Beyond bevacizumab:investigating new angiogenesisinhibitors in ovarian cancerFederica Tomao†, Anselmo Papa, Luigi Rossi, Davide Caruso,Federica Zoratto, Pierluigi Benedetti Panici & Silverio Tomao†‘ Sapienza’ University of Rome, Department of Gynaecology and Obstetrics, Policlinico ‘Umberto I’,
Rome, Italy
Introduction: Ovarian cancer is the most lethal gynecological cancer, mainly
because of the advanced stage of the disease at diagnosis, with recent
research investigating novel targets and agents into the clinical practice,
with the aim to improve prognosis and quality of life. Angiogenesis is a
significant target for ovarian cancer therapy.
Areas covered: Areas covered in this review include the most common
molecular pathways of angiogenesis, which have provided novel targets for
tailored therapy in ovarian cancer patients. These therapeutic strategies
comprise monoclonal antibodies and tyrosine kinase inhibitors. These drugs
have as molecular targets such as vascular endothelial growth factor (VEGF),
Epithelial ovarian cancer (EOC) is the fourth most frequent cause of cancer death inEuropean women and the most lethal gynecologic tumor in Western countries, withunfavorable impact from economic and social point of view. In United States, about22,240 new cases and 14,030 deaths are estimated to be caused by this disease for2013 [1,2].
The incidence of EOC increases with age and it is most prevalent in the eighthdecade of life, with a rate of 57/100,000 women. The median age at the time ofdiagnosis is 63 years, and > 70% of patients present with advanced disease [3].
About 80% of women present with late-stage disease and have a 5-year survivalrate of only 30%, while the 5-year survival rate is > 90% for women with earlystage EOC.
Because of EOC characteristic diffusion to peritoneal cavity and lymphatic vessels,radical surgery plays an important role in the diagnosis, staging, primary therapy andtreatment of recurrent disease [4]. Besides surgery, platinum/taxane-based chemo-therapy represents the standard approach to EOC [5]. According to the response totherapy, EOC can be divided in: platinum-refractory, if there is a progression within1 month or stable disease (SD) during first-line therapy; platinum-resistant, if there
is a response during therapy and a relapse within 6 months;platinum-sensitive, if there is a relapse after 12 months fromthe therapy [6]. EOC patients relapsing between 6 and 12months show an intermediate sensibility to platinum; for thisreason, they are called platinum-partially sensitive. Longerthe interval from the end of platinum-based chemotherapy,better is the outcome using platinum again [7,8].Moreover, based on the classical abdominal spread, besides
classical chemotherapy which has been in use over the years,an intraperitoneal chemotherapy has been developed [9].The response rate (RR) to chemotherapy is high, sometimes
impressive, but unfortunately 75% of patients who initiallyrespond to conventional chemotherapy relapse and die. Recur-rent EOC constitutes a very poor prognosis disease, forcingpatients to receive multiple lines of chemotherapy, with unsat-isfactory results due to the occurrence of drug-resistant cancerclones. For these reasons, and in order to identify more appro-priate therapeutic options, a considerable scientific interesttoward the identification of alternative molecular pathways,involved in ovarian carcinogenesis, has developed; moreover,a large number of novel molecular targeted agents and innova-tive therapeutic associations of chemotherapy are currentlyunder investigation for the treatment of EOC [7].Among the new drugs studied for EOC, bevacizumab (BV)
has shown activity in association with standard chemotherapyin several Phase III trials (Table 1) [10].ICON7 [11] and GOG218 [12] trials incorporated mainte-
nance BV for set periods of time after the completion of sixcycles of chemotherapy. Maintenance treatment with BVextended the length of progression-free survival (PFS) inboth studies, but the advantage of BV therapy stopped 10months after the cessation of treatment. The ICON7 studyshowed the best overall PFS advantage for high-risk subgrouppatients, which has characteristics more similar to thosepatients randomized in the GOG218 study. In this group,
a statistically significant overall survival (OS) benefit wasdemonstrated with the use of additional maintenance BV[13]. These results indicate that disease burden could play a crit-ical role in how tumors respond to vascular endothelial growthfactor (VEGF) pathway inhibition.
In the platinum-sensitive relapse, BV has also recently beenshown (OCEANS) to improve PFS when given in conjunc-tion with carboplatin--gemcitabine and then as single-agentmaintenance until disease progression [14,15]. Surprisingly, noOS benefit has been shown, which could be explained partlyby crossover but possibly also because most of these patientshad several further lines of chemotherapy.
In platinum-resistant relapse, a randomized Phase III trial(AURELIA) reported an increase in RR and a doubling ofPFS in those patients who received BV in addition to single-agent chemotherapy; OS data are expected in 2013 [16].
Based on the promising results obtained with BV in EOC,several studies have been conducted and others are underwayto evaluate new molecules active against angiogenesis.
2. Angiogenesis in EOC
In 1971, Folkman proposed that angiogenesis and neovascu-larization are capable of facilitating the tumor growth andthe metastatic process, allowing malignant cells to spread inthe circulatory system [17,18].
Angiogenesis is a multistep process driven by tumor-generated growth factors that operate along several convergentand divergent pathways, consisting of an initiation phase and amaturation phase. The initiation phase is activated by tumor-derived cytokines (as VEGF) and is characterized by the pro-duction and occurrence of permeable microvascular networksderived from existing blood and lymphatic vessels. In thesuccessive maturation phase, these morphological changesbecome functional by a biological point of view, favoring theactivation of tumor proliferation, invasion and metastasis [19].
Moreover, increased angiogenesis, as manifested by incre-ased tumor microvessel density (MVD) has been associatedwith a decreased delivery of chemotherapeutic agents andworse clinical outcome in a variety of solid tumors, includingEOC [20,21].
Overall, the published data indicate that a high degree oftumor angiogenesis is predictive of poor clinical outcome,with three studies reporting that higher MVD is an indepen-dent prognostic factor for improved survival in women withadvanced EOC [22-25].
The CD105 marker is actually utilized to measure MVD,because it is expressed almost exclusively on endothelial cellsin solid tumors undergoing neoangiogenesis and because itmodulates angiogenesis by regulating cellular proliferation,differentiation and migration [26]. Two studies investigatedCD105/MVD in EOC and found it to be an independentpredictor of poor survival [27,28].
Further, clusterin (CLU), a multifunctional glycoprotein,is ubiquitously produced in mammalian tissues and its
Article highlights.
. Ovarian cancer is the most lethal gynecological cancerwith a high rate of recurrence. The introduction of newtherapies is an urgent objective.
