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Anti-angiogenic therapy in ovarian
cancer: Current understandings
and prospects of precision
medicine
Chao Mei
1†
, Weijing Gong
1
,
2†
, Xu Wang
1
, Yongning Lv
1
, Yu Zhang
1
,
Sanlan Wu
1
,
2
*
†
and Chunqi Zhu
1
*
†
1
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China,
2
Hubei Province Clinical Research Center for Precision Medicine for Critical
Illness, Wuhan, China
Ovarian cancer (OC) remains the most fatal disease of gynecologic malignant
tumors. Angiogenesis refers to the development of new vessels from pre-existing
ones, which is responsible for supplying nutrients and removing metabolic waste.
Although not yet completely understood, tumor vascularization is orchestrated by
multiple secreted factors and signaling pathways. The most central proangiogenic
signal, vascular endothelial growth factor (VEGF)/VEGFR signaling, is also the
primary target of initial clinical anti-angiogenic effort. However, the efficiency
of therapy has so far been modest due to the low response rate and rapidly
emerging acquiring resistance. This review focused on the current understanding
of the in-depth mechanisms of tumor angiogenesis, together with the newest
reports of clinical trial outcomes and resistance mechanism of anti-angiogenic
agents in OC. We also emphatically summarized and analyzed previously reported
biomarkers and predictive models to describe the prospect of precision therapy of
anti-angiogenic drugs in OC.
KEYWORDS
ovarian cancer, angiogenesis, biomarker, anti-angiogenic therapy, precision medicine
1 Introduction
Ovarian cancer (OC) possesses the highest death rate among gynecological malignant
tumors (Bray et al., 2018). While treatments have been improving over the past few decades,
the survival rate has barely improved (Liu et al., 2021). According to statistics, 60%–80% of
patients achieved complete remission after first-line therapy, but 80% of them finally die of
therapy resistance or relapse (Agarwal and Kaye, 2003;Lengyel, 2010). Approximately 70%
of patients relapse within 3 years after initial therapy (Viallard and Larrivee, 2017). Recurrent
OC is incurable and the progression-free survival (PFS) decreases at each subsequent relapse
treatment (Papa et al., 2016). The 5-year survival rate of OC patients is lower than 30%, while
the PFS is about 16–22 months (Bray et al., 2018).
Angiogenesis is indispensable for tumor growth and development. Under physiological
conditions, angiogenesis is a complicated and dynamic process that grows new vessels from
existing ones, supplying the requirement alterations in tissue. However, angiogenesis is
abnormally stimulated in the majority of cancers. Blood vessels provide oxygen and nutrients
for tumors to survive and growth, without which tumors cannot develop to larger than
1–2mm (Viallard and Larrivee, 2017). Therapeutic strategies targeting angiogenesis has
OPEN ACCESS
EDITED BY
Nayiyuan Wu,
Xiangya School of Medicine, Central
South University, China
REVIEWED BY
Chen Zhao,
Nanjing Medical University, China
Alexey Goltsov,
Moscow State Institute of Radio
Engineering, Electronics and Automation,
Russia
Liudmila V. Spirina,
Tomsk National Research Medical Center
(RAS), Russia
Dmitry Aleksandrovich Zinovkin,
Gomel State Medical University, Belarus
*CORRESPONDENCE
Sanlan Wu,
wusanlan@hust.edu.cn
Chunqi Zhu,
780904451@qq.com
†
These authors have contributed equally
to this work
SPECIALTY SECTION
This article was submitted to
Pharmacology of Anti-Cancer Drugs,
a section of the journal
Frontiers in Pharmacology
RECEIVED 19 January 2023
ACCEPTED 23 February 2023
PUBLISHED 07 March 2023
CITATION
Mei C, Gong W, Wang X, Lv Y, Zhang Y,
Wu S and Zhu C (2023), Anti-angiogenic
therapy in ovarian cancer: Current
understandings and prospects of
precision medicine.
Front. Pharmacol. 14:1147717.
doi: 10.3389/fphar.2023.1147717
COPYRIGHT
© 2023 Mei, Gong, Wang, Lv, Zhang, Wu
and Zhu. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original author(s)
and the copyright owner(s) are credited
and that the original publication in this
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which does not comply with these terms.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 07 March 2023
DOI 10.3389/fphar.2023.1147717
been accepted for several types of solid tumors. The anti-angiogenic
drug was the first targeted drug approved for OC. An increasing
amount of innovative anti-angiogenesis agents are now being
assessed in clinical trials of OC and mixed results are presented
(Papa et al., 2016). However, individual differences and widespread
resistance greatly limit the effectiveness of anti-angiogenic therapy.
The above underscore the urgent need of discovering reliable
molecular biomarkers to avoid resistance and improve the
prognosis of OC patients.
2 Angiogenesis in tumor pathogenesis
In the pathological state of cancer, angiogenic signals will be
exploited in a deregulated condition. Malignant cells release a series
of growth factors, cytokines, and chemokines to stimulate quiescent
cells to activate a cascade of signals. Except these, tumors may also
trigger inflammatory reaction to recruit myeloid cells, releasing the
stored soluble factors to facilitate the angiogenic response. These
events quickly become deregulated and incline the balance toward
secreting pro-angiogenic factors, thereby driving blood vessel
growth (Ronca et al., 2015). These signals initiate formerly
quiescent endothelial cell (EC) to sprout and proliferate on
nearby vascular. Research indicated that tumor ECs lining blood
vessels have a significant growth advantage, which probably divides
50 times quicker than in normal physiological conditions.
Normal vasculatures are arranged with a single-layer of tightly
connected adherent ECs, which are polarized and aligned along the
bloodstream for optimal perfusion. In comparison, tumor
vasculature possesses the characteristics of abnormal structural
dynamics, vascular immaturity, strikingly heterogeneous,
tortuous, and high permeability (Dewhirst and Ashcraft, 2016;
Dewhirst and Secomb, 2017;Zhang et al., 2019). Activated tumor
ECs depolarize, slough off and piled up against each other, creating
portals for malignant cells to entry the blood circulation. Tumor ECs
are usually loosely connected and leaky, containing multiple
fenestrations and trans-endothelial channels. In some tumors,
these holes are more than 100 times larger than those in healthy
blood vessels. Due to upregulated vessel resistance as well as
disordered regulation, the bloodstream in the tumor is chaotic.
The focal leaks and enhanced interstitial fluid pressure further
create obstacles to the blood stream. The blood may flow rapidly
in some vessels, but slowly in others, or even stagnant in some places
(Carmeliet and Jain, 2011a). This pattern of blood flow leads to an
abnormal microenvironment, seriously hindering the delivery of
nutrients and drugs (Dewhirst et al., 1999). Fast-growing and
metabolizing tumor cells constantly require abundant oxygen and
nutrients. However, the non-productive blood vessel is far from the
requirements of the tumor, which in turn stimulates tumor cells to
produce an excess of pro-angiogenic factors. This leads to even more
abnormal blood vessels, eventually creating an excess of the vicious
cycle (Carmeliet and Jain, 2011a).
Tumor vessels often possess abnormal structure and function.
This leads to a tumor microenvironment of hypoxia, inflammation,
acidic pH and high interstitial hostile fluid pressure that interferes
with the immune cellular function and the transport of
chemotherapy drugs and oxygen. Therefore, abnormity of tumor
vasculature leads to radiotherapy and chemotherapy resistance, and
the escape of tumor cells through leaky vessels. In addition, hypoxia
stimulates tumor and stromal cells to secrete large amounts of
angiogenic factors, further exacerbating vascular disorders and
accelerating non-productive angiogenesis in an interminable self-
enhanced circle.
To date, a large number of promoters of tumor angiogenesis
have been discovered (Figure 1), such as the vascular endothelial
growth factor (VEGF) family, angiopoietins (ANGPTs), fibroblast
growth factors (FGFs), platelet-derived growth factor (PDGF),
APLN (Apelin)/APLNR (G protein-coupled receptor APJ)
pathway, hepatocyte growth factor (HGF)/hepatocyte growth
factor receptor (c-MET), chemokines, Eph/Ephrin signaling, etc.
Their targets, mechanisms, downstream signals and research status
in OC are discussed below in detail.
3 Characteristics and functions of
angiogenesis-related factors in OC
3.1 VEGF
VEGF, the most well-known pro-angiogenic factor, contains a
group of ligands including VEGF-A to -D, as well as placental
growth factor (PlGF) (Zhao and Adjei, 2015). VEGF can be secreted
by malignant cells, fibroblasts, and inflammatory cells, usually in
response to increased tissue hypoxia (Carmeliet and Jain, 2011b).
VEGF binds to its receptor VEGFR tyrosine kinase and is activated
to form homo- or heterodimers. VEGF-A tends to bind VEGFR-
1 and 2. VEGF-B, PIGF-1, and PIGF-2 bind preferentially with
VEGFR-1, while VEGF-C and -D mainly interact with VEGFR3
(Zhao and Adjei, 2015). The interaction between ligand and receptor
triggers intracellular signaling cascades to promote the survival,
proliferation, motility, permeability, and tube formation ability
of ECs.
VEGF-A, VEGF-B, and PlGF play the uppermost functions in
tumor angiogenesis, most of which are owing to the activation of
VEGFR-2 by VEGF-A (Zhao and Adjei, 2015). PIGF binds to
VEGFR-1 and its co-receptors neuropilin 1 (NRP1) and 2, which
can directly facilitate vascular growth and maturation, or indirectly
promote angiogenesis by recruiting monocyte-macrophage lineage
cells and bone marrow-derived progenitors (De Falco, 2012). PIGF
has been suggested as a potential participant in anti-VEGF
resistance because of its upregulation in patients receiving anti-
VEGF therapy (Willett et al., 2009;Bagley et al., 2011;Chiron et al.,
2014). Aflibercept, which inhibits both VEGF-A and PIGF, has
shown efficacy in cancer patient-derived xenograft models (Zhang
and Lawler, 2007). VEGF-C and -D have the strongest binding
affinity to VEGFR-3 and appear to be important in promoting
lymph-angiogenesis.
The VEGF signaling is ubiquitous and upregulated in most
cancer types. This overexpression is secondary to hypoxia and
related transcription factors, like hypoxia-inducible factor -1α
(HIF-1α) and HIF-2α. HIF-1αcan stimulate several downstream
proangiogenic growth factors, especially VEGF (Dewangan et al.,
2019). Except this, insulin-like growth factor 1 (IGF-1), interleukin 6
(IL-6) (Salgado et al., 2002;Spiliotaki et al., 2011), and mutations in
genes like p53, RAS, SRC, and VHL have also been shown to
upregulate VEGF (White et al., 1997;Burger, 2011). Targeting
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VEGF can promote vascular normalization by recruiting pericytes,
reducing the enlargement and tortuosity of vessels, and facilitating
the normalization of the basement membrane (Carmeliet and Jain,
2011a). This results in a reduction in interstitial fluid pressure or
edema, a transient increase in blood perfusion, oxygenation and
improved efficiency of drug delivery.
