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Published in final edited form as: Gynecol Oncol. 2015 Dec 31;141(1):80–85. doi: 10.1016/j.ygyno.2015.12.033

Prediction and failure of anti-angiogenesis escape

Takashi Mitamura a, Charlie Gourley b, Anil K Sood a,c,d
PMCID: PMC4808422  NIHMSID: NIHMS751807  PMID: 26748214

Abstract

Many clinical trials have demonstrated the benefit of anti-angiogenesis therapy in the treatment of gynecologic cancer. However, these benefits have often been in terms of progression-free rather than overall survival and in some cases, the magnitude of benefit demonstrated in the pivotal phase 3 trials has been disappointing when compared with the percentage of patients who responded in earlier phase 2 trials. Two potential explanations for this are the current inability to stratify patients according to chance of benefit and the development of resistance mechanisms within the tumor. In this article, we review the prediction of response and the proposed resistance and escape mechanisms involved in anti-angiogenesis therapy, including the up-regulation of alternative proangiogenic pathways, vascular co-option, and resistance to hypoxia. These insights may offer a personalized strategy for anti-angiogenesis therapy and help us to consider the best selection of other therapies that should be combined with anti-angiogenesis therapy to improve the outcome of patients with gynecologic cancer.

1. Introduction

Oxygen supplied by the vasculature is crucial for cell function and survival, and all cells typically reside within 100 μm of a capillary blood vessel [1]. Angiogenesis, the formation of new blood vessels, is required for tumor growth beyond a millimeter and for metastasis [2]. Tumors can recruit vasculature by releasing various growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and placental growth factor. The successful inhibition of human tumor xenograft growth by a monoclonal antibody specific for VEGF [3] motivated the development of anti-angiogenesis therapy. In 2004, bevacizumab became the first anti-VEGF agent to be approved by the U.S. Food and Drug Administration (FDA) for cancer patients. In phase 3 trials, bevacizumab showed evidence of efficacy in metastatic colorectal [4], lung, [5], breast [6], and renal [7] cancers and in glioblastoma [8].

In gynecologic cancers, the phase 3 first-line GOG-218 trial enrolled 1,873 women with previously untreated macroscopic residual stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma [9]. In this three-arm study, patients received carboplatin and paclitaxel chemotherapy (all three arms) and either concomitant and maintenance placebo every 3 weeks (with up to 16 cycles of maintenance) (control group), or concomitant bevacizumab and maintenance placebo (the bevacizumab-initiation group), or concomitant and maintenance bevacizumab (the bevacizumab-throughout group). The median progression-free survival (PFS) was 10.3 months in the control group, 11.2 months in the bevacizumab-initiation group, and 14.1 months in the bevacizumab-throughout group.

The other phase 3 first-line trial (ICON7) randomized 1,528 women with high-risk early-stage or advanced epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. When PFS was assessed at 36 months, it was determined that PFS was 20.3 months with standard therapy (carboplatin and paclitaxel chemotherapy) but was 21.8 months (a statistically significant increase of 1.5 months) when bevacizumab was added to standard therapy and continued as subsequent maintenance for up to 12 additional cycles. The addition of bevacizumab, however, did not increase overall survival in the intention-to-treat population [10]. Two randomized trials in recurrent ovarian cancer have shown significant improvement in PFS as a result of adding bevacizumab to conventionally administered chemotherapy in patients with platinum-sensitive or platinum-resistant disease. In the phase 3 OCEANS trial, 484 patients with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer and measurable disease were randomly assigned to gemcitabine and carboplatin plus either bevacizumab or placebo. The median PFS was 12.4 vs 8.4 months, respectively [11]. In the phase 3 AURELIA trial, 361 women with measurable epithelial ovarian, primary peritoneal, or fallopian tube cancer that had progressed within 6 months after the women had completed platinum-based therapy (platinum-resistant) were randomized to one of six arms (paclitaxel, topotecan, or pegylated liposomal doxorubicin with or without bevacizumab). This trial showed that bevacizumab plus chemotherapy doubled the median PFS duration of women who received chemotherapy alone (median PFS: 6.7 vs. 3.4 months) [12]. VEGF receptor tyrosine kinase inhibitors have also demonstrated encouraging activity in patients with ovarian cancer, primary peritoneal, or fallopian tube cancer. Pazopanib is a multitargeted tyrosine kinase inhibitor whose main targets include VEGF and PDGF receptor families. Maintenance pazopanib therapy provided a median improvement of 5.6 months in PFS in patients with advanced ovarian cancer whose disease had not progressed after first-line chemotherapy [13]. Phase 2 studies of cediranib monotherapy (an inhibitor of VEGFR 1–3 and C-KIT) showed response rates of 17%–23% in heavily pretreated ovarian cancer patients [14, 15].