. Angiogenesis is one of the biological phenomena ofmajor interest in the development of newtarget therapies.
. BV, a monoclonal anti-VEGF antibody, is the moststudied drug in this area, and results in ovarian cancershow interesting results.
. Other angiogenesis inhibitors show promising andattractive activity in EOC; in particular, aflibercept seemsto play an interesting role in the clinical management ofneoplastic ascites.
. TKI and other target therapies are now extensivelyinvestigated but currently lack definitive results thatallow us to use these drugs in clinical practice.
This box summarizes key points contained in the article.
overexpression in EOC appears to be correlated with increasedtumor angiogenesis. This established the role of CLU as anoncogene in the biology of EOC [29].
3. Angiogenesis regulation
Without vascular provided oxygen and nutrients, tumorsstruggle to grow beyond 2 mm in diameter. Blood vessel for-mation in tumors involves several different processes and isregulated by the balance of proangiogenic and antiangiogenicfactors [30,31].
VEGF family members are believed to be the most impor-tant proangiogenic factors. VEGF-A is thought to be thekey controller of the angiogenic switch. VEGF-A promotesangiogenesis by stimulating endothelial cell proliferation andmigration, altering blood vessel permeability and controll-ing the functional and morphological form of these vessels;it also can play a role in the non-sprouting vascularizationprocesses [32,33].
Although VEGF-A has been the most investigated in termsof its role in angiogenesis, other factors in the VEGF familysuch as VEGF-B and placental growth factor (PlGF) mayplay a role in tumor angiogenesis and/or escape from angio-genesis inhibition [34].
Thrombospondin, angiostatin and endostatin are principalantiangiogenic factors involved in downregulation of neo-angiogenesis [32,35].
Hypoxia is a major molecular controller of this switch.Transcriptional regulation of various angiogenesis-related pro-teins is exerted through hypoxia-inducible factors (HIFs) [36].
Many environmental factors, including hypoxia and lowpH, hormones (progesterone and estrogen), growth factors(endothelial growth factor, transforming growth factor-b,fibroblast growth factor [FGF], platelet-derived growth factor[PDGF] and insulin-like growth factor-1) and cytokines(interleukin [IL]-1 and IL-6), stimulate VEGF expression.In addition to exogenous factors, many tumorigenic muta-tions lead to VEGF upregulation. These can include muta-tions in cellular oncogenes, such as src, ras and bcr-abl, andin tumor suppressor genes, such as p53, p73 and vHL [37].
Further, angiopoietins, which are protein growth factorsthat promote angiogenesis -- the mechanism that drives theformation of blood vessels -- are added to these angiogenicfactors. There are now four identified angiopoietins: Ang1,Ang2, Ang3 and Ang4. Ang1 and Ang4 function as agonisticor activating ligands for Tie-2, whereas Ang2 andAng3 behave as competitive antagonists. They function bybinding their physiological receptors, Tie-1 and Tie-2. Theseare receptor tyrosine kinases, so named because they mediatecell signals by inducing the phosphorylation of key tyrosines,thus initiating cell signaling. It is somewhat controversialwhich of the Tie receptors mediate functional signals down-stream of Ang stimulation. But it is clear that at least Tie-2is capable of physiological activation as a result of bindingthe angiopoietins [38].
EOC overexpress proangiogenic factors including VEGFs,FGF, angiopoietin, PDGFs and proangiogenic cytokinessuch as tumor necrosis factor-a and IL-6 and IL-8 [37,39,40].
The VEGF axis consists of a family of structurally relatedproteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E
Table 1. BV in ovarian cancer.
Trial Phase Treatment Patients RR
(%)
p PFS
(m)
p OS
(m)
P
GOG 218 (2011) III CPCP--BVCP--BVBV
625625625
---
---
10.311.214.1
0.16< 0.001
39.338.739.7
0.760.45
ICON 7 (2011) III CP--BVCP--BVBV
764764
4867
< 0.001 17.419.8
0.004 NRNR
--
OCEANS (2012) III CGCG--BV
242242
57.478.5
< 0.0001 8.412.4
< 0.001 35.233.3
AURELIA III ChemotherapyChemotherapy--BV
182179
12.630.9
0.001 3.46.7
< 0.0001 --
--
GOG170d (2007) II BV 62 21 - 4.7 - 17 -Garcia et al. (2007) [132] II Methronomic cyclophosphamide--BV 70 24 - 7.2 - 16.9 -Cannistra et al. (2008) [133] II BV 44 15.9 - 4.4 - 10.7 -Micha et al. (2007) [134] II CP--BV 20 80 - - - - -Penson et al. (2010) [135] II CP--BVBV 62 76 - 36 (58%) - - -Rose et al. (2009) [136] II Oxaliplatin--docetaxel--BV 95 62 - 12 (70 %) - - -Konner et al. (2011) [137] II Paclitaxel--BV--paclitaxel/CP i.p. 41 - - 28.6 - - -Tillmanns et al. (2010) [138] II Nab-paclitaxel--BV 48 50 - 8.08 - 17.5 -Horowitz et al. (2011) [139] II Oxaliplatin--gemcitabine--BV 19 - - 9.2 - 28 -OCTAVIA (2012) II CP--BVBV 189 - - - - - -
and PlGF, with VEGF-A being the major mediator ofangiogenesis [41].These proteins interact with three VEGF tyrosine kinase
receptors (VEGFR-1 -- 3) [42,43].Various factors such as inositol 1,4,5-trisphosphate (Ins-P3),
phosphoinositide 3-kinase (PI3-kinase), mitogen-activated pro-tein kinase (MAP kinase) and Janus associated kinase-signaltransducer and activator of transcription (JAK-STAT) havebeen implicated in VEGF signal transduction [44]. Neuropilin-1 and neuropilin-2 are non-tyrosine kinase co-receptors thatenhance VEGF binding to its receptors and [45] high levels ofthese have been observed in EOC [46].Notably, in EOC cells, VEGF expression was correlated
with activation of signal transducers and activators of trans-cription (STAT) 3 and 5.Moreover, VEGFR-1 and VEGFR-2expression was correlated with STAT3 and STAT5 expression,respectively [47].These findings suggest that VEGF/VEGFR autocrine loops
may play a role in stimulating the growth and progression ofEOC. Accordingly, one could speculate that blocking VEGFin EOC may produce direct antitumor effects in addition toantiangiogenic effects [48].Recently, it has been suggested that VEGF also exerts an
immunosuppressive effect in cancer as it is correlated withlow levels of IL-12, inhibition of dendritic cell maturation,low numbers of natural killer T cells and upregulation ofT-regulatory cells [49-53].Also, VEGF inhibits apoptosis of the newly formed hyper-
have been associated with advanced stage, poorly differenti-ated tumors, increased incidence of metastases, occurrenceof large volume ascites and decreased survival [60-65].Regarding the PDGF that have been detected in EOC, its
receptors are essential to recruitment of pericyte, a criticalcomponent of maturing blood vessels, and are associatedwith higher grade tumors and decreased survival. PDGFsecretion by tumor cells may also recruit stromal cells that fur-ther support angiogenesis through the release of VEGF [60].Moreover, there are a number of other antiangiogenic tar-
gets that have emerged that are becoming more clinically rele-vant and include Zeste homolog 2 (EZH2) and some miRNAssuch as miR-10b and miR-196b. EZH2 is the catalytic subunitof polycomb repressive complex 2, which generates a methyla-tion epigenetic mark at lysine 27 residue of histone H3(H3K27me3) to silence gene expression. EZH2 is often over-expressed in EOC cells and in ovarian cancer-associated stro-mal endothelial cells. Notably, EZH2 has been linked toincreased angiogenesis through methylation and silencing ofthe antiangiogenic factor vasohibin 1 in EOC [61-65].Further, recent studies have shown that some miRNAs are
involved in the regulation of vascular development andangiogenesis [62].The global inhibition of Dicer and Drosha, two key enzy-
mes for miRNAs biogenesis, led to impaired angiogenesis [63].