In OC, VEGF signaling is highly activated and closely
associated with metastatic potential, disease grade as well as
poor prognosis (Wang et al., 2008). It is also a vital promotor of
ascites production in the latter stage of OC cancer (Bamberger and
Perrett, 2002;Numnum et al., 2006). VEGF activates its receptor
VEGFR-2 on ECs to initiate multiple signaling pathways to mediate
angiogenesis, for example, promoting EC proliferation and survival
through extracellular signal-regulated kinase (ERK) and
phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)
pathways (Takahashi et al., 2001;Jiang and Liu, 2009); inducing
cell invasion by activation of PI3K and Rho GTPases (Lamalice
et al., 2007); mediating the basement membrane and extracellular
matrix degradation as well as capillary sprout formation by
mitochondrial membrane potential-2 (MMP-2), MMP-9, and
urokinase plasminogen activator (uPA) (van Hinsbergh and
Koolwijk, 2008;Jiang and Liu, 2009). VEGF–Akt–NF-κB
signaling activation also induces an inflammatory response and
promotes the recruitment of leukocytes, thereby contributing to the
angiogenic process (Jiang and Liu, 2009). In addition, intracellular
signaling including Janus kinase (JAK)-signal transducing activator
of transcription (STAT), PI3K, and mitogen-activated protein
kinase (MAPK) pathways have also been demonstrated to be
related to VEGF signal (Banerjee and Kaye, 2011;Gavalas et al.,
2013).
3.2 FGFs
The FGF family consists of 22 factors, 18 of which can bind and
trigger the dimerization of their receptors FGFR1-4, initiating a
series of intracellular signaling cascades (Turner and Grose, 2010).
FGF is secreted by malignant cells, stromal cells, extracellular matrix
and acts on ECs through paracrine signal. Among the FGF family,
FGF1 and FGF2 exhibit uppermost proangiogenic abilities (Byron
et al., 2010). In addition, the FGF/FGFR signal also contributed to
tumor resistance to chemotherapy, radiotherapy, and targeted
therapy (Katoh, 2016;Ghedini et al., 2018;Xie et al., 2020;Zhou
et al., 2020). In OC, a spliced variant of FGFR and mutation events
may confer binding sensitivity to the ligand and disrupt the
downstream signaling cascade (Steele et al., 2001;Presta et al.,
2005). The downstream signal pathways include the ERK/MAPK,
JAK-STAT, phospsholipase-C (PLC)-inositol 1,4,5-triphosphate
(IP3) cascade and PI3K-AKT pathway, which promotes
angiogenesis, cell cycle progression as well as cell survival,
proliferation and differentiation (Greenberg et al., 2008). FGFs
also interferes with other signals like the Notch signal (Akai
et al., 2005). In addition, FGF degrades the extracellular matrix
via the promotion of plasminogen activators, MMPs, and
collagenase (Turner and Grose, 2010). FGF also regulates cell
metabolism through MYC-mediated glycolysis, which is essential
for the proliferation, motility as well as sprouting of vascular ECs
(Yu et al., 2017).
FGF signaling may be a compensatory angiogenesis mechanism
that leads to VEGF-targeted therapy resistance. Increased FGF
expression was found in patients with anti-VEGF therapy
resistance. As FGF acts synergistically with VEGF to facilitate
FIGURE 1
Major mechanisms of tumor angiogenesis and therapeutic agents implicated in OC. Tumor angiogenesis is induced by a series of proangiogenic
factors. This diagram exhibits the principal angiogenic signaling pathways, as well as the molecular targets and therapeutic mechanisms of anti-
angiogenic agents implicated in OC. CAFs, cancer associated fibroblasts; TAMs, tumor-associated macrophages.
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angiogenesis in cancer, simultaneously inhibiting the FGF signal
effectively decreased vascular density and reverted sensitivity to
anti-VEGF agents (Burbridge et al., 2013;Lee et al., 2015;Norden
et al., 2015).
3.3 PDGF
There are four isoforms, PDGF-A to -D, in PDGF family
(Heldin and Westermark, 1999). These ligands appear to have
potent angiogenic activity by interacting with PDGFR-αand -β
(Franco et al., 2011). PDGF signaling is involved in the survival,
proliferation and migration of multiple types of cells (Ghedini et al.,
2018). Hyperactivated PDGF signal, alone or accompanied with
FGF and VEGF, result in excessive tumor angiogenesis, comprising
but not limited to OC (Cao, 2013;Cantanhede and de Oliveira,
2017). In various types of cancer, aberrant PDGF signaling mediates
the secretion of pro-angiogenic factors; promotion of pericyte
recruitment and vascular maturation; facilitation of proliferation,
migration, sprouting of ECs; interference with stroma formation;
stimulation of lymph-angiogenesis and subsequent lymphatic
metastasis (Levitzki, 2004;Cao, 2013;Zhao and Adjei, 2015).
PDGF is also cross-linked to VEGF, by either converging their
signaling cascades or being activated following the resistance to anti-
VEGF therapy (Erber et al., 2004;Lu et al., 2008;Pietras et al., 2008).
PDGF receptors are highly expressed in the pericytes of solid
tumors, together with the critical role of PDGF signaling in
mediating the immune microenvironment, targeting PDGF/
PDGFR signal is expected to be a prospective therapeutic strategy
(Heldin, 2013;Ostman, 2017;Bartoschek and Pietras, 2018;
Papadopoulos and Lennartsson, 2018). The downstream signaling
activated by the PDGF pathway includes PI3K/Akt, MAPK,
Phospholipase C-γ(PLC-γ), Src, Ras and STAT, etc. (Gavalas
et al., 2013).
According to previous studies, PDGF expression level in OC
cells is approximately five to six-fold higher than that in normal
ovarian ECs (Matei et al., 2002). In human OC tissue samples, PDGF
was highly expressed in tumor stroma instead of the corresponding
epithelial components, while PDGFR was mainly expressed in
tumor stroma but not in OC cells (Li et al., 2022). In addition,
high serum PDGF-BB and FGF2 were of prognostic significance.
PDGFR-αand serum PDGF-BB expression have been reported to
correlate with the prognosis of OC patients (Lassus et al., 2004;
Madsen et al., 2012). Studies further supported the potency of PDGF
in the anti-vascular therapeutic approach, by demonstrating that
PDGFR blocking effectively improves the antitumor effect of
bevacizumab (Lu et al., 2010). Taken together, PDGF is a key
regulatory molecule in angiogenesis and ovarian carcinogenesis.
Further studies are needed in the hope of developing more
effective anti-tumor approaches.
3.4 ANGPTs
The ANGPTs family of ligands, ANGPT1 and ANGPT2, play a
crucial role in vascular maintenance, remodeling, and development
by interacting with the receptor tyrosine kinase TIE2 receptor
(Aghajanian et al., 2012;Pujade-Lauraine et al., 2014;Coleman
et al., 2017). ANGPT1 is an angiogenesis suppressor that mediates
the neovascularization and maturation through Akt/surviving
pathway, and is probably involved in the stabilization and
protection of existing blood vessels (Thurston et al., 2000). As an
endogenous antagonist of ANGPT1 function, ANGPT2 mainly
mediates the remodeling process or vascular sprouting in
response to VEGF (Scharpfenecker et al., 2005). Similar to cancer
angiogenesis, ANGPT2 mostly promotes vascular instability and
disruption that is characterized by unstable and leaky blood vessels
(Tait and Jones, 2004;Reiss et al., 2009). ANGPT2 is involved in the
predisposition of the endothelium towards the angiogenic statues
required for angiogenic initiation and vascular destabilization
(Scharpfenecker et al., 2005). It has also been suggested that
ANGPT2 acts as an agonist in the absence of ANGPT1, while
functioning as a dose-dependent antagonist when ANGPT1 exists
(Yuan et al., 2009). The responders of ANGPT/Tie2 receptor include
PI3K, MAPK/Erk, Ras signaling, etc. (Gavalas et al., 2013).
The serum levels of ANGPT1 and ANGPT2 were higher in
ovarian tumor than normal ovaries, benign and/or borderline
ovarian neoplasms (Sallinen et al., 2010;Sallinen et al., 2014).
ANGPT1, ANGPT2 and ANGPT4 are upregulated in OC cells
and tissues and indicate poor survival and a more aggressive
phenotype, suggesting an attractive target in OC therapy
(Brunckhorst et al., 2014). Upregulation of ANGPT2 is associated
with decreased patient survival and resistance to anti-VEGF agents
(Chae et al., 2010;Brunckhorst et al., 2014). Dual blocking of
ANGPT2 and VEGFR2 effectively impaired glioma progression,
promoted vascular normalization, blocked macrophage recruitment,
and prolongered the prognosis of tumor-bearing mouse models
(Kloepper et al., 2016;Peterson et al., 2016). This co-targeting effect
has also been demonstrated in early colorectal, breast, and kidney
cancer (Kloepper et al., 2016;Tuppurainen et al., 2017). However,
ANG2/TIE2-induced tumor vessel instability may also make the
established vasculature more resistant to anti-angiogenic agents
(Gerald et al., 2013). Focusing on ANG/TIE2 signal to develop a
targeted agent has proved to be challenging.
3.5 APLN/APLNR
APLN is a small, secreted peptide ligand of APLNR, which is
predominantly expressed in ECs. APLN/APLNR signal is
upregulated in several types of malignant T-cells and tumor
ECs (Kalin et al., 2007;Seaman et al., 2007;Berta et al., 2010;
Tolkach et al., 2019). APLN/APLNR signaling has been
demonstrated to associate with neovascularization, tumor
vessel density, microvascular proliferation, and tumor growth
in other types of tumors (Sorli et al., 2006;Kalin et al., 2007;Sorli
et al., 2007;Berta et al., 2010;Wu et al., 2017). APLN level is
correlated with disease progress and worse clinical outcome, but
its role in OC angiogenesis has seldom been identified (Berta
et al., 2010;Heo et al., 2012;Lacquaniti et al., 2015;Feng et al.,
2016). In OC, APLN functions as a mitogenic factor to promote
cell proliferation (Hoffmann et al., 2017). APLN/APLNR
signaling also drives OC metastasis in an angiogenesis-
independent manner. Adipocyte-derived APLN promotes the
uptake and utilization of lipids of OC cells, thus providing
energy for the survival of OC cells in metastasis tissue (Dogra
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Mei et al. 10.3389/fphar.2023.1147717
et al., 2021). Targeting APLN/APLNR for OC therapy is of
certain prospect, but extensive research is still needed.