For patients with recurrent, persistent, or metastatic cervical cancer, the GOG-0240 clinical trial showed that the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 vs. 13.3 months, respectively) and higher response rates (48% vs. 36%) [16]. A subsequent randomized phase 2 study in the same patient population demonstrated that when cediranib was administered concomitantly with chemotherapy and then as maintenance thereafter, it significantly increased PFS compared with placebo [17].

However, some tumors do not respond and others eventually become unresponsive. As such, PFS or overall survival benefits in patients receiving anti-angiogenesis therapy for gynecologic malignancies are usually measured in months. Therapeutic resistance and escape have become practical limitations. In this article, we summarize clinical and translational research on predictors of response to anti-angiogenesis therapy and also review potential resistance and escape mechanisms to such therapy in gynecologic malignancies.

2. Prediction of response

There is now clear molecular evidence that ovarian cancer is a highly heterogeneous disease. The five main immunohistological subtypes (by order of incidence: high-grade serous, endometrioid, clear cell, low-grade serous, and mucinous) differ vastly in terms of their stage of presentation [18], chemosensitivity [19], overall survival, and driver genetic mutations [20]. Within high-grade serous ovarian cancer, numerous studies have demonstrated heterogeneity at the level of gene sequence, gene expression, copy number, or methylation [21–27]. Despite these clear differences, most clinical trials of anti-angiogenesis therapy have been performed in unselected patient populations, and progress in terms of defining clinical or molecular predictors of sensitivity has been limited.

In the setting of cervical cancer, again clinical studies have largely been performed in unselected patient populations, and little progress has been made in defining subpopulations of patients according to their expected benefit from anti-angiogenesis therapy.

2.1. Clinical predictors of response to anti-angiogenesis therapy in ovarian cancer

A retrospective but predefined subgroup analysis of 502 patients with high-risk disease (defined as suboptimally debulked stage III or stage IV) from the ICON7 study demonstrated a significant overall survival benefit for women who received bevacizumab plus chemotherapy compared with those who received chemotherapy alone (restricted mean survival time was 34.5 months with standard chemotherapy compared with 39.3 months with bevacizumab) [28]. When a similar retrospective analysis was performed in the GOG218 dataset [29], no overall survival benefit was demonstrated in suboptimally debulked stage III patients (total of 751 patients in three arms). However, in patients with stage IV disease who received concomitant and maintenance bevacizumab, the overall survival duration was 40.6 months compared with 32.8 months in the control arm. These findings raise the possibility that patients with stage IV disease potentially gain more from first-line bevacizumab therapy (overall survival benefits were not seen in the intention-to-treat populations in either the ICON7 or GOG218 studies). Investigation of the clinical utility of anti-angiogenesis therapy within a histotype-specific ovarian cancer context has to date been extremely limited. Grisham et al. [30] performed a retrospective analysis of 17 patients with low-grade serous or serous borderline ovarian tumors who received bevacizumab and demonstrated a response rate of 40% (55% in the low-grade serous ovarian tumors alone). Although many of these patients also received chemotherapy, it has become clear that the response rate to chemotherapy alone in low-grade serous ovarian cancer is approximately 5% [31, 32], suggesting that bevacizumab has significant efficacy in this subtype. An attempt to establish the value of bevacizumab in mucinous ovarian cancer in the mEOC/GOG241 trial was unsuccessful; the study had to be closed because of poor patient recruitment, despite international collaboration. Likewise, the efficacy of anti-angiogenesis therapy in clear cell ovarian cancer remains poorly defined. These areas are major priorities for future research.