Some miRNAs such as miR-10b and miR-196b have beenidentified to promote angiogenesis by directly regulating bonemarrow-derived endothelial progenitor cells, whereas miR-126induces angiogenesis by increasing VEGF expression [64,65].
Conversely, miR-221 and miR-222 inhibit angiogenesis bytargeting human proto-oncogene c-Kit receptors in endothe-lial cells [66].
Data from miRNAmicroarray analysis show that some miR-NAs are aberrantly expressed in ovarian cancer, thus indicatingthe involvement of miRNAs in ovarian cancer development [67].
Overexpression of miR-199a and miR-125b inhibitedtumor-induced angiogenesis associated with the decrease ofHIF-1a and VEGF expression in EOC cells. Direct targetsof miR-199a and miR-125b HER2 and HER3 were function-ally relevant. Forced expression of HER2 and HER3 rescuedmiR-199a- and miR-125b-inhibiting angiogenesis responsesand Akt/p70S6K1/HIF-1a pathway. These evidences providea rationale for new therapeutic approach to suppress tumorangiogenesis using miR-199a, miR-125b or their mimics forovarian cancer treatment in the future [68].
4. Antiangiogenic target therapies in EOC
Blocking proangiogenic factors has been shown to be an effec-tive strategy for controlling EOC tumor growth [35].
There are two primary strategies to inhibit the VEGFpathway: i) inhibition of the VEGF ligand with antibodiesor soluble receptors and ii) inhibition of the VEGFR withtyrosine kinase inhibitors (TKIs) or receptor antibodies. Ther-apies that specifically target the VEGF ligand or its receptors,VEGFR-1 and VEGFR-2, inhibit only the VEGF pathwayand therefore inhibit angiogenesis without disrupting ‘off-target’ pathways (Table 2). In contrast, TKIs that target thereceptor have a wider range of inhibitor effects and may dis-rupt other secondary pathways that are mediated throughreceptor kinases (Table 3). To improve the therapeutic benefitand counteract compensatory escape mechanisms, anotherapproach to antiangiogenic therapy is the simultaneous target-ing of multiple angiogenic pathways at once, including thePDGF and FGF pathways. FGF and its receptors play animportant role in the development of resistance to VEGFpathway inhibitors [35].
In preclinical models, blocking VEGF, PDGF and FGFpathways suppress tumor angiogenesis and MVD to a greaterextent than selectively blocking the VEGF pathway. Severalagents that target two or three pathways have been evaluatedin Phase II trials in women with recurrent EOC. The maindisadvantage is the potential for enhanced side effects [69].
Another potential target is Ephrin type-A receptor 2(EphA2), an oncoprotein and tyrosine kinase receptor that isassociated with high MVD. EphA2 is overexpressed in a num-ber of malignancies, including EOC, but it is absent orexpressed at low levels in normal epithelial tissue [70].
An alternative approach to thwarting angiogenesis is todisrupt the newly established vessels supplying the cancers
by vascular disruptive agents (VDAs). These generally causerapid blood vessel shutdown (within minutes) and subsequenttumor necrosis. Strategies such as photodynamic therapy andradiofrequency ablation that directly damage tumor massescan be considered as VDAs (they also damage existing bloodvessels), as are some cytotoxics such as vinca alkaloids thatinhibit spindle formation causing cell-cycle arrest in the rapidlydividing endothelial cells as well as malignant populations [71].
5. Monoclonal antibodies
5.1 AfliberceptAflibercept (VEGF-Trap) is a soluble fusion protein compris-ing truncated VEGFR-1 and VEGFR-2-binding domainscombined with the Fc portion of IgG1 [72]. This moleculeserves to function as a decoy receptor, binding with high affin-ity to the VEGF-A ligand and thus preventing VEGFR-1 andVEGFR-2 binding and subsequent stimulation [72]. It wasfound to have impressive picomolar-binding affinity toVEGF ligand and promising antitumor activity in trans-formed cancer cell lines [72]. Two single-agent randomizedPhase II studies were done in patients with recurrent EOC.
Results from these studies showed that in heavily pretreatedpatients, single-agent aflibercept could induce tumor response,delay progression, prevent new occurrence of ascites and sub-stantially prolong the need for paracentesis.
From Phase I study, the recommended Phase II doses of afli-bercept and docetaxel were found to be 6mg/kg and 75mg/m2,respectively. A total of 46 evaluable patients were enrolled in thePhase II trial. The overall RR was 54%. Adverse events (AEs)specifically associated with aflibercept were grade 1 -- 2 hyper-tension and grade 2 proteinuria. Of the five complete responses(CRs) achieved with the combination aflibercept--docetaxel,one was in a patient with a former use of BV [73].
In another Phase II study [74], 55 patients with advanced che-moresistant EOC and recurrent symptomatic malignant asciteswere randomly assigned to either aflibercept or placebo. Mean
time to repeat paracentesis was significantly longer with afliber-cept than with placebo (p = 0.0019) [74]. The most commongrade 3 or 4 treatment-emergent AEs were dyspnea, fatigue orasthenia and dehydration. The frequency of fatal gastrointestinal(GI) events was higher with aflibercept than with placebo [74].