3.6 HGF/c-MET
HGF/c-MET exerts pro-angiogenic effects by both directly
activating epithelial cells as well as indirectly stimulating VEGF
and other proangiogenic factors (Cloughesy et al., 2017;Lopes-
Coelho et al., 2021). c-MET is upregulated in patients with
bevacizumab resistance (Shojaei et al., 2010). Concurrent
administration of sunitinib (VEGFR and PDGFR receptor
tyrosine kinases inhibitor (RTKI)) and HGF/c-MET inhibitors
effectively inhibited angiogenesis and tumor growth (Lu et al.,
2012). However, the combination of obinutuzumab (anti-c-Met)
and bevacizumab has not brought significant clinical benefit(Rini
et al., 2008;Kim et al., 2021).
c-MET is a prognostic factor of OC patients, targeting c-MET
inhibits peritoneal dissemination, tumor invasion, and metastasis in
vivo (Sawada et al., 2007;Mitra et al., 2011). Cabozantinib is the only
approved TKI targeting VEGFRs, MET, and AXL (Maroto et al.,
2022). A phase II trial reported the clinical benifit (objective
response rate, 21%) and improved PFS (5.9 vs. 1.4 months) of
cabozantinib in OC patients compared with the placebo arm
(Vergote et al., 2017).
3.7 Eph/Ephrin signaling
The large family of receptor tyrosine kinases (RTK), Ephs and
their binding ligands Ephrins exhibit oncogenic transformation,
angiogenesis, vascular remodeling, malignant T-cell survival,
migration, and invasion (Lisle et al., 2013). Ephs and Ephrins are
sorted into two groups, A and B: EphrinA1-5, EphrinB1-3 and
EphA1-10, EphB1-6. EphA2 and EphrinA1 expression is critical for
tumor neovascularization and progression (Ogawa et al., 2000;
Brantley et al., 2002;Cheng et al., 2003;Dobrzanski et al., 2004).
Ephrb4-Ephrinb2 signaling was correlated with angiogenesis, tumor
progression and anti-angiogenic drug resistance (Noren et al., 2004;
Krusche et al., 2016;Uhl et al., 2018). The relationship between
Ephrin and VEGF signaling has also been demonstrated. Ephrin-B2
regulates VEGF signaling by inducing the internalization of
VEGFR2 and VEGFR3, thus mediating angiogenesis and
lymphangiogenesis in both physiological and tumor conditions
(Sawamiphak et al., 2010;Wang et al., 2010).
The expression of EphA1-2, B1-2, B2-4, -A1, -A5 was increased
in OC cells (Herath et al., 2006;Alam et al., 2008). Ephrin-A1, -A5,
and -A2 were associated with poor prognosis (Han et al., 2005;
Herath et al., 2006). Ephrin-B2 and -B4 were in proportion to the
disease stage (Alam et al., 2008). Ephrin-A4 is upregulated in OC
and recognized as a novel tumor-initiating marker. PF-06647263, a
monoclonal antibody against Ephrin-A4 conjugated with the DNA
damage agent calicheamicin, showing limited antitumor efficiency
in OC (Garrido-Laguna et al., 2019). EphA8 mRNA levels are
upregulated in OC tissues compared with normal ovarian and
fallopian tube tissues (Liu et al., 2016). High EphA8 protein level
was correlated with later-stage, metastatic disease, serum levels of
tumor and positive ascetic fluid, and has been regarded as a
prognostic biomarker in epithelial ovarian cancer (EOC) patients
(Liu et al., 2016). The above studies suggested the significant role of
Eph/Ephrin signaling in OC.
3.8 Galectins
Apart from the factors described above, there are still several
pro-angiogenic factors contribute to angiogenesis in OC.
Galectins are a class of endogenous lectins, whose family
members have been reported to correlate with cancer stage
and disease recurrence of OC patients, as well as the
proliferation, migration, invasion of OC cells (Shimada et al.,
2020;Mielczarek-Palacz et al., 2022). Among them, Galectin-1
was the first identified and the most intensively studied member,
whichisanimportantproangiogenicfactorinseveraltypesof
carcinomas. Research has shown the positive correlation between
Galectin-1 expression and number of micro vessels (Pranjol et al.,
2019). Galectin-1 mediates angiogenesis mainly by enhancing the
VEGF signaling pathway. Galectin-1 interacts with NRP-1, the
co-receptor for VEGF, thereby activating VEGFR2 and
downstream SAPK/JNK signaling to induce endothelial cell
migration and adhesion. It has been shown that Galectin-1
can directly bind and activate VEGFR2, leading to anti-VEGF
therapeutic resistance in the absence of VEGF. In addition to
VEGF-VEGFR pathway, Galectin-1 also regulates H-Ras and
Raf/MEK/ERK signals to promote endothelial cell activation,
proliferation, migration and angiogenesis process (Martinez-
Bosch and Navarro, 2020).Asfortheothermember,Galectin-
3 promotes angiogenesis via VEGF, basic FGF (bFGF) and
modifies N-glycans on integrin αvβ3. Galectin-8 is expressed
on the vascular endothelial cells of both normal and tumor-
associated vessels, and facilities angiogenesis by promoting
endothelial cell migration (Delgado et al., 2011;Troncoso
et al., 2014).
3.9 Anti-angiogenic factors
Except the pro-angiogenic factors described above, anti-
angiogenic factors, such as Thrombospondin-1 (TSP-1),
Angioarrestin and Endostatin also play indispensable roles in
OC progression and clinical treatment. TSP-1, the first identified
endogenous anti-angiogenic factor, possesses a well-established
anti-angiogenic and anti-tumor activity. TSP-1 is highly
expressed in ovarian tumors. It can be secreted by a series of
cell types including ECs, fibroblasts and immune cells, etc., and is
highly located in the tumor stroma instead of tumor cells (Zhao
et al., 2018). Based on its anti-angiogenic properties, high TSP-1
expression has been demonstrated to correlate with higher
survival rates in OC, colon cancer, lung cancer and cervical
cancer, etc. However, this conclusion is inconsistent or even
opposite in other types of tumors, such as hepatocellular
carcinoma, breast cancer and melanoma, etc. (Grossfeld et al.,
1997;Zhao et al., 2018). These inconsistent conclusions led to
controversy over its use as a survival predictor in different types
of cancer. Similarly, existing studies has not shown a clear
correlation between VEGF and TSP-1 expression in different
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tumor types. A recent meta-analysis included 24 studies revealed
high TSP-1 expression may be a promising biomarker of poor
prognosis in cancer, especially in breast and gynecologic cancers
(Sun et al., 2020). ABT-510, a TSP-1 mimetic peptide, is the first
TSP-1 inhibitor. ABT-510 effectively reduced the abnormal
vasculature increased mature blood vessels within tumor, but
failed to pass the phase II clinical study (Campbell et al., 2010;
Zhao et al., 2018). Besides, the interaction between TSP-1 with
CD47 directly inhibits tumor adaptive immunity. TAX2 is a
selective antagonist against the interaction between TSP-1 and
CD47. It effectively suppresses CD47 activation by targeting TSP-
1, and reprograms highly vascularized ovarian tumors into
poorly angiogenic ones, while concurrently activating anti-
tumor immunity (Jeanne et al., 2021). TSP-1 derived peptides
and peptide mimetics showed satisfied efficiency in the treatment
of tumors driven by excessive angiogenesis, and hold great
promise to become innovative drugs in the future.
Angioarrestin is another angiogenesis-inhibiting protein that
endogenously produced by the tumor. Angioarrestin is
downregulated in many types of tumor tissues and exhibited
strong anti-angiogenic ability both in vitro and in vivo (Dhanabal
et al., 2005). Angioarrestin is involved in the migration, adhesion
and tube formation abilities of endothelial cells. Mechanistically, it
has been reported to inhibit VEGF/bFGF-induced endothelial cell
proliferation in a dose-dependent manner (Dhanabal et al., 2005).
Endostatin is also an anti-angiogenic factor and has a potent activity
on the migration, survival, proliferation and apoptosis of endothelial
cells (Poluzzi et al., 2016). A genome-wide expression profiling
demonstrated that about 12% of human genes are regulated by
Endostatin in human endothelial cells (Abdollahi et al., 2004).
Research indicated that Endostatin participates in MMPs, FAK/
Ras/p38-MAPK/ERK, HIF-1α/VEGFA and Wnt signal (Dhanabal
et al., 2005). Elevated Endostatin serum level may be a prognostic
indicator for EOC patients. Either RGD-P125A-Endostatin-Fc
fusion proteins alone or in combination with bevacizumab can
effectively inhibit angiogenesis and OC progression (Jing et al.,
2011).
4 Molecular targets and agents against
angiogenesis
Bevacizumab has been approved in stage III or IV EOC
patients after primary surgical resection, for either combining
with carboplatin and paclitaxel, or maintaining as monotherapy
(Table 1). In addition to bevacizumab, several other anti-
angiogenic agents have also been tested clinical studies in OC
(Table 2).
4.1 Bevacizumab
Bevacizumab (Avastin
®
) is a humanized anti-VEGF
monoclonal antibody. It was the firsttargetmedicine
approved in 2014 and used for platinum-resistant OC in
combination with chemotherapy (Monk et al., 2016a). It exerts
therapeutic efficiency by blocking VEGF-A to bind VEGFR,
destroying existing vessels, disturbing neovascularization, and
releasing intratumor pressure, etc. (Reinthaller, 2016). Studies
have shown that blocking VEGF signaling not only leads to the
depletion of tumor vascularization, but also promotes the
normalization of the remaining blood vessels in morphology
and function. In addition, the pericyte coverage of remaining
vessels increased to about 75% after bevacizumab treatment,
compared with 7% in the placebo group (Arjaans et al., 2013).
The application of bevacizumab in OC was initially used as
monotherapy in pretreated patients. The GOG-0170D trial
evaluated the benefit of bevacizumab single agent in 62 recurrent
OC patients that had been treated with up to two prior lines of
chemotherapy. Bevacizumab was well tolerated. The ORR was 21%.
PFS and overall survival (OS) was 4.7 and 17 months respectively
(Burger et al., 2007). Other phase II studies evaluated the benefitof
bevacizumab in OC patients that had experienced disease progression
after multiple chemotherapeutic regimens (Monk et al., 2006;
Cannistra et al., 2007). Single-agent bevacizumab showed modest
benefits, but less than combination therapy (Fuh et al., 2015).
TABLE 1 Summary of anti-angiogenic agents in OC.