2.2. Molecular predictors of response to anti-angiogenesis therapy

A number of blood or tissue biomarkers have been postulated to predict sensitivity to anti-angiogenesis agents on the basis of preclinical studies, but convincing clinical validation remains elusive. Collinson et al. [33] demonstrated that a signature of four serum proteomic biomarkers (mesothelin, fms-like tyrosine kinase-4, α1-acid glycoprotein, and CA125) was able to predict benefit from bevacizumab in a cohort of patients from the ICON7 study. The predictive ability was less strong in a second cohort from the same study, but patient numbers were small and it is likely that the validation analysis was underpowered. In another translational plasma-based study using material from patients in the ICON7 study, the combination of high plasma ANG-1 and low plasma TIE-2 was found to predict improved PFS in bevacizumab-treated patients [34]. However, in a large retrospective analysis of plasma biomarkers in prospectively collected samples from the GOG218 study, no predictive biomarkers for bevacizumab efficacy were identified [35].

Tissue biomarkers have been sought using translational research samples from both the GOG218 and ICON7 studies. Birrer at al. [36] performed an exploratory retrospective analysis of candidate predictive biomarkers of efficacy in the GOG218 trial. Of the five biomarkers explored, one (CD31, a marker of blood vessel density) was able to discriminate patients according to their degree of benefit from bevacizumab when a median cut-off level was used (test for interaction, p=0.003 and p=0.016 for PFS and OS, respectively). When the cut-off was adjusted to the highest quartile, the test was even more discriminatory in terms of OS benefit from bevacizumab (test for interaction, p=0.008).

The translational specimens from the ICON7 study have been analyzed in two cohorts. Winterhoff et al. used the four gene expression subtypes from the Cancer Genome Atlas (TCGA) project [21] to classify 425 tumors from patients enrolled into ICON7 [37]. Patients with serous cancer in the mesenchymal subgroup had a 9.5-month PFS benefit if they received bevacizumab (25.5 vs. 16 months, p=0.053). The extent of median PFS benefit from bevacizumab in the three other molecular subtypes (differentiated, immunoreactive, and proliferative) was 5.8, 3.4, and 3.2 months, respectively.

Previous gene expression analysis and unsupervised hierarchical clustering of tumors from a conventionally treated Scottish cohort of patients with high-grade serous ovarian cancer identified three molecular subgroups: the Immune subgroup, characterized by up-regulation of genes involved in immune response; the Angio subgroup, characterized by up-regulation of genes involved in angiogenesis; and the Angioimmune subgroup, characterized by up-regulation of both immune response and angiogenesis genes [38]. Patients in the Immune subgroup were found to have improved survival compared with patients in the other two subgroups. Since this subgroup was characterized by repression of angiogenic processes, it was hypothesized that these patients may not derive as much benefit from anti-angiogenesis therapy, and a 63-gene signature was generated to identify this subgroup. When this signature was applied to 284 translational research samples from the ICON7 study, it was found that the 63-gene signature was able to predict benefit from bevacizumab therapy (test for interaction, p=0.016) [39]. Patients in the Immune subgroup had inferior PFS (HR = 1.73 [1.12–2.68]) and OS (HR = 2.00 [1.11–3.61]) if they received bevacizumab compared with chemotherapy alone. In patients outside of the Immune subgroup, there was a nonsignificant trend to improved PFS for the addition of bevacizumab (median, 17.4 vs 12.3 months in controls). The findings from both of these translational studies in the ICON7 dataset require urgent validation in the GOG218 dataset in order to determine not only whether the degree of benefit can be predicted but also whether there is a subgroup of patients who are actually harmed if they receive first-line bevacizumab in the fashion administered in these trials.