In a Phase II study [75], 215 women with advanced chemo-resistant EOC were treated with single-agent aflibercept at adose of either 2 or 4 mg/kg every 2 weeks. RECIST RR was7.3 and 3.8% for the 4 and 2 mg/kg dose, respectively. Themedian PFS was 13.3 and 13 weeks with the 4 and 2 mg/kgdoses, respectively. The median OS was 49.3 and 55.4 weekswith the 4 and 2 mg/kg doses, respectively. Of the 40 patientsin both dose groups who had evaluable ascites at baseline,77.5% had either a complete disappearance or stabilizationof their ascites [75,76].
In the antiangiogenesis targeting scenario, mainly with anti-VEGF agents and in particular with VEGF-Trap agents, theemerging role of aflibercept is becoming an attractive therapeu-tic strategy in EOC. Certainly, the favorable pharmacokineticcharacteristics, the demonstrated activity of the drug as singleagent and in patients with BV refractory disease and the poten-tial synergic clinical activity in association with chemothera-peutic drugs and other targeted agents, will favor in the nextfuture further investigations in randomized clinical trials withaflibercept. Given the expensive costs deriving from an exten-sive use of antiangiogenesis inhibitors in clinical oncology, itis evident that population-wide use of these drugs should becarefully justified from a pharmacoeconomic point of view.
5.2 Ramucirumab (IMC-1121B)Ramucirumab is a fully human IgG1 monoclonal antibody(mAb) targeting VEGFR-2 [77]. Unfortunately, there are actu-ally few trials concluded with this novel antiangiogenic agent.In a Phase I study, one partial response (PR) and one diseasestabilization in two heavily pretreated EOC patients wererecently reported [77]. Currently, this drug is undergoingdifferent Phase II and Phase III studies in recurrent EOC.
Table 2. Aflibercept and other antiangiogenic drugs in ovarian cancer.
Trial Phase Treatment Patients RR
(%)
P PFS
(m)
p OS
(m)
p
Coleman et al. (2011) [73] I/II Docetaxel--aflibercept 46 54 - 6.4 - 26.6 -Gotlieb et al. (2012) [74] II Aflibercept
Placebo2926
--
--
--
--
12.916.0
0.93
Van Cutsem et al. (2008) [140] I Aflibercept 38(5) - - - - - -Moroney et al. (2009) [75] II Aflibercept 4 mg/kg
Aflibercept 2 mg/kg215 7.8
3.8--
13.313.0
--
49.355.4
--
Isambert et al. (2008) [141] I Docetaxel--aflibercept 54 - - - - - -Spratin et al. (2010) [142] I Ramucirumab 36 - - - - - -Herbst et al. (2009) [143] I AMG386 32 - - - - - -Karlan et al. (2012) [81] II Paclitaxel--AMG386 10 mg/kg
5.3 EA5EA5 is a monoclonal EphA2-agonist antibody. Preclinicalstudies show promise for the treatment of EOC with anti-EphA2 agents. Further EphA2 specificity has been achievedby conjugating an anti-EphA2 mAb (1C1) with a chemother-apeutic agent (monomethyl auristatin phenylalanine,MMAF). The 1C1--MMAF conjugate bound to EphA2-pos-itive EOC cells but not to EphA2-negative cells. In an ortho-topic murine model, treatment with 1C1--MMAFsignificantly inhibited tumor growth by 85 to 98% andincreased survival from a mean of 29.4 to 60.6 days [78].A Phase I clinical trial is being developed.
5.4 VolociximabVolociximab is a chimeric mAb directed against a5b1-integrin, which is found on activated endothelial cells inangiogenesis. Delmonte et al. reported on their Phase I/IIdata in platinum-resistant ovarian cancer patients treatedwith liposomal doxorubicin and volociximab. Only prelimi-nary results are available from the Phase I portion of the study,which reveal that the combination is well tolerated [79].
6. Angiopoietin peptibodies
6.1 Trebananib (AMG386)AMG386 is a peptide--Fc fusion protein that targets angiogen-esis by inhibiting the binding of both angiopoietin 1 and 2
to the Tie-2 receptor, thereby inhibiting vascular maturationand reducing the impact of VEGF stimulation [80].
In a Phase II randomized trial, 161 patients with recurrentEOC were randomly assigned to receive paclitaxel (80 mg/m2
once weekly [QW], 3 weeks on/1 week off) plus intravenousAMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kgQW (arm B) or placebo QW (arm C) [80]. Median PFSwith AMG386 at 10 and 3 mg/kg was 7.2 and 5.7 months,respectively, compared to 4.6 months with placebo (hazardratio [HR] = 0.76; p = 0.165) [81]. Severe AEs ‡ 3 that weremore common in patients treated with AMG 386 includedhypokalemia, peripheral neuropathy, anorexia, neutropenia,dyspnea and peripheral edema [81].
The result of this study suggests that inhibiting angiogenesisvia Tie-2/angiopoietin pathway inhibition may offer an effec-tive approach for the treatment of advanced recurrent ovariancancer. Treatment with QW AMG386 plus paclitaxel mayresult in prolonged median PFS. The therapy was well toler-ated with a distinct and manageable toxicity profile. WeeklyAMG386 plus paclitaxel for the treatment of recurrent ovariancancer is being further investigated in a Phase II study (Trialin Ovarian Cancer 1 [TRINOVA-1]; ClinicalTrials.gov,NCT01204749). This Phase II study, evaluating trebananibplus paclitaxel versus placebo plus paclitaxel in recurrentovarian cancer, met its primary end point of PFS.A statistically significant difference was observed in PFS witha 34% reduction in the risk of disease progression or death(HR = 0.66; 95% CI: 0.57, 0.77; p < 0.001). The median
Table 3. TKI in ovarian cancer.