Drug
name
Targets Approved indications Adaptation in OC Route of
administration
Bevacizumab VEGFR OC; Colorectal cancer; Non-small cell lung cancer; Recurrent
glioblastoma; Hepatocellular carcinoma; Cervical cancer; Renal
carcinoma; Breast cancer
Combination with chemotherapy;
Maintenance monotherapy
I.V.
Pazopanib VEGFR, PDGFR,
FGFR, c-Kit, c-Fms
Soft tissue sarcoma; Advanced renal carcinoma Clinical study Oral
Nintedanib VEGFR, FGFR,
PDGFR
Idiopathic pulmonary fibrosis Clinical study Oral
Cediranib VEGFR / Clinical study Oral
Sunitinib PDGFR, VEGFR, Flt3,
c-Kit
Kidney cancer; Gastrointestinal stromal tumor; Neuroendocrine
tumor
Clinical study Oral
Sorafenib VEGFR, PDGFR,
Raf, ERK
Renal cell carcinoma, Hepatocellular carcinoma, Thyroid
carcinoma
Clinical study Oral
Trebananib Tie2 / Clinical study I.V.
I.V., intravenous injection; OC, ovarian cancer.
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In 2011, the outcomes of two prominent phase III trials,
ICON7 and GOG-0218, were published simultaneously, which
were the first attempt to add bevacizumab to standard adjuvant
chemotherapy as a frontline maintenance of OC. In GOG-0218,
incorporation of bevacizumab within 10 months after carboplatin
(CBP) and paclitaxel (TAXOL) chemotherapy has been shown to
prolong the PFS for approximately 4 months in 1873 newly
diagnosed advanced EOC patients (medium PFS, 14.1 vs.
10.3 months; 95% CI, 0.625-0.824; p<0.001) (Burger et al.,
2011). As for the ICON7 trial, bevacizumab combination therapy
improved the PFS to 24.1 months in 1528 OC patients compared
with CBP and TAXOL chemotherapy alone (22.4 months). The
benefit was more obvious in patients with high progression risk
(PFS, 18.1 vs. 14.5 months; OS, 36.6 vs. 28.2 months) (Perren et al.,
2011).
Platinum (Pt) resistance is a serious problem that hinders the
therapeutic benefit of OC. Factors leading to Pt resistance are
various, including angiogenesis, hypoxia, immune infiltration,
and abnormal regulation of breast cancer susceptibility gene
(BRCA), ATP binding cassette subfamily B member 1 (ABCB1)
and cyclin E1 (CCNE1), etc. (Pennington and Swisher, 2012;Patch
et al., 2015). Anti-angiogenic drugs exert a satisfying therapeutic
benefit in Pt-resistant OC (Haunschild and Tewari, 2020). An open-
label, randomized, phase III trial, AURELIA, demonstrated that
bevacizumab incorporated with standard-of-care chemotherapy
(TAXOL or topotecan (TPT) or pegylated liposomal doxorubicin
TABLE 2 Summary of phase III studies of antiangiogenic agents in OC.
Clinical
trials
Disease
condition
Patient
number
Drug Treatment arm Clinical outcomes References
PFS OS
OVAR 12 Newly diagnosed
advanced OC
1366 Nintedanib CBP + PTX + PBO 16.6 / du Bois et al. (2016)
CBP + PTX +
Nintedanib
17.2 (HR, 0.84; 95%
CI, 0.72 to 0.98]; p=
0.024)
/
OVAR 16 Advanced OC 940 Pazopanib PBO 12.3 / du Bois et al. (2014)
Pazopanib 17.9 (HR, 0.77; 95%
CI, 0.64 to 0.91; p=
0.0021)
/
ICON6 PT-sensitive
recurrent OC
456 Cediranib PBO + CBP, PBO
maintenance
8.7 19.9 Ledermann et al. (2016),
Ledermann et al. (2021)
Cediranib + CBP, PBO
maintenance
10.1 (HR, 0.67; 95%
CI, 0.53-0.87; p=
0.0022)
/
Cediranib + CBP,
Cediranib maintenance
11.1 (HR 0.57, 0.44-
0.72, p<0.00001)
27.3(HR, 0.85; 95%
CI, 0.66-1.10; p= 0.21)
NRG-GY004 Recurrent Pt-
sensitive OC
565 Cediranib chemotherapy 10.3 / Liu et al. (2022)
Olaparib 8.2 (HR, 1.2; 95%CI,
0.93-1.5)
/
Olaparib + Cediranib 10.4 (HR, 0.856; 95%
CI, 0.66-1.10; p=
0.077)
/
TRINOVA-1 Recurrent OC 919 Trebananib Weekly PTX + PBO 5.4 18.3 Monk et al. (2016b),
Vergote et al. (2019a)
Weekly PTX +
Trebananib
7.2 (HR, 0.66; 95%CI,
0.57-0.77; p<0.0001)
19.3 (HR, 0.95; 95%
CI, 0.81-1.11; p= 0.52)
TRINOVA-2 Recurrent OC 223 Trebananib PLD + PBO 7.2 17 Monk et al. (2014)
PLD + Treban anib 7.6 (HR, 0.92; 95%CI,
0.68-1.24; p= 0.57)
19.4(HR, 0.94; 95%CI,
0.64-1.39; p= 0.76)
TRINOVA-3 Advanced OC 1015 Trebananib PBO + PTX + CBP 15.0 43.6 Marth et al. (2017)
Trebananib + PTX
+ CBP
15.9 (HR, 0.93; 95%
CI, 0.79-1.09;
p= 0.36)
46.6(HR, 0.99; 95%CI,
0.79-1.25; p= 0.94)
AGO-
OVAR16
Stage II-IV EOC 940 Pazopanib PBO maintenance 17.9 18.3 du Bois et al. (2014),
Vergote et al. (2019b)
Pazopanib
maintenance
12.3 (HR, 0.77; 95%
CI, 0.64-0.91; p=
0.0021)
59.1 (HR, 0.960; 95%
CI: 0.805-1.145; p=
0.6431)
OC, ovarian cancer; CBP, carboplatin; PTX, paclitaxel; PBO, placebo; HR, hazard ratio; CI, confidence interval; PLD, pegylated liposomal doxorubicin.
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(PLD)) improved the PFS of Pt-resistant OC patients compared to
chemotherapy alone (medium PFS, 6.7 vs. 3.4 months; HR, 0.42;
95%CI, 0.32-0.53) (Pujade-Lauraine et al., 2012). The subsequent
analysis indicated combining with TAXOL was the most effective
regimen (Poveda et al., 2015). Based on the AURELIA trial, the Food
and Drug Administration (FDA) had approved bevacizumab plus
weekly TAXOL, PLD, or TPT for patients with Pt-resistant OC
(Pujade-Lauraine et al., 2014).
Bevacizumab combination therapy has also been evaluated in
Pt-sensitive OC patients. A phase III trial, OCEANS, was
performed in 484 patients with Pt-sensitive recurrent OC. The
medium PFS was 12.4 months in the bevacizumab/gemcitabine/
CBP and 8.4 months in chemotherapy only group (HR, 0.48; 95%
CI, 0.39-0.61) (Aghajanian et al., 2012). GOG-0213 trail
evaluated the efficiency of combining bevacizumab with CBP
and TAXOL. The median OS (49.6 vs. 37.3 months; HR, 0.823;
95% CI, 0.680-0.996; p= 0.0447) was improved in the
bevacizumab group compared with chemotherapy only group
(Coleman et al., 2017). Both therapy regimens in the above two
trials have been approved by FDA for this usage. The MITO16b
phase III trial was performed in 406 Pt-sensitive recurrent OC
patients and compared the PFS benefits of bevacizumab
combination with standard chemotherapy. Continuing
bevacizumab combination therapy significantly prolonged the
PFS (medium PFS, 11.8 vs. 8.8 months; HR, 0.51; 95% CI, 0.41-
0.65; p<0.0001) (Pignata et al., 2021).
Taken together, the vast majority of clinical studies suggested
that bevacizumab significantly extended PFS in OC patients by
several months, while the improvement in OS was not obvious.
Up to now, mechanism studies focused on bevacizumab
resistance have achieved certain progress, and several
multitargeted antiangiogenic agents have been tested in
clinical studies. However, no effective clinical methods has
been applied to overcome bevacizumab resistance. In addition,
there is growing evidence that the combination of bevacizumab
with immunotherapy or PARP inhibitors may improve the
therapeutic outcome of OC patients. Further attempts of novel
combination therapies hold promising prospects and are one of
the major trends in antiangiogenic therapy.
4.2 Pazopanib
Pazopanib, an oral tyrosine kinase inhibitor (TKI) of multiple
targets, inhibits VEGFR, PDGFR-αand -β,FGFR-1and-3and
c-Kit. Pazopanib treatment significantly reduced the tumor
microvessel density and pericyte coverage in the mouse orthotopic
OC model (Merritt et al., 2010). Pazopanib has been approved by the
FDA and European Medicines Agency (EMA) for soft tissue sarcoma as
well as advanced renal carcinoma therapy. Although not yet approved
in OC, many phase II and III clinical trials have evaluated the potential
role of pazopanib in the therapy of OC (Plummer et al., 2013;du Bois
et al., 2012;Davidson and Secord, 2014). The AGO-OVAR16 study
assessed the potential role of pazopanib maintenance therapy in 940 OC
patients without progressive disease after receiving the first-line
chemotherapy. Pazopanib, when given as maintenance therapy,
yielded a meaningful improvement in median PFS (17.9 v
12.3 months; HR, 0.77; 95% CI, 0.64-0.91; p= 0.0021), albeit with
added adverse event-induced therapy interruption (33.3% vs. 5.6%).
However, no significant benefitofOSwasidentified (du Bois et al.,
2014).
So far, there have been few phase III clinical trials of
pazopanib in OC treatment, but it has already exhibited clear
clinical benefit and future studies will gradually establish its value
in OC. In addition, the curative effect of pazopanib in
bevacizumab-resistant patients remains undefined and requires
further investigation. Importantly, it is more necessary to
discover valid predictive biomarkers to avoid potential toxicity
and identify patients who are more likely to benefitfrom
pazopanib treatment. A previous study showed that [
18
F]
Fluciclatide-PET uptake parameters may predict clinical
outcomes of pazopanib treatment in patients with platinum-
resistant/refractory OC, but studies in larger sample size are
still needed for validation (Sharma et al., 2020). Besides, soluble
VEGFR-2 and IL-8 have been revealed to be potential predict
biomarkers in predict the therapeutic efficiency of pazopanib
(Davidson and Secord, 2014). In summary, though the
application of pazopanib in OC is still being explored and
debated, the results of combination studies and further phase
III studies will hopefully provide a rational foundation for the
optimal role of pazopanib in OC treatment.