3. Resistance and escape mechanisms

3.1. Alternatives to angiogenesis for neovascularization

It has become clear that angiogenesis is not the only mechanism by which tumors develop a vascular supply; there is increasing evidence of adaptation by invasion without angiogenesis. One of these mechanisms is vascular co-option [40, 41], also known as perivascular tumor invasion. Glioma, the most typical example, grows by co-opting existing host vessels. These tumor cells do not rely on a cytokine-driven neovascular response and are favored in an environment exposed to anti-angiogenesis therapy.

For gynecologic cancers, vessel co-option has been observed in mouse ovarian cancer models [42]. In such cases, the secondary effect of direct impairment of tumor cell viability by multitargeted anti-angiogenesis agents such as sorafenib and cabozantinib would be expected, in addition to the original anti-angiogenesis effect on the new lesion that is dependent on neovascularization. Although sorafenib (a kinase inhibitor targeting RAF, VEGF receptor [VEGFR], and platelet-derived growth factor receptor [PDGFR]) has modest antitumor activity, it caused significant toxic effects in several trials [43, 44]. Cabozantinib, a kinase inhibitor of MET, VEGFR2, FLT3, c-KIT, and TIE-2, is currently undergoing clinical trials for patients with recurrent or progressive ovarian, fallopian tube, or primary peritoneal cancer. In advanced, progressive epithelial ovarian cancer, this agent showed a promising clinical response rate (overall, 24%). Dose reductions and permanent discontinuations for adverse effects occurred in 43% and 10% of cases, respectively, which is consistent with rates for other tyrosine kinase inhibitors [45].

Vascular mimicry refers to the formation of fluid-conducting channels by highly invasive and genetically dysregulated tumor cells [46]. Immunohistochemical analysis in an ovarian cancer model showed that matrix metalloproteinases (MMP)-1, -2, and -9 and MT1-MMP were discretely localized to these networks. Because the formation of these networks was inhibited by treatment with MMP inhibitors [47], these inhibitors could be effective in combination with anti-angiogenesis drugs.

3.2. Acute hypoxia

At the peak of the response phase of anti-angiogenesis therapy, tumors have regions of acute hypoxia [48]. Hypoxia is often implicated in the promotion of tumor progression and resistance to therapy [49]. High intratumoral hypoxia is associated with worse clinical outcomes in cancer patients [50]. A clinical investigation involving a study of glioblastoma patients being treated with the VEGFR inhibitor cediranib pointed to adaptive resistance mechanisms involving FGF-dependent revascularization [51]. Tumors subjected to hypoxic conditions also expressed higher levels of proangiogenic factors including angiopoietin [48] and hepatocyte growth factor receptor (MET) [52, 53] than did unperturbed tumors, suggesting that these angiogenic pathways are potential targets to overcome adaptive resistance induced by hypoxia.

Drugs targeting the mechanisms described above have entered into clinical testing. BIBF-1120 is a triple-angiokinase inhibitor of VEGFR, PDGFR, and FGF receptor. In a randomized, phase 2 placebo-controlled trial, patients who had completed chemotherapy for relapsed ovarian cancer with evidence of response were treated with BIBF-1120. Three-year PFS rates were 16.3% and 5.0% in the BIBF-1120 and placebo groups, respectively [54]. A Phase 3 (NCT01015118) clinical trial is evaluating the addition of BIBF-1120 to carboplatin/paclitaxel in first-line chemotherapy in ovarian cancer. AMG386 is an angiopoietin antagonist that selectively binds angiopoietin 1 (ANG1) and angiopoietin 2 (ANG2). This binding prevents the interaction of ANG1 and ANG2 with TEK tyrosine kinase, endothelial (TIE-2) and inhibits tumor endothelial cell proliferation and tumor growth [55]. In a phase 2 study of AMG386 combined with paclitaxel, the addition of AMG386 to paclitaxel demonstrated dose-responsive improvements in PFS with a manageable safety profile distinct from that of VEGF inhibition [56]. AMG386 has entered phase 3 clinical investigation in the setting of recurrent ovarian cancer.

