppress the increased invasion and metastasis observed in preclinical models of PNET and glioblastoma [ — ].

Another possible causative factor in the enhanced metastasis observed in angiogenesis inhibitor treated mice is a drug-induced change in circulating factors. For example, it has been shown that TKIs in particular can induce a significant change in a number of circulating factors implicated in tumour progression including G-CSF, SDF-1α and osteopontin [ ].

A change in levels of these factors could potentially contribute to tumour progression at distant sites. In support of this concept, a recent study showed that changes in circulating levels of interleukinb were required for the enhanced metastasis observed upon sorafenib treatment in a preclinical model of hepatocellular carcinoma [ ].

It is known that the integrity of the vasculature is important in controlling metastasis [ , ]. Therefore, another possible mechanism could be that VEGF-targeted therapies damage the vasculature, leading to enhanced tumour cell extravasation at the primary site or increased seeding at the metastatic site.

There is some direct evidence in preclinical models that TKIs may promote metastasis by damaging the integrity of the vasculature [ , , ]. Despite these data, more work is required to understand in which settings increased aggressiveness may be relevant and how it occurs at the mechanistic level.

Beyond its role in stimulating angiogenesis in endothelial cells, it is now apparent that VEGF can play a signalling role in many other cell types. These include: endothelial cells of the normal vasculature [ ], dendritic cells [ ], myeloid cells [ ], neurons [ ], pericytes [ ] and tumour cells [ , , — ].

Identification of these additional physiological and pathophysiological roles for VEGF has led to some surprising observations. For example, inhibition of VEGF in the normal vasculature may be the cause of certain side effects seen in patients treated with VEGF-targeted agents, such as hypertension [ 81 ], whilst suppression of VEGF signalling in myeloid cells was shown to accelerate tumourigenesis in mice [ ].

This latter phenomenon may be another mechanism leading to increased aggressiveness in cancers treated with anti-angiogenic therapy. In addition, there are numerous studies documenting a role for VEGF signalling in tumour cells, but the data are conflicting.

Several studies have shown that cancer cell lines can express VEGFR1 or VEGFR2 and that signalling through these receptors in cancer cells can promote events associated with tumour progression, including cancer cell survival, proliferation, invasion or metastasis [ — ].

Based on these data it has been proposed that inhibition of VEGF signalling in tumour cells may, at least in part, be mediated by direct activity against tumour cells [ 4 ]. In contrast, more recent preclinical studies have shown that inhibition of VEGF signalling in CRC and glioblastoma cells made these cells more invasive [ , ].

These latter data suggest that, in fact, targeting VEGF signalling in cancer cells may actually be deleterious. Further studies are warranted to untangle this dichotomy. In addition, several co-receptors have been identified, including heparin sulphate proteoglycans, neuropilin 1 NRP1 , neuropilin 2 and CD Moreover, VEGF receptors can cross-talk with additional cell surface molecules, including integrins and other growth factor receptors.

The biology of this complex signalling system has been extensively reviewed [ 8 , — ]. Here we will focus on some selected studies that examined the relevance of these interactions in determining response or resistance to VEGF-targeted therapies in cancer.

Furthermore, anti-tumor activity was enhanced with less toxicity Tumor blood vessels were found to be highly abnormal, with tumor vessels showing structural abnormalities, leading to hypoxia, acidity, and a high interstitial fluid pressure microenvironment.

These microenvironmental abnormalities can affect immune cell proliferation, infiltration, survival, and function Myeloid-derived suppressor cells MDSCs are one of the most important stromal cells of the TME, and protect tumor cells from the host immune system by suppressing T-cell function There is evidence to support the hypothesis that anti-angiogenic therapy and immunotherapy act synergistically GM-CSF, a potent cytokine promoting the differentiation of myeloid cells such as dendritic cells, macrophages and granulocytes, which elicits antitumor immunity by enhance tumor antigen presentation to T cells, has been proven to be effective across numerous clinical trials 46 — And Sylvie et al.

also included that human GFs in vitro actively inhibit the differentiation of monocyte-derived dendritic cells through the secretion of IL-6 and VEGF, limiting the immunotherapy of GM-CSF Furthermore, it also promotes proliferation of immunosuppressive cells, such as Tregs and MDSCs, and inhibits DC maturation, and restricts the development of T lymphocytes from the lymphoid progenitors 30 , 53 — A study 56 on three different NSCLC animal models demonstrated that combining adoptive transfer of cytokine-induced killer CIK cells with recombinant human endostatin significantly inhibited angiogenesis and tumor growth, whereas neither was effective when used alone.