Trial Phase Treatment Patients RR
(%)
p PFS
(m)
p OS
(m)
p
Siu et al. (2006) [144] I Gemcitabine--sorafenib 42 - - - - - -Matei et al. (2011) [89] II Sorafenib 71 - - 2.1 - 16.33 -Bodnar et al. (2011) [90] II Sorafenib 11 - - 2.0 -- 11.78 -Rasumabbaiah et al. (2011) [91] II Sorafenib--weekly topotecan 28 16.7 - 3.7 - 14.0 -Welch et al. (2010) [92] II Gemcitabine--sorafenib 43 - - - - 13.0 -Kohn et al. (2011) [93] II BV--sorafenib 25 - - - - - -Faivre et al. (2006) [145] I Sunitinib 15 3.3 - 6.4 - - -Biagi et al. (2011) [146] II Sunitinib 30 - - 4.1 - - -Baumann et al. (2012) [96] II Sunitinib 50 mg intermittent
Sunitinib 37.5 mg continuous3637
16.75.4
4.82.9
0.3048 13.613.7
0.838
Du Bois et al. (2010) [147] I Carboplatin--paclitaxel--nintedanib 22 - - 6 -- 10 - - -Ledermann et al. (2011) [98] II Nintedanib
Placebo4340
- 9 (16.3%)9 (5%)
0.06 - 0.51
Friedlander et al. (2010) [102] II Pazopanib 36 18 - - - - -Matulonis et al. (2009) [105] II Cediranib 46 - - 5.2 - 16.3 -Hirte et al. (2008) [106] II Cediranib in platinum-sensitive
Cediranib in platinum-resistant2634
4129
--
--
--
11.9 --
Matulonis et al. (2012) [148] II ENMD-2079 64 - - 6 (22%) - 12 -Alberts et al. (2007) [149] II Imatinib 19 - - 2 - 10 -Matei et al. (2008) [113] II Docetaxel--imatinib 23 21.7 - 1.77 - 9.56 -Coleman et al. (2006) [150] II Imatinib 16 - - - - -Russel et al. (2008) [114] II Imatinib 60 - - 1.74 - 16.39 -Posadas et al. (2007) [151] II Imatinib 23 - - - - - -
PFS was 7.2 months in the trebananib arm versus 5.4 monthsin the control arm.
Important questions are: i) based on efficacy and a moretolerable toxicity profile, could trebananib replace BV andii) can targeting the angiopoietin axis address resistance toBV in patients progressing on this treatment?
The ongoing first-line (TRINOVA-3) and recurrent(TRINOVA-1 and 2) ovarian cancer clinical trials will helpto answer these questions.
6.2 Asparagine--glycine--arginine--human tumor
necrosis factorAsparagine--glycine--arginine--human tumor necrosis factor(NGR-hTNF) is a therapeutic agent that specifically targetstumor blood vessels. It is formed by the fusion of thepeptide cyclic peptide Cys-Asn-Gly-Arg-Cys (CNGRC),which binds to tumor vessels, with the hTNF-a [82,83].
The peptide CNGRC interacts selectively with tumorblood vessels by binding to an isoform of the receptorCD13, located on endothelial cells of tumor vessels, but notto the molecules of CD13 expressed by normal tissues. Invivo, the binding of NGR-hTNF to TNF receptor and toCD13 expressed on endothelial cells of tumor vessels inducesan increase of vascular permeability, thus enhancing the effi-cacy of chemotherapeutic agents administered in combina-tion, as well as the death by apoptosis of endothelial cells,with the result of limited tumor growth [84].
Lorusso et al. conducted a Phase II study to evaluate theactivity and safety of the combination of NGR-hTNF anddoxorubicin in advanced ovarian cancer patients who hadrelapsed after platinum/taxane-based chemotherapy. A totalof 37 patients with radiologically documented tumor progres-sion after the last treatment regimen were enrolled to receiveNGR-hTNF 0.8 mg/m2 and doxorubicin 60 mg/m2 every 3weeks. The results of this study are interesting. A 23% RR,with an overall disease control rate (DCR) of 66% maintainedfor a median time of 6.6 months, a 5 months median PFS and17 months median OS were achieved. Moreover, the combi-nation of the two drugs has been well tolerable [85].
Given the outstanding use of doxorubicin in ovarian can-cer, and the preclinical synergism between low-dose TNFand liposomal formulation of doxorubicin, a randomizedPhase II trial is ongoing to compare PFS in platinum-resistantovarian cancer patients randomized to NGR-hTNF plus ananthracycline versus anthracycline alone [86].
7. Small molecules
7.1 SorafenibSorafenib is an oral kinase inhibitor with several targets: Ras/Raf/Mek/ERK pathways, VEGFR-2 and -3 and PDGFR-b [87].
A German Phase II trial found that adding sorafenib to car-boplatin/paclitaxel as neoadjuvant therapy for patients withadvanced stage IIIC/IV EOC and large-volume ascites wasnot feasible [88]. Phase II trial by Matei et al. [89], in 2011,
investigated the use of sorafenib in monotherapy. The trialenrolled 71 patients with recurrent EOC [89]. Grades 3 to4 toxicities were dermatological, metabolic, GI, constitu-tional, cardiovascular, hematological and pulmonary. Antian-giogenic class AEs were hypertension and proteinuria. At afollow up of 6 months, there were two PR by RECIST criteria,while 14 patients showed SD [89].
A Phase II trial to evaluate toxicity and efficacy of sorafenibin third-line treatment of EOC was started byBodnar et al. [90] in 2011. No CR or PR was observed andtwo patients had a SD for 4 months. No one achieved6 months PFS and the study was closed. Grade 3 AEs wereleukopenia and neutropenia and hand-foot syndrome.
Phase I/II by Ramasubbaiah et al. [91], published in 2011,investigated the use of sorafenib and weekly topotecan inpatients with platinum-resistant EOC. Twenty-eight patientswere evaluated for efficacy: no CR occurred; four PR in thePhase I and one PR in the Phase II were observed [91]. Totalobjective response was 16.7%; 10 patients had SD amongPhase I and Phase II. Duration of SD was short, with amedian of 3.9 months for all patients and 4.2 months forthe Phase II cohort [91]. Topotecan/sorafenib showed animportant myelotoxicity, in particular thrombocytopenia [91].Responses were better in the Phase I study, probably becausein this setting sorafenib and topotecan were used in a higherdose [91].
Another Phase II clinical trial [92] was conducted byWelch et al., in 2010, with the combination sorafenib--gemcitabine; 43 patients were enrolled: two had a PR; tenhad a response or SD for at least 6 months. Median time toprogression was 5.4 months [92].
Preliminary results from an ongoing Phase II study [93] ofintermittent sorafenib and BV in BV-naıve patients withrecurrent EOC showed PR in 6 of 25 evaluable patients andclinical benefit rate of 88% [93]. Grade 3/4 AEs includedhypertension, thrombosis and elevated liver enzymes; grade2 hand-foot syndrome occurred in 80% of patients [93].