Certain anti-angiogenesis agents can transiently normalize the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. In patients with glioblastoma, cediranib, a pan-VEGFR inhibitor, resulted in decreased tumor edema by dynamic magnetic resonance imaging. Although this vascular normalization is still controversial, drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if carefully scheduled. Administration of metronomic topotecan was able to significantly decrease cell proliferation and angiogenesis by reducing VEGF and HIF-1α [14]; thus, its combination with anti-VEGF therapy could be beneficial.

3.3. Recruitment of bone marrow–derived cells

3.3.1. Monocytes and macrophages

Hypoxia caused by vessel regression during the course of anti-angiogenesis therapy can lead not only to up-regulation of proangiogenic factors within the tumors but also to the recruitment of various bone marrow–derived cells, including monocytes, macrophages, and endothelial progenitors, which have the capacity to fuel tumors by eliciting new blood vessels [48]. Monocytes and macrophages deliver VEGF and other angiogenic molecules in a temporal and spatial fashion to avascular areas, resulting in angiogenesis [57]. Compared with controls, macrophages co-cultured with ovarian cancer cells showed significant up-regulation of proangiogenic genes including tumor necrosis factor α (TNF-α), CXCR4, CXCL12 (also known as SDF-1), colony-stimulating factor 1 (CSF-1), and VEGF [58], suggesting that these proangiogenic factors are potential targets for therapy under settings of adaptive resistance. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-α renders it biologically unavailable, and infliximab is an anti–TNF-α monoclonal antibody. These agents showed biologic activity (17% to 20% of patients experienced disease stabilization) and safety in recurrent and advanced ovarian cancer in a phase 1 trial [59, 60]. For CXCR4, the phase 1 trial of the CXCR4 receptor antagonist plerixafor is ongoing in patients with advanced pancreatic, ovarian, and colorectal cancers. Macrophage CSF-1 is widely overexpressed in ovarian cancer [58, 61], and the expression is highest at the invasive edge, a site abundantly populated by macrophages. The PLX3397 clinical trial, designed to target the receptor for CSF-1, is ongoing in ovarian cancer patients.

3.3.2. Endothelial progenitors

Proangiogenic bone marrow–derived cells also include endothelial progenitors that differentiate into endothelial cells to form the inner lining of blood vessel walls. Recruitment of endothelial progenitors is an essential step for tumors that have undergone anti-angiogenesis therapy to acquire adaptive resistance by re-neovascularization. Cancer-associated fibroblasts promote angiogenesis by recruiting endothelial progenitor cells into carcinomas, in part through their ability to secrete CXCL12 (SDF-1), an independent predictor of tumor progression and poor survival in ovarian cancer [62, 63]. The antagonist of CXCR4 that is a receptor of CXCL12, for example plerixafor, mentioned earlier, could be active in preventing this resistance mechanism.

The origin of endothelium may be either bone marrow–derived endothelial progenitors or local endothelial progenitors rooted within organs or vascular parenchyma. The only source of endothelial progenitors was believed to be a hematopoietic stem-cell–containing CD34 population. However, a population of CD11c+ cells exhibiting simultaneous expression of both endothelial and dendritic cell markers (vascular leukocytes) was recently discovered; this population of cells is highly represented in human ovarian cancers and can assemble into functional blood vessels. Since a decrease in tumor growth was associated with a reduced number of CD11c+ infiltrating cells, vascular leukocytes could be therapeutic targets. Antibodies directed against specific antigens and conjugated to toxins may contribute to blocking tumor vascularization [64].

3.4. Pericyte coverage

One of the potential mechanisms of resistance to anti-angiogenesis therapy is the increased coverage of blood vessel with pericytes. The morphology of resistant tumor vessels is distinguishable from the typically dilated tumor vessels of untreated animals, which are, by contrast, variably covered with less closely associated pericytes. Tumor vessels lacking adequate pericyte coverage are more vulnerable to VEGF inhibition [65, 66].