4.3 Nintedanib
Nintedanib (BIBF 1120) is an orally available, multitargeted
antiangiogenic agents that approved for idiopathic pulmonary
fibrosis treatment by FDA in 2014. Nintedanib competitively
inhibits RTK (including VEGFR, FGFR, PDGFR-αand -βand
FLT3 kinases) as well as non-RTK (including lymphocyte-specific
protein tyrosine kinase (Lck), tyrosine-protein kinase Lyn (Lyn) and
proto-oncogene tyrosine-protein kinase Src (Src)) (Cortez et al.,
2018). Dynamic MRI assessments indicated that nintedanib
treatment led to significant reduction of blood flow in about 55%
OC patients. It also promotes the vascular normalization and
regression of tumor in pre-clinical models (Khalique and
Banerjee, 2017). A phase II trial investigated the efficacy of
nintedanib maintenance therapy after chemotherapy for relapsed
OC. 83 patients were included in this study. 36 weeks PFS rate was
improved to some extent, but no statistical significance (16.3% and
5.0%; HR, 0.65; 95% CI, 0.42-1.02; p= 0.06) (Ledermann et al.,
2011). A recent phase II study assessed the benefit and tolerance of
combining nintedanib with oral cyclophosphamide in 117 relapsed
OC. The median OS in nintedanib and placebo group were 6.8 and
6.4 months respectively (HR, 1.08; 95% CI, 0.72-1.62; p= 0.72), and
the 6-month PFS rates were 29.6% and 22.8%, respectively (p=
0.57). No meaningful improvement was observed when nintedanib
was added to oral cyclophosphamide (Hall et al., 2020). Another
phase II trial investigated whether nintedanib is effective in
bevacizumab-resistant recurrent EOC. According to research
findings, nintedanib monotherapy was tolerable and showed
minimal efficiency in bevacizumab-resistant EOC patients
(Secord et al., 2019). In the AGO-OVAR 12 phase III clinical
trial, nintedanib combined with CBP and TAXOL had a modest
efficacy in patients with FIGO IIB-IV OC (PFS, 17.2 vs. 16.6 months;
HR, 0.84; 95%CI, 0.72-0.98; p= 0.024), but was also accompanied by
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more gastrointestinal adverse events (Secord et al., 2019). The
follow-up study continually reported no significant different in
OS (62.0 vs. 62.8 months; HR, 0.99; 95% CI, 0.83-1.17; p= 0.86).
The updated PFS difference was in line with the primary report
(17.6 vs. 16.6 months; HR, 0.86; 95% CI, 0.75-0.98; p= 0.029)
favoring nintedanib (Ray-Coquard et al., 2020).
Based on the limited prognostic benefit and non-negligible toxic
effects reported in clinical trials to date, it is not expected to approve
nintedanib for OC therapy. Nevertheless, these studies were
informative and suggested the demand of patient selection and
tolerated therapy. Nintedanib may have a role in recurrent OC.
The ongoing clinical trials and predictive biomarker identification
will help to determine this (Khalique and Banerjee, 2017).
4.4 Cediranib
Cediranib (AZD2171) is an oral TKI that inhibits VEGFR-1,
VEGFR-2, VEGFR-3 and c-kit. In preclinical models of OC,
cediranib treatment led to significantly reduction of tumor
vascular density and vessel regression (Ruscito et al., 2016). A
phase II trial reported a significant activity of cediranib in Pt-
sensitive instead of Pt-resistant patients with recurrent OC (Hirte
et al., 2015). The ICON6 phase III study further evaluated whether
orally given cediranib plus Pt-based chemotherapy and continued as
maintenance therapy provided PFS benefits in 456 Pt-sensitive OC
patients. A significantly prolonged PFS was found in the cediranib
combination and maintenance group (11.0 vs. 8.7 months; HR, 0.56;
95%CI, 0.44-0.72; p<0.0001), accompanied by added toxic effects
(Ledermann et al., 2016). However, no significant difference was
found in the extended follow-up of OS results (OS, 27.3 vs.
19.9 months; HR, 0.86; 95% CI, 0.67-1.11; p= 0.24). Even so, the
result of OS was underpowered due to several limitations like drug
supply restriction and the non-proportionality of the survival
curves, and further research should be undertaken (Ledermann
et al., 2021).
Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor
that applied for OC therapy, but widespread resistance greatly
hindered its clinical benefit. Better strategies and potential
combination administrations are in urgent need to overcome the
resistance. A phase II study investigated whether combining
cediranib with olaparib could improve the PFS of patients with
Pt-sensitive recurrent OC. Median PFS were 9.0 and 17.7 months in
the olaparib monotherapy and cediranib plus olaparib group,
respectively (HR, 0.42; 95% CI, 0.23-0.76; p= 0.005) (Liu et al.,
2014). The follow-up study characterized OS and updated PFS
outcomes. The updated PFS result was consistant (16.5 vs.
8.2 months; HR, 0.50; p= 0.007). The OS showed no statistical
difference (44.2 vs. 33.3 months, HR, 0.64; p= 0.11). Notably, for the
subgroup of patients that did not carry deleterious germline BRCA1/
2 mutation, both OS (37.8 vs. 23.0 months; p= 0.047) and PFS
(23.7 vs. 5.7 months; p= 0.002) were significantly improved by
adding cediranib to olaparib, suggesting that the further study
should designed on the basis of BRCA status (Liu et al., 2019a).
The EVOLVE trail evaluated the benefit of cediranib plus olaparib
when confronted with PARPi treatment resistance. The
cediranib–olaparib combination was tolerable and the efficiency
was various in patients with different resistance mechanism.
Individuals with upregulated ABCB1 and/or abnormal
homologous recombination repair activity should probably be
considered for other treatment options (Lheureux et al., 2020).
Several clinical trials have compared the clinical benefitof
olaparib and/or cediranib with that of chemotherapy. A phase II
study reported no PFS improvement was identified in cediranib plus
olaparib versus chemotherapy in unscreened, heavily pretreated Pt-
resistant OC patients (Colombo et al., 2022). Consistent findings
were reported in NRG-GY004 phase III trial which performed in
565 recurrent Pt-sensitive OC patients. The median PFS were 10.3,
8.2, and 10.4 months in the chemotherapy, olaparib, and olaparib +
cediranib groups, respectively. Combining olaparib with cediranib
showed no more PFS benefit than chemotherapy (HR, 0.86; 95%CI,
0.66-1.10; p= 0.077). However, for the subgroup with germline
BRCA mutation, significant clinical activity was observed both in
olaparib alone or in combination with cediranib (Liu et al., 2022).
The above studies suggested the critical role of valid genetic
biomarkers in screening susceptible individuals and predicting
the efficacy of cediranib.
In addition to the clinical trials described above, numerous
studies are ongoing. A phase II trial aims to compare the benefit
and tolerability of olaparib plus cediranib versus olaparib
monotherapy in Pt-resistant OC (Mansouri et al., 2021). The
ICON 9 phase III randomized study assessed the maintenance
treatment of olaparib plus cediranib in relapsed Pt-sensitive OC.
The trail is ongoing and the primary results are expected in 2024
(Elyashiv et al., 2021).
Although not yet approved by FDA, the landscape of cediranib
in OC therapy appears promising. Cediranib exhibited encouraging
results when combined with chemotherapy or olaparib.
Nevertheless, many key questions remain to be addressed in the
future, such as which clinical regimen provides the best benefit;
biomarkers to identify patients with higher probability to benefit are
urgently needed; the unclear role of cediranib in bevacizumab
resistant patients. In the near future, the outcomes of phase II/III
clinical trials will help to better establish the role of cediranib in OC
treatment.
4.5 Sunitinib
Sunitinib is a multiple-target TKI that inhibits PDGFR, VEGFR,
Flt3, and c-Kit. The FDA granted sunitinib for the treatment of
advanced kidney cancer and partial gastrointestinal stromal and
neuroendocrine tumors, while its application in OC remains in
clinical trials (Leone Roberti Maggiore et al., 2013). In a xenograft
mouse model, sunitinib therapy significantly reduced the tumor
microvascular density, and also inhibited tumor growth and
peritoneal metastasis (Bauerschlag et al., 2010). The AGO-
OVAR2.11 phase II trial showed that sunitinib exhibited feasibly
and moderate activity in patients with recurrent Pt-resistant OC,
and the non-continuous therapy schedule showed better superiority
compared with continuous treatment (Baumann et al., 2012).
Attached to this, the predictive value of VEGF, VEGFR-3 and
Ang-2 was evaluated. Decreased serum Ang-2 levels were found
to associate with longer PFS (8.4 vs. 2.7 months). However, the
difference is not significant (p=0.0896) and further research is
needed (Bauerschlag et al., 2013). Another phase II trial also
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reported a modest activity of 50 mg intermittent regimen of
sunitinib monotherapy in recurrent Pt-sensitive OC (Biagi et al.,
2011). The dosage regimen may be a vital consideration in further
studies of sunitinib in OC (Biagi et al., 2011). Susana M Campos
et al. demonstrated a modest response rate (8.3%) of sunitinib in
recurrent OC in a phase II trial (Bodnar et al., 2011). Another phase
II evaluation of sunitinib also reported limited effectiveness in
persistent or recurrent clear cell OC (Campos et al., 2013).
Based on the above studies, sunitinib exhibited moderate
antitumor activity together with acceptable toxicity in the OC
treatment. However, given that serious adverse events have been
reported (Abdollahi et al., 2004;Dhanabal et al., 2005;Poluzzi et al.,
2016;Jeanne et al., 2021), more insight understanding of toxicity,
elucidating the specific toxic mechanisms, and determination of
optimal administration dosage are required in the future. It is also
important to identify predictable biomarkers to guide individualized
medication. In addition, current clinical studies have not attempted
the combination therapy of sunitinib with cytotoxic agents, which
may significantly improve therapeutic outcome and control toxicity.
4.6 Sorafenib
Sorafenib targets multiple kinases including VEGFR, PDGFR,
Raf, MEK and ERK. It has been approved for renal cell carcinoma,
hepatocellular carcinoma and differentiated thyroid carcinoma by
FDA. A phase II trial indicated sorafenib provided no adequate
objective response when given as a third-line therapy in EOC (Chan
et al., 2018). In another phase II study, sorafenib was assessed as
maintenance therapy in 246 EOC patients that had achieved a
complete response in first-line therapy. Compared with placebo
group, no obvious PFS improvement was achieved in sorafenib
400 mg BID treatment (median PFS, 12.7 vs. 15.7 months; HR, 1.09;
95% CI, 0.72-1.63). Adverse effects induced discontinuations were
more frequently in the sorafenib group (37.4% vs. 6.5%) (Herzog
et al., 2013).