Moreover, at the recent 2013 ASCO annual meeting, datafrom a randomized Phase II trial were reported that comparedefficacy of paclitaxel/carboplatin (PC) with and without sora-fenib in first-line chemotherapy of patients with stage III/IVEOC. The addition of sorafenib did not improve the efficacy(PFS and OS) of standard first-line PC in patients with stageIII/IV ovarian carcinoma, resulting in additional toxicity [94].
7.2 SunitinibSunitinib is a novel multitargeted small molecule TKI. Potentactivity was demonstrated in preclinical models againstVEGFR and PDGFR [95].
Seventy-three patients were randomly allocated to receiveeither 50 mg/day sunitinib for 4 weeks in a 6-week cycle(arm 1) or 37.5 mg/day sunitinib continuously (arm 2) [86].Only 5.6% of patients in the arm 1 completed the treatmentas planned, whereas none in the other group did. In arm 2,46 grade 3 and grade 4 AEs occurred in 22 patients, whereas
Beyond BV: investigating new angiogenesis inhibitors in ovarian cancer
in the arm 1, 60 grade 3 and grade 4 AEs were reported in25 patients. We observed six objective responses (CR or PR)in arm 1, and two in arm-2. Both treatment schedules resultedin similar median PFS and median OS [96].
7.3 Nintedanib (BIBF1120)Nintedanib (BIBF1120) is a novel agent targeting VEGFR-1,-2 and -3, PDGFR, FGFR-1, -2 and -3, members of the v-srcsarcoma viral oncogene homolog (Src) family and fms-liketyrosine kinase 3 (Flt3) [97].BIBF1120 was studied in a randomized Phase II trial in
83 patients who had just completed chemotherapy forrelapsed EOC, with evidence of response, but at high risk offurther early recurrence [98]. A treatment-free interval £ 12months between the two last therapies was required. Thepatients were randomly assigned to receive maintenance ther-apy using BIBF1120 continuously for 36 weeks or placebo.The study suggested that BIBF1120 has efficacy in this setting(HR = 0.65; p = 0.06) [98]. There was a higher rate of grade3 or 4 liver toxicity in patients treated with BIBF1120compared with patients on placebo (p < 0.001) [98].Probably during 18th ESGO congress, preliminary data
from LUME-ovar 1 study will be presented. The trial was per-formed to evaluate if BIBF1120 in combination with PC ismore effective than placebo in combination with PC infirst-line treatment of patients with advanced ovarian cancer.The primary end point of the study was PFS, and safety infor-mation about BIBF1120 plus PC will be obtained [99].
7.4 PazopanibPazopanib targets VEGFR-1, -2 and -3, PDGFR, FGFR-1and -3 and c-kit [100]. Pazopanib demonstrated manageablesafety profile and clinical activity in a Phase I study in patientswith different types of tumors, including EOC [101].VEG104450 is a Phase II study [102] evaluating pazopanib
in patients with pretreated recurrent EOC with completeCA-125 response to initial platinum-based chemotherapyand subsequent CA-125 elevation. The primary end pointof CA-125 response was seen in 11 of 36 patients, with amedian duration of response of 113 days; an additional20 patients had SD with a median duration of 80 days [102].In patients with measurable disease at baseline, the overallCA-125-assessed RR was 18% [102]. The most common grade3 AEs were fatigue and g-glutamyl transpeptidase elevationfollowed by diarrhea and alanine transaminase elevation [102].Recently, a Phase III trial, evaluating pazopanib versus pla-cebo in women who have not progressed after first-line che-motherapy, showed interesting results at the first evaluation:patients in the pazopanib arm had a median PFS of17.9 months compared with 12.3 months in the placebogroup (HR = 0.766; 95% CI: 0.64 -- 0.91; p = 0.0021);data regarding OS showed similar results in both arms, butthis interim analysis has been conducted only on a smallpart of the entire population enrolled in the trial [103].
7.5 CediranibCediranib targets VEGFR-1, -2 and -3, PDGFR, FGFR-1and c-kit [104]. Cediranib has been evaluated in two Phase IIstudies in patients with either platinum-resistant or -sensitiverecurrent EOC.
In the first study, the primary end point of clinical benefitrate (CBR) was observed in 30% of patients with a mean dura-tion of response of 3.9 months. Themost common drug-relatedgrade ‡ 3 AEs were hypertension, fatigue and diarrhea [105].
In the second study, platinum-sensitive and platinum-resistant patients had RR of 41 and 29%, respectively andmedian survival was 11.9 months. The most common grade‡ 3 AEs were hypertension and fatigue [106]. ICON6 studiedcediranib or placebo plus carboplatin and paclitaxel: in thefirst phase of the trial where 60 patients were evaluated, theprimary outcome was safety: 19 of 60 patients discontinuedcediranib or placebo during chemotherapy; grade 3 and grade4 toxicity was experienced by 50% of population included inthe cediranib arm; however, 86% of patients in the cediranibarm completed six cycles of chemotherapy [107].
In April 2013, the final analysis of all 486 patients enrolledin this trial was started and definitive results are awaited.
7.6 Vatalanib (PTK787)Vatalanib is a TKI most selective for VEGFR-2, but it inhibitsother well-known targets, such as VEGFRs, PDGFR and c-kit[108]. A Phase I study of escalating doses of vatalanib in com-bination with chemotherapy revealed that the combinationwas feasible and well tolerated as first-line therapy in patientswith stages IC -- IV disease [109].
7.7 ENMD-2076ENMD-2076 is a novel orally active, small molecule kinaseinhibitor with mechanisms of action that involve inhibitionof VEGFRs, FGFRs, Flt3 and c-kit [110].
In a Phase II study, ENMD-2076 was taken daily withoutinterruption [111]. While 52% of patients dropped out of thestudy for progressive disease, 19% were discontinued forAEs. The PFS rate at 6 months was 22% with a mediantime to progression of 3.6 months. About 58% of patientshad SD or a PR. Five patients had PRs and the median dura-tion of response was 7 months [98]. Median OS was estimatedat 12 months. About 64% of patients had some reduction inCA125 during the study. However, CA125 responses werenot predictive of CBR in all cases. The mostcommon > grade 3 AEs were hypertension and fatigue [111].
7.8 ImatinibImatinib mesylate is a 2-phenylaminopyrimidine derivativethat selectively inhibits the abl, c-kit and PDGFR tyrosinekinases [112].
In a Phase II trial, 23 eligible patients had recurrent,platinum-resistant or refractory EOC. Imatinib mesylate wasadministered with docetaxel. The overall RR was 21.7% and
included 1 CR and 4 PRs. An additional three patients hadSD for > 4 months [113].