Lydia Meder et al. conducted an experiment on five groups on the combined use of vehicle, IgG, VEGF inhibitor, PD-L1 inhibitor, VEGF inhibitor, and PD-L1 inhibitor in a mouse model of small cell lung cancer.

The results indicate that treatment with VEGF, compared to any other treatment methods, the combination of inhibitor and PD-L1 inhibitor greatly improved PFS and OS in mice Yasuda et al.

reported that in a mouse model of colon cancer, the combined use of PD-1 inhibitors and VEGFR2 inhibitors demonstrated no obvious toxicity.

Compared to the control group, the experimental group drugs were found to better inhibit tumor growth. The author believes that the combined use of inhibitors can produce a synergistic anti-tumor effect in the body through a variety of mechanisms, including anti-VEGFR2 therapy resulted in a significant decrease of tumor micro vessels as well as reducing tumor vasculature and anti-PD-1 mAb treatment enhanced the infiltration of T cells into tumors.

And that the two drugs are not mutually exclusive Since immunotherapy has been proved to be effective against CSCs and the immunosuppressive TME, it is reasonable to surmise that a combination of anti-angiogenesis and immunotherapies would have a synergistic effect against recalcitrant tumors.

Indeed, studies have shown that 38 targeting the angiogenic factor VEGF, as well as its receptors, stimulates onco-immunity, since VEGF is known to be involved in the immune escape of tumors.

The VEGF signaling pathway can abrogate the effects of anti-tumor therapy via various mechanisms. Usually, is LFA1 that can interact on ICAM1.

LFA1 is expressed on lymphocytes and it is a crucial for T cell entry into mammalian lymph nodes and tissues while ICAM1 on tumor target cells or endothelial cells Previous study showed that clustering of ICAM-1 was indeed prevented by VEGF and a reduced induction of ICAM-1 and VCAM-1 mRNA transcripts by TNF in the presence of VEGF Therefore, blocking VEGF and its receptor can help stimulate immune responses and improve immunotherapy outcomes.

Similarly, sunitinib inhibited the expansion of Tregs and MDSCs in patients with renal cell carcinoma 30 , 63 , In a mouse model of colon cancer, anti-PD-1 monoclonal antibodies and VEGFR2 resulted in significantly greater tumor inhibition compared to either monotherapy The relationship between angiogenesis and immune therapy has been suggested to be a complicated interplay Anti-angiogenic agents are known to stimulate the immune system and improve the immune suppression environment Furthermore, immunotherapy can also cause anti-angiogenesis effects, and there is a synergistic relationship between the two treatment methods Tumor cells can evade T cell-mediated killing by up-regulating the interaction of PD-L1 with the inhibitory receptor PD-1 that is expressed on tumor-infiltrating T cells.

Thus, it is inevitable that patients develop resistance to immune checkpoint inhibitors due to a lack of PD-L1 and the inhibitory effect in the tumor microenvironment.

The therapy should inhibit angiogenesis, on the other hand trigger anti-tumor immunity The formation of blood vessels in malignant tumors is mainly caused by hypoxia and excessive secretion of vascular endothelial growth factor VEGF.

Recently, an accumulating number of clinical trials have been conducted to explore the efficacy of the combination of anti-angiogenesis and immunotherapy Table 1. Table 1 Principal clinical trials for the approval of antiangiogenic and or immunotherapy agents.

In a phase 3 clinical trial IMpower NCT , patients with metastatic non-squamous NSCLC ns-NSCLC were treated with a combination of Atezolizumab to Bevacizumab-based chemotherapy, including three groups: 1 Atezolizumab, Carboplatin, and Paclitaxel ACP ; 2 Atezolizumab, Bevacizumab, Carboplatin and Paclitaxel ABCP ; 3 Bevacizumab, Carboplatin and Paclitaxel BCP.

The results demonstrated that the ABCP group had significantly improved PFS and OS, with an average of 8. The median OS was not estimated in the ABCP, but it was In addition, patients with advanced NSCLC receiving treatment with a combination of Nivolumab and Bevacizumab were recruited for a phase 1 study NCT , which aimed to evaluate whether the combination therapy improves PFS and OS.

The experimental results indicate that the combined treatment group had significant safety, and the incidence of grade 3 and above adverse reactions is low.

Therefore, it has shown excellent therapeutic effects compared to the single-agent treatment group The combined treatment group had a median PFS of Additionally, the median OS of the combined treatment group was In , results of the phase 1 study NCT were reported. Among the total 27 enrolled patients with previously treated advanced NSCLC that received Ramucirumab plus Pembrolizumab, 8 patients achieved an objective response.