The platelet-derived growth factor (PDGF) ligand/receptor system is one of the major signaling pathways for regulating pericyte coverage. In orthotopic murine models of advanced ovarian carcinoma, dual targeting of endothelial cells and pericytes has been evaluated [67]. PDGF/PDGFR-targeting agents, including pazopanib, sunitinib, BIBF-1120, and dovitinib, are being tested in clinical trials. The most promising of these is a phase 3 trial of pazopanib, VEGFR-1, -2, -3, c-kit, and PDGFR inhibitor, in advanced renal cell carcinoma. Compared with placebo, pazopanib increased PFS from 4.2 to 9.2 months. The difference in PFS was even more striking in patients who were treatment-naive (11.1 vs 2.8 months). The response rate was also improved (30% vs 3%), and the median duration of response was more than 1 year [68]. Additional testing is necessary to determine the full potential of dual targeting of endothelial cells and pericytes in the tumor microenvironment.

4. Discussion

There is non-conclusive but accumulating evidence to suggest that certain histological subtypes of ovarian cancer (e.g., high-grade serous and low-grade serous) are more responsive to anti-angiogenesis therapy than are other subtypes (such as clear cell ovarian cancer). First-line phase 3 bevacizumab studies suggest that patients presenting with later-stage disease derive greater benefit. More work is required to clarify the value of stratification on the basis of these simple clinicopathological factors in both ovarian and cervical cancers. In terms of molecular markers, some candidate proteomic markers were suggested from ICON7, but further validation is required. In addition, molecular subgroups based on gene expression analysis from two translational ICON7 datasets suggest that stratification on this basis may have value. In GOG218, CD31 expression (as a surrogate of vascular density) appears to predict benefit from bevacizumab. The translational studies performed in ICON7 require additional validation.

In terms of precision medicine, tumor imaging or biopsy could be useful for patient selection, but such approaches require further development. Dynamic contrast-enhanced MRI enables quantitation of blood volume, blood flow, relative vessel size, and vascular permeability in measurable tumor [51]. This kind of vascular imaging could be used to evaluate neovascularization and vascular response. Tumor biopsy either percutaneously or via minimally invasive surgery [69, 70] could enable assessment of potential resistance mechanisms.

Recently, clinical trials of anti-angiogenesis therapy in combination with other targeted therapies such as PARP inhibitors have produced intriguing results. In addition, the ongoing MITO16MANGO2b study is evaluating whether administering bevacizumab in combination with chemotherapy as second-line therapy to patients with recurrent ovarian cancer who have received first-line bevacizumab will be more effective than chemotherapy alone. A greater understanding of optimal stratification based on tumor/stromal characteristics and resistance mechanisms will allow us to benefit from the results of these clinical trials by personalizing anti-angiogenesis therapy for each patient.

HIGHLIGHTS.

  • A better understanding of the resistance and escape mechanisms of anti-angiogenesis therapy will facilitate the choices of predictive biomarkers.

  • Precision medicine has the potential to improve the prognosis of patients with gynecologic cancer treated with anti-angiogenesis agents.

Acknowledgments

Financial support

Portions of this work were supported by the National Institutes of Health (CA177909, CA016672, CA109298, UH3TR000943, P50 CA083639, and P50 CA098258), Cancer Prevention and Research Institute of Texas (RP110595, RP120214), Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), Department of Defense (OC073399, OC120547), The RGK Foundation, The Gilder Foundation, The Judi A Rees ovarian cancer research fund, The Blanton-Davis Ovarian Cancer Research Program and the Betty Anne Asche Murray Distinguished Professorship.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of interest statement

Charlie Gourley’s employer (University of Edinburgh) has received compensation for his advisory board attendance (Roche, AstraZenenca, GlaxoSmithKline and Nucana) and for his lecturing (Roche and AstraZeneca). Charlie Gourley (through the University of Edinburgh) has also received research funding from AstraZeneca, GlaxoSmithKline, and Aprea.

Contributor Information

Takashi Mitamura, Email: tmitamura@mdanderson.org.

Charlie Gourley, Email: Charlie.Gourley@ed.ac.uk.

Anil K. Sood, Email: asood@mdanderson.org.

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