In Phase II trial by Russel et al. [114], 60 EOC patients wereenrolled. The median PFS for the whole group was 1.74months. The only complete responder had a PFS of 8.05months and duration of response of 6.34 months. Themedian OS was 16.39 months. The most commonly observedgrade 3/4 toxicities were neutropenia, GI events, dermatologiceffects and pain and electrolyte disturbances [114].
7.9 BrivanibBrivanib is a TKI with a selective action on VEGF and FGFsignaling [115].
It is orally administered as L-alanine ester prodrug, brivanibalaninate [116] with strong antiangiogenic effects on differentkind of tumors.
On this basis brivanib was tested in EOC in a Phase IIrandomized discontinuation trial in which the drug wasadministered for 12 weeks, after which patients with CR orPR continued in open-label brivanib and patients with pro-gressive disease went off the study and patients with SDwere randomized to receive brivanib or placebo. Of the126 patients, 12 had PR and 43 had SD. Among the 39 ran-domized patients, median PFS was 4 months for brivanib and2 months for placebo (HR = 0.54; p = 0.11). Grade 3 AEswere about 5%, an increase of liver enzyme being the mostfrequent [117].
7.10 CabozantinibCabozantinib is an orally bioavailable TKI, with action againstMet and VEGFR-2. Cabozantinib showed tumor regression inxenograft models [118], particularly in progression of osteolyticand osteoblastic lesions from castration-resistant prostatecancer [119].
These fascinating results led to a trial of non-discontinuationin several tumors, with a population of 68 EOC patients. After12 weeks of open-label treatment, patients with SD were ran-domized to receive cabozantinib or placebo, while patientswith PR continued open-label cabozantinib. Patients with pro-gressive disease (PD) discontinued treatment. The overallDCR (PR + SD) at 12 weeks is 58% (30 of 51). The medianduration of response and PFS have not been reached [120].
8. New others anti-angiogenic agents
8.1 Vascular disruptive agentsAn alternative approach to thwarting angiogenesis is to disruptthe newly established vessels supplying the cancers by VDAs.These generally cause rapid blood vessel shutdown (withinminutes) and subsequent tumor necrosis [73].
Conventionally, the molecules known as VDAs are eitherderivatives of flavone acetic acid that are thought to act byinvoking cytokine release such as TNF-a or tubulin-bindingagents such as combretastatin. The selectivity of the tubulin-binding agents is thought in part to be due to the rapid
division of endothelial cells but these agents also cause distor-tion of immature endothelial cells which lack a pericyte coating.This distortion induces thrombosis and vessel collapse [121].
VDAs have minimal single-agent activity because, despitecausing necrosis of the main cancer mass, a viable rim is left,which repopulates the cancer. Based on preclinical studies itappears that VDAs eliminate the less vascularized cells wheresystemically administered chemotherapeutic drugs are lesseffective and which are resistant to radiotherapy. Based onthis, a combination of standard chemotherapy and VDAshould be a well-balanced combination, acting on tumor tissuein all its parts.
Early single-arm Phase II studies in patients have shownthat the addition of VDAs such as vadimezan (DMXAA) orfosbretabulin (CA4P) to standard chemotherapy is well toler-ated and appears to produce a higher RR in platinum-resistantpatients [122].
Recruitment for two Phase II studies, ombrabulin/placebowith conventional carboplatin and paclitaxel chemotherapyand BV with or without fosbretabulin, is underway inplatinum-sensitive ovarian cancer in the United States(NCT01305213 and NCT01332656).
8.2 EZH2’s methyltransferase inhibitorsDZNep is the first reported inhibitor of EZH2’s methyltrans-ferase; it is an inhibitor of S-adenosylhomocysteine (SAH)hydrolase [123]. However, DZNep indirectly inhibits EZH2activity by causing the degradation of components of PRC2through increasing the cellular levels of SAH, the inhibitoryby-product of methyltransferase reaction. In addition, DZNepis non-specific with major effects on a number of other histonemethyl marks and, consequently, has been shown to be verytoxic [124]. In contrast, a number of new specific EZH2 meth-yltransferase inhibitors have been reported very recently,including most notably GSK126 and EPZ005687 and EI1[125-127]. Thus, inhibiting EZH2/PRC2 activity representsan attractive strategy for developing EOC therapeutics bytargeting both ovarian cancer cells and ovarian tumormicroenvironment.
8.3 OmbrabulinOmbrabulin, a synthetic water-soluble analog of combretasta-tin A4, is a tubulin-binding agent that targets the immatureneovasculature of tumors. Preclinical studies have shownthat ombrabulin causes shutdown of vascular blood flow byattacking endothelial cells within the tumor vasculature [128-130].
Unfortunately, data about ombrabulin in EOC treatmentwere negative; in fact, at the recent 2013 ASCO annual meet-ing, data from the Phase II trial OPSALIN, evaluatingwhether adding ombrabulin to CP improves outcomes inpatients with platinum-sensitive recurrent EOC was submit-ted. This analysis has suggested that there are no safety con-cerns or efficacy advantage in adding ombrabulin to CP inpatients with platinum-sensitive recurrent EOC. The study
Beyond BV: investigating new angiogenesis inhibitors in ovarian cancer
was discontinued due to limited probability of the ombrabu-lin arm to demonstrate PFS superiority at final analysis [131].
9. Conclusion
The treatment of ovarian cancer patients continues to be chal-lenging. Opportunities identified in the molecular microcosmof neoplastic pathways yield many promising targets (Table 4).High-grade serous EOC is characterized by the overexpres-
sion of VEGF, which has been recognized as a central promoterof the activation phase of angiogenesis.Angiogenesis is an important contributor to ovarian carci-
nogenesis and progression, providing a clear rationale for theuse of antiangiogenic drugs.VEGF expression and indices of angiogenesis in primary
tumors have been correlated directly with the extent of diseaseand inversely with PFS or OS. This growth factor is also pri-marily responsible for the development of malignant ascitesand pleural effusions characteristic of EOC, by increasingthe microvascular permeability, which is the biological mech-anism related to the activation phase of angiogenesis. Directtargeting of this pathway can be achieved by sequestration ofthe VEGF protein using mAbs or engineered binding-sitemolecules. Blockade of VEGFR-2 can be achieved withmAbs or inhibition of receptor-associated tyrosine kinasesusing low molecular weight agents. Besides the laboratory evi-dences, clinical trials also showed promising results with theinhibition of VEGF pathway, in particular BV, that hasbeen studied in several Phase III trials both in combinationwith chemotherapy and as a maintenance therapy after che-motherapy, even if there is a greater improvement in PFSrather than in OS.Although many other angiogenesis inhibitors are under
preclinical and clinical evaluation, in the next future there isa need to start large Phase III studies in order to test theirpotential efficacy and their toxicity profile in EOC; however,
at the same time, given the high cost of such trials and the ele-vated number of patients required, randomized Phase II trialswith enriched population, according to the selection oftargets, would be preferable.