Another phase 1 study NCT indicated that the combination of Ramucirumab plus Durvalumab led to an enhancement of preliminary antitumor activity in heavy pre-treated NSCLC patients with a median PFS of 1.

A first randomized phase 2 IMmotion study NCT for patients with previously untreated mRCC treated with Atezolizumab combination Bevacizumab or single Atezolizumab or single sunitinib showed that the PFS of this combination group significantly improved within the population, whatever the PD-L1 status Immunotherapy with PD-1 and PD-L1 inhibitors or combined with antiangiogenic therapy i.

VEGF inhibitors or CTLA-4 antibodies has become a first line therapy for advanced RCC patients Another phase 3 study NCT validated that the combination of Avelumab plus axitinib enhanced the curative effect in patients with advanced RCC, leading to remarkable improvement in median PFS In , a pivotal phase 3 study NCT demonstrated that Avelumab or Pembrolizumab Plus axitinib were more efficacious than sunitinib, a previous standard of care.

This study recruited metastatic renal cell carcinoma mRCC patients with results showing an improvement in PFS, a high response rate, and a low rate of intrinsic resistance Phase 1 study NCT of the VEGFR2 inhibitor apatinib plus anti-PD1 antibody SHR in patients with advanced hepatocellular carcinoma HCC has demonstrated manageable toxicity and encouraged clinical activity at recommended single-agent doses of both drugs These cohort results suggest that Nivolumab, plus Ipilimumab, may provide an improved ORR and OS, especially in arm A lower dose Nivolumab and higher dose Ipilimumab , relative to anti-PD-L1 monotherapy The combination of lenvatinib plus Pembrolizumab for unresectable HCC uHCC patients in the Phase 1b trial NCT represented a promising antitumor activity with an ORR of Moreover, an ongoing double-blind randomized controlled phase 3 study NCT of lenvatinib plus Pembrolizumab treatment of uHCC is currently being undertaken Imbrave NCT , a randomized, multicenter phase 3 clinical study aims to evaluate the efficacy and safety of Atezolizumab plus Bevacizumab versus Sorafenib among patients with advanced HCC.

The results indicated that, among patients in the combination group and in the Sorafenib group with HCC, the combination group showed a remarkable improvement in median PFS and OS with tolerated and controllable toxicity, compared to the Sorafenib group The results from this study indicated that the treatment had an ORR of Preliminary results from the phase 1 clinical trial NCT showed that Ipilimumab CTLA-4 antibody plus Bevacizumab VEGF inhibitors in patients with metastatic melanoma MM had favorable clinical outcomes, for reasons of increasing tumor vascular expression of ICAM-1 and VCAM-1 and lymphocyte infiltration in tumors Another open-label phase 1b trial NCT validated the efficacy of axitinib in combination with Toripalimab among patients with advanced melanoma with an ORR of In addition, a phase 2 study NCT in mCRC patients also demonstrated that the addition of Atezolizumab to Bevacizumab, as well as capecitabine, improved the median PFS of 4.

The results demonstrated that the combination was generally well tolerated, with an acceptable toxicity profile without any unexpected findings Anti-tumor angiogenesis was found to be favorable to T-cell infiltration and drug delivery to the tumor, thereby enhancing the efficacy of immunotherapy.

Additionally, immunotherapy can also increase tumor vascular normalization and form positive feedback to anti-angiogenesis. Therefore, the combination of anti-angiogenic agents and immunotherapy provides a new therapeutic approach for tumor patients. A large number of studies have demonstrated that the combination therapy has good clinical application prospects.

However, the relationship between tumor angiogenesis and immune response is intricate, and some tough problems still need to be solved for future practical application.

Firstly, there is no way to identify tumor patients that can benefit from combination therapy 93 , and anti-angiogenesis therapy has a lack of biomarkers, as mentioned above. In order to address the problem, oncologists have to identify the biomarkers that can be associated with patient groups that would be advantaged with this therapy.

Secondly, the dose of each drug, the optimal sequence, and the time of the combination also remain significant. The high or low dose, simultaneous or sequential treatment, will have an effect on the efficacy of the combination therapy.

Furthermore, studies have demonstrated that high doses of anti-angiogenic drugs can directly damage tumor blood vessels, which results in more serious disturbances of tumor microenvironment, such as hypoxia and immunosuppression Therefore, it is necessary to choose the appropriate drug dosage, and optimize the schedule of tumor immunotherapy and anti-angiogenesis therapy in order to obtain improved anticancer efficacy.