A phase II study evaluated the efficiency and tolerability of
sorafenib plus CBP/TAXOL in EOC. This study was terminated
after patients occurred life-threatening toxicities (Erber et al.,
2004), suggesting that sorafenib plus CBP/TAXOL cannot be
recommend as neoadjuvant treatment in patients with primary
advanced OC (Polcher et al., 2010). This result was consistent
with another randomized phase II trial, which reported that the
combination of sorafenib to standard TAXOL/CBP provided no
benefit but more serious toxicity in patients with advanced EOC
(Hainsworth et al., 2015). Another randomized phase II trial
compared the benefit of sorafenib monotherapy, or combined
with CBP/TAXOL in Pt-sensitive EOC. The median PFS of
sorafenib monotherapy and combination group were 5.6 and
16.8 months, respectively (p= 0.012), while difference was not
observed in OS (25.6 vs. 25.9 months, p= 0.974) (Schwandt et al.,
2014).
The combination of sorafenib with TPT was evaluated in Pt-
resistant or -refractory OC. Sorafenib combination significantly
prolonged PFS versus placebo (6.7 vs. 4.4 months; HR, 0.60; 95%
CI, 0.43-0.83; p= 0.0018) (Chekerov et al., 2018). However, another
phase II trial reported conflicting results, pointing a significant
toxicity but modest clinical efficacy in Pt-resistant OC patients
(Ramasubbaiah et al., 2011). The combination of sorafenib with
TPT still required further investigation.
Continuous daily sorafenib combined with bevacizumab caused
moderate toxicity in OC patients, whereas intermittent sorafenib
plus bevacizumab had promising clinical efficacy with few side
effects (Lee et al., 2010). A phase II trial reported potential
clinical activity of bevacizumab plus sorafenib in bevacizumab-
naive, Pt-resistant OC, whereas no activity was observed in the
bevacizumab-prior group (Lee et al., 2020).
According to previous phase II studies, sorafenib showed limited
clinical benefit in advanced relapsing OC when given as single agent
or combination therapy. Sorafenib in combination with cytotoxic
agents also provided less benefit, and severe adverse events were
reported. Nonetheless, sorafenib combined with bevacizumab
exhibited encouraging efficacy in advanced OC patients, but the
cumulative toxicity also posed an ongoing therapeutic challenge.
Future research should therefore focus on developing reliable
predictive biomarkers to guide patient selection, optimal
combination, order and dose of administration, so as to
maximize clinical benefit and minimizing toxicity.
4.7 Trebananib
Trebananib (ANG386) targets and blocks the binding of
ANGPT to their receptor Tie2. A study used photoacoustic
tomography to detect changes in tumor vascularization in
response to trebananib treatment. It showed that trebananib
induced obvious vessel regression and reduced vessel density. It
is worth noting that trebananib treatment did not completely block
angiogenesis but promoted more stable and less permeable residual
vascular structures (Bohndiek et al., 2015). The TRINOVA-1 trial
assessed the benefit of trebananib plus TAXOL in 919 recurrent
EOC patients. The median PFS was meaningfully improved in the
trebananib plus TAXOL arm compared with placebo arm (7.2 vs.
5.4 months; HR, 0.66; 95% CI, 0.57-0.77; p<0.0001). The adverse
events were 125 (28%) and 159 (34%) in the placebo monotherapy
group and trebananib combination group, respectively (Monk et al.,
2014). The ENGOT-ov-6/TRINOVA-2 study investigated the
potential benefit of combining trebananib with PLD in
223 recurrent EOC patients. The objective response rate (ORR,
46% vs. 21%) and duration of response (DOR, 7.4 vs. 3.9 months)
were improved, while the median PFS had no obvious improvement
(7.6 vs. 7.2 months; HR, 0.92; 95% CI, 0.68-1.24) (Marth et al., 2017).
The TRINOVA-3 trail assessed the combination of trebananib with
paclitaxel and carboplatin in 1015 advanced OC patients. However,
no significant improvement was observed in PFS compared with
placebo group (15.9 vs. 15.0 months; HR, 0.93; 95%CI, 0.79-1.09; p=
0.36). No new safety signals were produced, either Vergote et al.
(2019a).
To summarize, the TRINOVA-1 trail showed that trebananib
significantly improved PFS in recurrent OC compared with
paclitaxel alone. The TRINOVA-2 trail compared paclitaxel plus
placebo or paclitaxel plus trebananib in recurrent OC, and the PFS
was modestly improved but no significant difference. The
TRINOVA-3 trail indicated that trebananib + carboplatin +
paclitaxel failed to improve PFS of advanced OC patients
compared with placebo group. Based on the available studies and
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FIGURE 2
Clinical trials assessing biomarkers in relation to PFS of anti-angiogenic drugs in OC. BEV: Bevacizumab; CT: Chemotherapy; PC:TAXOL and CBP;
DNA, Deoxyribonucleic Acid; RNA, Ribonucleic Acid; cfDNA, cell-free DNA; EGFR, Epidermal Growth Factor Receptor; HER2, Human Epidermal
GrowthFactor Receptor 2; MYC, MYC Proto-Oncogene; CCNE1, Cyclin E1; ADAM17, a disintegrin and metalloprotease 17; MVD, microvessel density;
SMA_MVD: Alfa-Smooth Muscle Actin + microvessel density; Ratio, α-SMA + MVD/ MVD ratio; miRNA, microRNA; VEGFA, vascular endothelial
growth factor A; VEGFB, vascular endothelial growth factor B; HIF-a, Hypoxia-Inducible Factor 1-alpha; OPN, osteopontin; SDF-1, stromal cell–derived
factor-1; IL6R, IL6 receptor; FLT4, fms-like tyrosine kinase-4; AGP, a 1 -acid glycoprotein; BMI, body mass index; VFA, visceral fat area; SFA, subcutaneous
fat area; ΔBF, change of Tumor Blood Flow; ΔBV, change of Tumor Blood Volume; ΔPS, change of Vessel Permeability Surface Product; PDS/NACT,
Primary Debulking Surgery/Neoadjuvant chemotherapy; RT, Residual Tumor; PS, Performance Status; CR, Completeness of resection; NLR, neutrophil-
to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune inflammation index.
Frontiers in Pharmacology frontiersin.org11
Mei et al. 10.3389/fphar.2023.1147717
in the absence of effective biomarkers, trebananib possessed an
adequate safety profile, but its efficacy in the selected OC population
was not significant.
5 Biomarkers of anti-angiogenic
therapy in OC
Anti-angiogenic agents have demonstrated significant efficacy
benefits in OC as single-agent or combination therapy. However, not
all patients can benefit from these agents. It is crucial to identify
clinical biomarkers to select sensitive population and monitor
curative effect of anti-angiogenic drugs. So far, numerous studies
focused on the research in OC and provided evidence indicating
several predictive values for clinical, radiological, molecular, and
gene profiling markers (Supplementary Table S1). The biomarkers
related to PFS and OS that assessed in clinical trials were
systematically summarized in Figures 2,3, respectively.
Circulating cell-free DNA was shown to be an independent
prognostic importance in multi-resistant epithelial OC patients
FIGURE 3
Clinical trials assessing biomarkers in relation to OS of anti-angiogenic drugs in OC. BEV: Bevacizumab; CT: Chemotherapy; PC:TAXOL and CBP;
DNA, Deoxyribonucleic Acid; RNA, Ribonucleic Acid; cfDNA, cell-free DNA; ADAM17, a disintegrin and metalloprotease 17; MVD, microvessel density;
SMA_MVD: Alfa-Smooth Muscle Actin + microvessel density; Ratio, α-SMA + MVD/MVD ratio; miRNA, microRNA; VEGFA, vascular endothelial growth
factor A; VEGFB, vascular endothelial growth factor B; HIF-a, Hypoxia-Inducible Factor 1-alpha; OPN, osteopontin; SDF-1, stromal cell–derived
factor-1; IL6R, IL6 receptor; FLT4, fms-like tyrosine kinase-4; AGP, a 1 -acid glycoprotein; BMI, body mass index; VFA, visceral fat area; SFA, subcutaneous
fat area; ΔBF, change of Tumor Blood Flow; ΔBV, change of Tumor Blood Volume; ΔPS, change of Vessel Permeability Surface Product; PDS/NACT,
Primary Debulking Surgery/Neoadjuvant chemotherapy; RT, Residual Tumor; PS, Performance Status; CR, Completeness of resection; NLR, neutrophil-
to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune inflammation index; SFD, subcutaneous fat density; VFD, visceral fat
density.
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Mei et al. 10.3389/fphar.2023.1147717
treated with bevacizumab (Steffensen et al., 2014). Epidermal growth
factor receptor (EGFR), BRCA, and human epidermal growth factor
receptor-2 (HER2) mutational status might be predictors for PFS of
chemotherapy and bevacizumab combination therapy in
retrospective studies (Lorusso et al., 2020;Gao et al., 2021). The
protein expression of angiogenesis-related genes such as CCNE1, a
disintegrin and metalloprotease 17 (ADAM17), mevalonate
diphosphate decarboxylase (MVD), SMA_MVD, VEGFA,
VEGFB, VGFR2, HIF-1αin tumor tissues was explored (Fabbi
et al., 2022). Only CCNE1 and VEGFB were proved to be
predictive markers for the efficacy of bevacizumab (Califano
et al., 2021;Ribeiro et al., 2021). Circulating plasma or serum
proteomic biomarkers are also assessed to their predictive value
for PFS and OS. Chitinase three like 1 (YKL-40), osteopontin
(OPN), IL-6, Ang-2, Mesothelin (MSLN), fms-like tyrosine
kinase-4 (FLT4), Alpha-1 acid glycoprotein (AGP), and cancer
antigen 125 (CA-125) might be predictive of therapeutic benefit
from bevacizumab (Collinson et al., 2013;Backen et al., 2014;Boisen
et al., 2016;Alvarez Secord et al., 2020). OPN, IL-6, TIMP-1, Ang-2
were also correlated with PFS in OC patients treated with olaparib +
cediranib (Nixon et al., 2021). VEGR, Ang-2, VEGFR-3 were
explored for the predictive value for PFS in Pt resistant or
refractory OC patients with the treatment of sunitinib. However,
there was no significance (Bauerschlag et al., 2013). Circulating
microRNAs were also investigated to identify candidate predictive
biomarkers for anti-angiogenic drugs in OC. The level of miR-200b,
and miR-200c might be predictive of the effect of treatment with
bevacizumab (Halvorsen et al., 2017). Low expression of miR-34a-
5p and miR-93-5p were correlated with PFS and OS improvements
in OC patients with the treatment of chemotherarpy ± nintedanib
(Robelin et al., 2020). As obesity was associated with the level of
VEGF, the main target of bevacizumab, adiposity was assessed. The
measurements of adiposity such as subcutaneous fat area or density
and visceral fat density are likely to be useful biomarkers for PFS or
OS (Halvorsen et al., 2017;Buechel et al., 2021). CT perfusion
biomarkers such as blood flow may offer early prognostic evidence
for patients with newly diagnosed OC and received chemotherapy ±
bevacizumab therapy (Ng et al., 2017). Baseline SUV
60,mean
(mean
standardized uptake value at 60 min) was negatively correlated with
PFS of patlinum-resistant/refractory OC patients received
pazopanib and TAXOL combination therapy, which indicated
[
18
F] Fluciclatide-PET uptake parameters may be a predictor of
clinical outcome in patients treated with pazopanib (Sharma et al.,
2020). Inflammatory Indexes were prognostic markers for OC
patients treated with chemotherapy, but not with chemotherapy
and bevacizumab (Farolfiet al., 2018). These findings need to be
validated in further different races and larger sample sizes. It is still
urgent to identify predictive biomarkers in treating OC patients with
anti-angiogenic agents.