10. Expert opinion
In addition, in recent years, the era of molecular-targetedtherapies have begun for ovarian cancer, in tune with whatis going on for other tumors.
In EOC, antiangiogenic agents have demonstrated aninteresting activity, in terms of both clinical response andPFS, in Phase II and III clinical trials; this activity was con-firmed both in the front line and relapsed setting.
Although the Phase III trials met their primary end pointsfor improvement in PFS, the magnitude of benefit was notas great as what had been anticipated based on the Phase IIdata in patients with recurrent disease. Owing to the designof the trials, it is not possible to state how much of theimprovement in PFS is related to the total duration of ther-apy, the integration with concurrent chemotherapy or themaintenance following chemotherapy. However, maximalbenefit was achieved in the population that received BV dur-ing and following chemotherapy. The combined impact ofcytoreductive surgery and chemotherapy would tend to mini-mize tumor-associated VEGF production, as well as the sizeof any residual disease, which is quite different from the man-agement of large-volume metastatic disease in other settings.Taken together, these effects could theoretically reduce theimpact of BV during primary chemotherapy and might favorusing BV in the setting of recurrent disease, as illustrated bydata from the OCEANS trial in platinum-sensitive recurrentdisease. Most of the serious events tended to occur during pri-mary chemotherapy and within the perioperative period, withfewer dose-limiting events noted during maintenance therapy.BV can be included as maintenance therapy in standard
Aflibercept X XRamucirumab XTrebananib XEA5 XSorafenib X X X XSunitinib X XImatinib X XCediranib X X X X XNintedanib X X X X Xbrivanib X XCabozantinib X XVatalanib X X XENMD-2076 X X X X X XPazopanib X X X X X X
chemotherapeutic regimens for advanced disease, and in thiscontext the use of other tyrosine kinases inhibitors need tobe elucidated.
However, according to the many experimental studies, thereis today a strong evidence for introducing novel angiogenesisinhibitors in the medical treatment of patients with advancedand recurrent EOC. BV in association with carboplatin andpaclitaxel, followed by maintenance treatment with BV, couldbe considered an attractive and active treatment for patientswith advanced EOC, but other angiogenesis inhibitors areunder careful evaluation for introduction to clinical practice.Nevertheless, further investigations and large clinical trials areneeded to understand the safety and effectiveness of the newagents in this setting, the optimal duration and timing of treat-ment, the activity in association with other targeted drugs andchemotherapeutic agents. Certainly, more important, it is nec-essary to identify biological factors predictive of efficacy inorder to choose the most appropriate antiangiogenic agentsin the integrated treatment of EOC.
However, critical issues remain unresolved, such as thecorrect identification of women most likely to benefit fromantiangiogenic agents, the elucidation of resistance to VEGFblockade and the development of targeted tumor-specificantiangiogenic therapies in order to avoid AEs associatedwith the inhibition of normal physiological angiogenesis.
Controversy still exists regarding when to start and to stopantiangiogenesis therapy as well as the choice of the optimalagent. Longer durations of maintenance therapy may improveefficacy because the benefit of therapy may be lost whenangiogenesis inhibition ends.
Mature data are awaited from ongoing studies evaluatingmultitargeted inhibitors of receptor-associated tyrosine kinasesin the setting of primary and maintenance therapy.
It is conceivable that clinical implementation is greatlyaided by uncovering predictive biomarkers that facilitateadministering these expensive drugs to a subgroup of patientsthat are likely to respond. Possibly, a more comprehensiveview on angiogenesis can help to determine which patientsmight benefit from antiangiogenic therapy. The contributionof different angiogenic factors and cell types involved in ovar-ian cancer-specific angiogenesis, as well as the mechanisms ofresistance to antiangiogenic drugs, might help to select theappropriate targets, and thereby drugs, for individual patients.
In this attractive and novel investigational field, certainlyangiogenesis represents a hallmark process that leads to cancerprogression and diffusion. According to this concept, it isabsolutely necessary to consider the different pathways thatare related to the angiogenic phenomenon; it consists of
several biochemical processes that occur as a result of interac-tion between molecules, such as VEGF, PDGF, FGF andprobably many others, and the related receptors.
Through studying these pathways, molecular targets fordeveloping therapeutic strategies have emerged. Antiangio-genic molecules have been developed and many clinical trialsare underway. It is of importance for angiogenesis researchin ovarian cancer to continue, since this is a promising areafor devising more effective treatments against ovarian andgynecological cancer.
Certainly, some critical aspects deserve careful reflection: alack of reliable predictors of therapeutic efficacy, the currentinability to prevent resistance to antiangiogenic treatment.,the most appropriate chemotherapeutic agents to be associ-ated with angiogenesis inhibitors, the duration of mainte-nance therapy with these novel targeted agents and the righttiming to use them.
An important and urgent topic is the identification of pre-dictive biomarkers in order to better tailor the treatment withVEGF-targeted therapy in ovarian cancer patients. In thisarea, prospective studies are in progress in breast and lungcancers, but unfortunately no data are available for ovariancancer.
In future, extensive clinical trials incorporating translationalresearch will be the best research model applied for the treat-ment of ovarian cancer. In this context, angiogenesis inhibitorswill have in the next future a growing role and importance inthe integrated therapy of ovarian cancer.
A careful andwell-documented interpretation of the ongoingstudies, involving targeted therapy with angiogenesis inhibitorsin ovarian cancer, may probably prevent the excessive and inap-propriate use of novel targeted agents and prevent the prema-ture discarding of drugs that could instead be of considerableinterest in this experimental field.
Therefore, there is full evidence that the refinements of theuse of antiangiogenic agents in clinical practice will requireadditional investigation in the next future in order to selectthe most active and safe targeted therapy in EOC.
Acknowledgment
F Tomao and A Papa have equally contributed to the prepa-ration of the article.
Declaration of interest
The authors state no conflict of interest and have received nopayment in preparation of this manuscript.
Beyond BV: investigating new angiogenesis inhibitors in ovarian cancer