Moreover, the most frequent side effect of anti-angiogenic is hypertension Therefore, primary or acquired resistance, including non-upregulation VEGF in tumors, changes in the TME, the presence of CSCs, and the patient with hypertension contribute to anti-angiogenesis failure Besides, resistance to immunotherapy, including lack of tumor-infiltrating lymphocytes in the tumor, accumulating immunosuppressive cells in the TME and secreting immunosuppressive cytokines in the tumor cells, contributes significantly to failure of immunotherapy.

FL and JH contributed to the study design. HH and YC were responsible for data collection. ST, YH, and SF drafted and prepared the manuscript. SW worked for the table and figures. All authors participated in the data interpretation and contributed to the manuscript writing with important intellectual input.

All authors approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Soria J-C, Mauguen A, Reck M, Sandler A, Saijo N, Johnson D, et al. Ann Oncol 24 1 — doi: PubMed Abstract CrossRef Full Text Google Scholar. Reck M, Kaiser R, Mellemgaard A, Douillard J, Orlov S, Krzakowski M, et al. Docetaxel Plus Nintedanib Versus Docetaxel Plus Placebo in Patients With Previously Treated Non-Small-Cell Lung Cancer Lume-Lung 1 : A Phase 3, Double-Blind, Randomised Controlled Trial.

Lancet Oncol 15 2 — Garon EB, Ciuleanu T-E, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab Plus Docetaxel Versus Placebo Plus Docetaxel for Second-Line Treatment of Stage Iv Non-Small-Cell Lung Cancer After Disease Progression on Platinum-Based Therapy Revel : A Multicentre, Double-Blind, Randomised Phase 3 Trial.

Lancet — Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis. Cancer Cell 15 3 — Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al.

Gemcitabine Plus Bevacizumab Compared With Gemcitabine Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B Calgb J Clin Oncol 28 22 Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SAA, Fack F, et al.

Anti-Vegf Treatment Reduces Blood Supply and Increases Tumor Cell Invasion in Glioblastoma. Proc Natl Acad Sci 9 — Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS.

Accelerated Metastasis After Short-Term Treatment With a Potent Inhibitor of Tumor Angiogenesis. Cancer Cell 15 3 —9.

Ramadan W, Zaher D, Altaie A, Talaat I, Elmoselhi A. Potential Therapeutic Strategies for Lung and Breast Cancers Through Understanding the Anti-Angiogenesis Resistance Mechanisms. Int J Mol Sci 21 2 CrossRef Full Text Google Scholar.

Missiaen R, Mazzone M, Bergers G. The Reciprocal Function and Regulation of Tumor Vessels and Immune Cells Offers New Therapeutic Opportunities in Cancer.

Semin Cancer Biol — Craven K, Gore J, Korc M. Overview of Pre-Clinical and Clinical Studies Targeting Angiogenesis in Pancreatic Ductal Adenocarcinoma. Cancer Lett 1 — Ioannidou E, Moschetta M, Shah S, Parker J, Ozturk M, Pappas-Gogos G, et al. Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets.

Int J Mol Sci 22 18 Kerbel R. Reappraising Antiangiogenic Therapy for Breast Cancer. Breast Edinburgh Scotland 20 Suppl 3 0 3 :S56— Ahir B, Engelhard H, Lakka S. Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma.

Mol Neurobiol 57 5 — Cascone T, Herynk M, Xu L, Du Z, Kadara H, Nilsson M, et al. Upregulated Stromal Egfr and Vascular Remodeling in Mouse Xenograft Models of Angiogenesis Inhibitor-Resistant Human Lung Adenocarcinoma. J Clin Invest 4 — Huijbers E, van Beijnum J, Thijssen V, Sabrkhany S, Nowak-Sliwinska P, Griffioen A.

Role of the Tumor Stroma in Resistance to Anti-Angiogenic Therapy. Drug Resist Updat: Rev Comment Antimicrob Anticancer Chemother — Chandra A, Rick J, Yagnik G, Aghi MK. Autophagy as a Mechanism for Anti-Angiogenic Therapy Resistance. Li C, Teixeira A, Zhu H, Ten Dijke P.

Cancer Associated-Fibroblast-Derived Exosomes in Cancer Progression. Mol Cancer 20 1 Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al.

Crosstalk Between Cancer-Associated Fibroblasts and Immune Cells in the Tumor Microenvironment: New Findings and Future Perspectives.