6 Models of anti-angiogenic therapy
in OC
Angiogenesis is an outcome of complex signaling involving a
plethora of cells, their cellular signal transduction, activation,
proliferation, differentiation, as well as their intercellular
communication. Zhang et al. provided a comprehensive review of
systems biology computational models of angiogenesis at the
pathway-, cell-, tissue-, and whole body-levels, which advanced
our understanding of signaling in angiogenesis and delivered new
translational insights for human diseases (Zhang et al., 2022). An
integrated model of VEGF-Ang-2 cooperation that accurately
recapitulates molecular events constituting the angiogenic switch
was proposed in ovarian cancer (Zhang et al., 2003). Adhikarla et al.
established a computational model to simulate tumor-specific
oxygenation changes based on the molecular image data, which
incorporating therapeutic effects might serve as a powerful tool for
analyzing tumor response to anti-angiogenic therapies (Adhikarla
and Jeraj, 2016). Models combining biomarkers with other risk
factors are also constructed to predict treatment outcomes of anti-
angiogenic agents in OC. Previs et al. found that prior number of
chemotherapy regimens, treatment-free interval (TFI), Pt
sensitivity, and the presence of ascites were significant predictors
of 5-year OS in 312 women with recurrent ovarian cancer treated
with bevacizumab and chemotherapy. Based on the multivariate
analysis, a nomogram for OS was constructed, which could provide
insight to those women who will benefit the most while avoiding
excessive costs and potentially catastrophic toxicities that would
ultimately require discontinuation of therapy (Previs et al., 2014).
Wang et al. reported three quantitative adiposity-related image
feature-based models (multiple linear, logistic and Cox
proportional hazards regressions), which provide a useful and
Supplementary Information that could yield higher
discriminatory power than BMI in predicting the association
between adiposity and clinical outcome of EOC patients
(including PFS and OS) treated with maintenance bevacizumab-
based chemotherapy (Wang et al., 2016). Sostelly. et al. constructed
an OS model combining tumor kinetics metrics describing the
change in tumor size over time in Pt-resistant OC (PROC)
patients treated with chemotherapy and bevacizumab, which
could effectively help to simulate and optimize future trials in
PROC population (Sostelly and Mercier, 2019).
7 Mechanisms of therapy resistance and
adverse reaction
Despite the ever-growing number of anti-angiogenic drugs
applied in clinical practice, the survival benefits to date have
been quite limited, which only temporarily inhibiting tumor
development before drug resistance occurs.
In OC, the vast majority of patients have innate or acquired
resistance to anti-angiogenic therapy and eventually recurrence (Ellis
and Hicklin, 2008). Even a small proportion of patients could benefit
from bevacizumab, the effective duration is relatively short (only
3–8 months with monotherapy). There are several explanations for
the modest efficacy, like the adoption of alternative patterns of
angiogenesis by the tumor and the development of resistance
mechanisms. In case of the high expense, adverse reactions and
modest clinical benefit of anti-angiogenic drugs, an insight
knowledge of resistance mechanisms and the exploration of reliable
predictive biomarkers are in urgent needs to provide a basis for
prolonging survival and overcoming resistance (Jin et al., 2022).
Both intrinsic and acquired resistance are considered the major
leading to the therapeutic failure of anti-angiogenic agents. The
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Mei et al. 10.3389/fphar.2023.1147717
most frequently proposed mechanism is the increase in tumor
hypoxia levels caused by anti-angiogenic therapy. Anti-angiogenic
agents aggravate intra-tumoral hypoxia and the abnormal
upregulation of HIF-1α, this further stimulates the production of
angiogenic factors like FGF, ANGPT2, and IL-8, eventually leading
to therapy resistance and higher risk of disease progression
(Casanovas et al., 2005;Huang et al., 2010;Rigamonti et al.,
2014). HIF-1 may be a promising target to improve
chemoradiotherapy sensitivity and patient prognosis,
upregulation of which greatly enhanced tumor angiogenesis,
malignant progression as well as apoptosis resistance. However,
there are no clinical studies focused on HIF-1 protein inhibitors yet
(Bhattarai et al., 2018). Secondly, when the VEGF/VEGFR pathway
is inhibited, other VEGF -independent angiogenic mechanisms such
as ANG1, ANGPT-2, FGF-2, IL-8, Dll4/Notch and miRNA46 will be
compensatively upregulated, ultimately causing resistance to anti-
VEGF drugs (Liu et al., 2021). Thirdly, the heterogeneity of tumor
cells is an important endogenous resistance mechanism of anti-
angiogenic therapy. Heterogeneity in tumor vasculature itself leads
to the differential requirement for VEGF. Among the different types
of the blood vessel, the first-formed mother vessels and glomeruloid
microvascular proliferations have a high response to anti-VEGF
therapy, while the “late”formed capillaries, vascular malformations,
feeder arteries, and draining veins are relatively insensitive (Nagy
and Dvorak, 2012). Therefore, individual differences, the proportion
of vascular subtypes varies in diverse tumor tissues, different ratios
of VEGF-dependent and -independent angiogenesis all contribute to
resistance to anti-angiogenic agents. Fourth, long-term anti-
angiogenic therapy would result in widespread vascular
morphological alterations via the regulation of pro-angiogenic
factors, and the remodeled neovascularization structure results in
resistance to existing anti-angiogenic drugs (Huang et al., 2004).
8 Combining with immunotherapy
Combination therapy holds great promise in overcoming
resistance and enhancing the antitumor efficacy of anti-
angiogenic drugs. Immune checkpoint inhibitors (ICIs) exert
anticancer effects by reactivating exhausted or dysfunctional
T-cells (Mellman et al., 2011;Topalian et al., 2016). Monoclonal
antibodies targeting cytotoxic T lymphocyte-associated protein
4 (CTLA-4), programmed cell death protein (PD-1) and its
ligand PD-L1 are the most wildly used ICIs. However, ICIs alone
showed limited efficacy in advanced or recurrent OC, with an
overall response rate (ORR) between 5.9% and 22.2% (Brahmer
et al., 2012;Hamanishi et al., 2015;Liu et al., 2019b;Disis et al.,
2019;Varga et al., 2019;Nishio et al., 2020;Hamanishi et al.,
2021). A phase III study (JAVELIN Ovarian 200) showed that
neither monotherapy nor combination of avelumab with
chemotherapy improved PFS or OS in patients with
platinum-resistant or platinum-refractory OC (Pujade-
Lauraine et al., 2021).
The antitumor effect of immunotherapy relies on the accumulation
of immune effector cells in tumor microenvironment (TME). The anti-
angiogenic therapy-mediated tumor vascular normalization effectively
increases the infiltration of immune effector cells in TME and promotes
the reprogramming of intrinsically immunosuppressive TME into
immune supportive one (Fukumura et al., 2018). Anti-angiogenic
therapyalsoamelioratesantitumorimmunitybyinhibitingmultiple
immunosuppressive properties of angiogenesis (Huinen et al., 2021). On
the contrary, ICIs-activated immunity improves anti-angiogenic
efficiency by reducing the expression of angiogenic factors and
alleviating hypoxia conditions (Song et al., 2020).
Mechanism studies have explained the immunosuppressive
function of VEGF. For example, VEGF inhibits the maturation
and differentiation of dendritic cells through NF-kB signaling
pathway (Oyama et al., 1998;Curiel et al., 2003;Huang et al.,
2007). It also upregulates the expression of PD-L1, thus inhibiting
the antigen presentation function of dendritic cells, and further the
activation and expansion of T-cells (Alfaro et al., 2009). Besides,
VEGF inhibits the differentiation of monocytes into dendritic cells,
which can be reversed by bevacizumab or sorafenib treatment (Motz
and Coukos, 2011). VEGF-activated VEGFR-2 stimulates the
expression of immune checkpoint molecules including PD-1,
T-cell immunoglobulin mucin receptor 3 (TIM-3), and cytotoxic
T lymphocyte antigen 4 (CTLA-4) on CD8
+
cells, resulting in the
exhaustion of CD8
+
cytotoxic T-cells (Burger et al., 2011;Perren
et al., 2011;Fuh et al., 2015). Moreover, VEGF facilitates the
proliferation of Tregs, thereby inhibiting anti-tumor immunity
and promoting the occurrence and tumor development
(Pennington and Swisher, 2012;Patch et al., 2015). In addition,
targeting VEGF/VEGFR can also enhance immunotherapy efficacy
by upregulating adhesion molecules and chemokines that are critical
for the capture and transendothelial migration of T-cells
(Georganaki et al., 2018;Khan and Kerbel, 2018). In view of the
demonstrated antitumor efficacy, the FDA has approved the
combination of anti-angiogenic agents with ICIs for certain
malignancies.
Improved antitumor efficacy and prolonged survival were observed
in many clinical trials following the combination of ICIs with anti-
angiogenic agents (Song et al., 2020). The combination of bevacizumab
and ICIs has been evaluated in phase I and II clinical trials, and the ORR
was between 15% and 32%, which was significantly higher than ICIs
alone (Langenkamp et al., 2015;Liu et al., 2019c;González-Martín et al.,
2020;Moroney et al., 2020). A phase Ib study in platinum-resistant OC
showed that the ORR of atezolizumab plus bevacizumab was 15%
(Moroney et al., 2020). Another phase II study in relapsed EOC
demonstrated that the combination of nivolumab with bevacizumab
had an ORR of 40.0% (19.1%-64.0%) and 16.7% (95% CI 3.6%-41.4%) in
the platinum-sensitive and -resistant group, respectively (Liu et al.,
2019c). In addition, LEAP-005 phase II study evaluated the efficacy
and safety of lenvatinib and pembrolizumab (a PD-1 immune checkpoint
inhibitor) in patients with OC. The combination reached an ORR of 32%
with manageable adverse events (González-Martín et al., 2020).