Deepak K, Vempati R, Nagaraju G, Dasari V, Nagini S, Rao D, et al. S NTumor Microenvironment: Challenges and Opportunities in Targeting Metastasis of Triple Negative Breast Cancer.

Pharmacol Res Zhang H, Wang Z, Peng Q, Liu Y-Y, Zhang W, Wu L, et al. Tumori J 99 6 — Wang Z, Li Z, Wang Y, Cao D, Wang X, Jiang M, et al. Versican Silencing Improves the Antitumor Efficacy of Endostatin by Alleviating Its Induced Inflammatory and Immunosuppressive Changes in the Tumor Microenvironment.

Oncol Rep 33 6 — Wang L, Wang J, Li Z, Liu Y, Jiang M, Li Y, et al. Silencing Stem Cell Factor Attenuates Stemness and Inhibits Migration of Cancer Stem Cells Derived From Lewis Lung Carcinoma Cells.

Tumor Biol 37 6 — Wang L, Guo H, Lin C, Yang L, Wang X. Mol Med Rep 9 6 — Lin C, Wang L, Wang H, Yang L, Guo H, Wang X. J Cell Biochem 9 — Cao L, Fan X, Jing W, Liang Y, Chen R, Liu Y, et al. Osteopontin Promotes a Cancer Stem Cell-Like Phenotype in Hepatocellular Carcinoma Cells Via an Integrin—Nf-κb—Hif-1α Pathway.

Oncotarget 6 9 Santoyo-Ramos P, Likhatcheva M, García-Zepeda EA, Castañeda-Patlán MC, Robles-Flores M. Hypoxia-Inducible Factors Modulate the Stemness and Malignancy of Colon Cancer Cells by Playing Opposite Roles in Canonical Wnt Signaling. PloS One 9 11 :e And, there are medicines can help manage these side effects when they do occur.

Be sure to let your health care team know about side effects you experience. If an angiogenesis inhibitor is recommended for you, talk with your doctor about the specific potential benefits and risks of that medication.

Also, ask about ways side effects can be managed and what side effects to watch for. Angiogenesis inhibitors for cancer can be prescribed by a doctor to take orally by mouth or intravenously by vein; IV.

If you are prescribed an oral angiogenesis inhibitor to take at home, ask if you need to fill the prescription at a pharmacy that handles complex medications, such as a specialty pharmacy. Check with the pharmacy and your insurance company about your insurance coverage and co-pay of the oral medication.

Also, be sure to ask about how to safely store and handle your prescription at home. If you are prescribed an IV treatment, that will be given at the hospital or other cancer treatment facility. Talk with your treatment center and insurance company about how your specific prescription is covered and how any co-pays will be billed.

If you need financial assistance, talk with your health care team, including the pharmacist or a social worker , about co-pay assistance options. National Cancer Institute: Angiogenesis Inhibitors. The Angiogenesis Foundation: Treatments. Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology ASCO , the voice of the world's oncology professionals.

org Conquer Cancer ASCO Journals Donate. What is Targeted Therapy? Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Understanding Pharmacogenomics Radiation Therapy Surgery When to Call the Doctor During Cancer Treatment What is Maintenance Therapy?

Veterans Prevention and Healthy Living Cancer. Net Videos Coping With Cancer Research and Advocacy Survivorship Blog About Us. Angiogenesis and Angiogenesis Inhibitors to Treat Cancer Approved by the Cancer.

What is angiogenesis?

Cancer is a group of diseases Anti-angiogenesis agents significant morbidity Anti-angiogenesiis mortality. In Anti-angiogenesis agents cells, Anti-angiogenesis agents energy requirements are Anti-anbiogenesis high, angiogenesis, Anti-angiogehesis is the sprouting Anti-angiogdnesis new blood vessels Anti-angiogenesis agents pre-existing Mental strength training, is an important process for tumour survival Anti-angiogenesis agents progression. Hence, extensive Liver health tips in recent years focuses on the discovery of new anticancer drugs that target angiogenesis. Several methodologies have been developed preclinically, including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones. The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years. Many new anticancer drugs targeting angiogenesis are identified in the literature.

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Anti-angiogenesis Drugs, Part III Skip to Content. Angiogenesis inhibitors are Anti-angiogenesis agents type of cancer treatment. Anti-angiogenesjs stop a process in the body Agentw angiogenesis, or blood vessel formation. Angiogenesis is how the body forms new blood vessels. This is a normal part of growth and healing. But sometimes angiogenesis can play a role in diseases such as cancer.