In conclusion, co-applied ICIs with anti-angiogenic agents has
shown satisfactory efficacy in several malignancies. However, several
obstacles still exist, like low tumor penetrance and increased adverse
reactions. New agents, such as engineered antibodies, may help provide
safer and more effective therapies (Anderson et al., 2022).
9 Conclusion and prospect
The limitations in the use of anti-angiogenic therapy may be in part
related to two main factors. First, the exact mechanisms of angiogenesis
Frontiers in Pharmacology frontiersin.org14
Mei et al. 10.3389/fphar.2023.1147717
and therapeutic resistance remain unclear. Secondly, the abrogation of
blood supply also limits the effective transport of antineoplastic agents
inside the tumor, thus weaken their anti-tumor effect. The vast majority
of clinical studies focused on bevacizumab suggested a meaningful
improvement in PFS of recurrent OC patients, regardless of the Pt
sensitivity. Similarly, anti-anti-angiogenic drugs targeting TKIs,
including sorafenib, pazopanib, cediranib, and nintedanib also
exhibited satisfactory improvementsinthePFSofOC.However,
only a few studies reported significant improvements in the OS of
OC patients. In addition, bevacizumab exerted its effectiveness in only a
small proportion of patients, while no reliable predictive biomarkers
have been identified and validated for more precise treatment with
bevacizumab. Regarding the obvious toxicity and high cost, biomarkers
are urgent and crucial for selecting patients with a higher possibility to
benefit from anti-angiogenic therapy.
Author contributions
CM and WG wrote the draft. CZ and SW designed the
organizational framework. XW, YL, and YZ made critical revisions.
Funding
The National Natural Science Foundation of China (No.
82003868). The National Natural Science Foundation of China
(No. 82203060). Scientific Research Projects of Union Hospital,
Tongji Medical College, Huazhong University of Science and
Technology (No. 2022xhyn055). Hubei Provincial Natural
Science Foundation of China (No. 2020CFB388). Hubei
Provincial Natural Science Foundation of China (No. 2022CFB592).
Conflict of interest
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.
Publisher’s note
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.
Supplementary material
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1147717/
full#supplementary-material
References
Abdollahi, A., Hahnfeldt, P., Maercker, C., Grone, H. J., Debus, J., Ansorge, W., et al.
(2004). Endostatin’s antiangiogenic signaling network. Mol. Cell 13, 649–663. doi:10.
1016/s1097-2765(04)00102-9
Adhikarla, V., and Jeraj, R. (2016). An imaging-based computational model for
simulating angiogenesis and tumour oxygenation dynamics. Phys. Med. Biol. 61,
3885–3902. doi:10.1088/0031-9155/61/10/3885
Agarwal, R., and Kaye, S. B. (2003). Ovarian cancer: Strategies for overcoming
resistance to chemotherapy. Nat. Rev. Cancer 3, 502–516. doi:10.1038/nrc1123
Aghajanian, C., Blank, S. V., Goff, B. A., Judson, P. L., Teneriello, M. G., Husain, A.,
et al. (2012). Oceans: A randomized, double-blind, placebo-controlled phase III trial of
chemotherapy with or without bevacizumab in patients with platinum-sensitive
recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J. Clin.
Oncol. 30, 2039–2045. doi:10.1200/JCO.2012.42.0505
Akai, J., Halley, P. A., and Storey, K. G. (2005). FGF-dependent Notch signaling
maintains the spinal cord stem zone. Genes Dev. 19, 2877–2887. doi:10.1101/gad.357705
Alam, S. M., Fujimoto, J., Jahan, I., Sato, E., and Tamaya, T. (2008). Coexpression of
EphB4 and ephrinB2 in tumour advancement of ovarian cancers. Br. J. Cancer 98,
845–851. doi:10.1038/sj.bjc.6604216
Alfaro, C., Suarez, N., Gonzalez, A., Solano, S., Erro, L., Dubrot, J., et al. (2009).
Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on
the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.
Br. J. Cancer 100, 1111–1119. doi:10.1038/sj.bjc.6604965
Alvarez Secord, A., Bell Burdett, K., Owzar, K., Tritchler, D., Sibley, A. B., Liu, Y., et al.
(2020). Predictive blood-based biomarkers in patients with epithelial ovarian cancer
treated with carboplatin and paclitaxel with or without bevacizumab: Results from
GOG-0218. Clin. Cancer Res. 26, 1288–1296. doi:10.1158/1078-0432.CCR-19-0226
Anderson, T. S., Wooster, A. L., Piersall, S. L., Okpalanwaka, I. F., and Lowe, D. B.
(2022). Disrupting cancer angiogenesis and immune checkpoint networks for improved
tumor immunity. Semin. Cancer Biol. 86, 981–996. doi:10.1016/j.semcancer.2022.
02.009
Arjaans, M., Oude Munnink, T. H., Oosting, S. F., Terwisscha van Scheltinga, A. G.,
Gietema, J. A., Garbacik, E. T., et al. (2013). Bevacizumab-induced normalization of
blood vessels in tumors hampers antibody uptake. Cancer Res. 73, 3347–3355. doi:10.
1158/0008-5472.CAN-12-3518
Backen, A., Renehan, A. G., Clamp, A. R., Berzuini, C., Zhou, C., Oza, A., et al. (2014).
The combination of circulating Ang1 and Tie2 levels predicts progression-free survival
advantage in bevacizumab-treated patients with ovarian cancer. Clin. Cancer Res. 20,
4549–4558. doi:10.1158/1078-0432.CCR-13-3248
Bagley, R. G., Ren, Y., Weber, W., Yao, M., Kurtzberg, L., Pinckney, J., et al. (2011).
Placental growth factor upregulation is a host response to antiangiogenic therapy. Clin.
Cancer Res. 17, 976–988. doi:10.1158/1078-0432.CCR-10-2687
Bamberger, E. S., and Perrett, C. W. (2002). Angiogenesis in epithelian ovarian cancer.
Mol. Pathol. 55, 348–359. doi:10.1136/mp.55.6.348
Banerjee, S., and Kaye, S. (2011). The role of targeted therapy in ovarian cancer. Eur.
J. Cancer 47 (3), S116–S130. doi:10.1016/S0959-8049(11)70155-1
Bartoschek, M., and Pietras, K. (2018). PDGF family function and prognostic val ue in
tumor biology. Biochem. Biophys. Res. Commun. 503, 984–990. doi:10.1016/j.bbrc.2018.
06.106
Bauerschlag, D. O., Hilpert, F., Meier, W., Rau, J., Meinhold-Heerlein, I., Maass, N.,
et al. (2013). Evaluation of potentially predictive markers for anti-angiogenic therapy
with sunitinib in recurrent ovarian cancer patients. Transl. Oncol. 6, 305–310. doi:10.
1593/tlo.13205
Bauerschlag, D. O., Schem, C., Tiwari, S., Egberts, J. H., Weigel, M. T., Kalthoff, H.,
et al. (2010). Sunitinib (SU11248) inhibits growth of human ovarian cancer in
xenografted mice. Anticancer Res. 30, 3355–3360.
Baumann,K.H.,duBois,A.,Meier,W.,Rau,J.,Wimberger,P.,Sehouli,J.,etal.
(2012). A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: A
randomized multicenter trial with sunitinib (SU11248) to evaluate dosage,
schedule, tolerability, toxicity and effectiveness of a multitargeted receptor
tyrosine kinase inhibitor monotherapy. Ann. Oncol. 23, 2265–2271. doi:10.
1093/annonc/mds003
Berta, J., Kenessey, I., Dobos, J., Tovari, J., Klepetko, W., Jan Ankersmit, H.,
et al. (2010). Apelin expression in human non-small cell lung cancer: Role in
angiogenesis and prognosis. J. Thorac. Oncol. 5, 1120–1129. doi:10.1097/JTO.
0b013e3181e2c1ff
Bhattarai, D., Xu, X., and Lee, K. (2018). Hypoxia-inducible factor-1 (HIF-1)
inhibitors from the last decade (2007 to 2016): A "structure-activity relationship"
perspective. Med. Res. Rev. 38, 1404–1442. doi:10.1002/med.21477
Frontiers in Pharmacology frontiersin.org15
Mei et al. 10.3389/fphar.2023.1147717
Biagi, J. J., Oza, A. M., Chalchal, H. I., Grimshaw, R., Ellard, S. L., Lee, U., et al. (2011).
A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary
peritoneal carcinoma: An NCIC clinical trials group study. Ann. Oncol. 22, 335–340.
doi:10.1093/annonc/mdq357
Bodnar, L., Gornas, M., and Szczylik, C. (2011). Sorafenib as a third line therapy in
patients with epithelial ovarian cancer or primary peritoneal cancer: A phase II study.
Oncol 123, 33–36. doi:10.1016/j.ygyno.2011.06.019
Bohndiek, S. E., Sasportas, L. S., Machtaler, S., Jokerst, J. V., Hori, S., and
Gambhir, S. S. (2015). Photoacoustic tomography detects early vessel regression
and normalization during ovarian tumor response to the antiangiogenic therapy
trebananib. J. Nucl. Med. 56, 1942–1947. doi:10.2967/jnumed.115.160002
Boisen, M. K., Madsen, C. V., Dehlendorff, C., Jakobsen, A., Johansen, J. S., and
Steffensen, K. D. (2016). The prognostic value of plasma YKL-40 in patients with
chemotherapy-resistant ovarian cancer treated with bevacizumab. Int. J. Gynecol.
Cancer 26, 1390–1398. doi:10.1097/IGC.0000000000000798
Brahmer, J. R., Tykodi, S. S., Chow, L. Q., Hwu, W. J., Topalian, S. L., Hwu, P., et al.
(2012). Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N.
Engl. J. Med. 366, 2455–2465. doi:10.1056/NEJMoa1200694
Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q., Brekken, R. A., Thorpe, P. E.,
et al. (2002). Soluble Eph A receptors inhibit tumor angiogenesis and progression in
vivo.Oncogene 21, 7011–7026. doi:10.1038/sj.onc.1205679
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., and Jemal, A. (2018).
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424. doi:10.
3322/caac.21492
Brunckhorst, M. K., Xu, Y., Lu, R., and Yu, Q. (2014). Angiopoietins promote ovarian
cancer progression by establishing a procancer microenvironment. Am. J. Pathol. 184,
2285–2296. doi:10.1016/j.ajpath.2014.05.006
Buechel, M. E., Enserro, D., Burger, R. A., Brady, M. F., Wade, K., Secord, A. A., et al.
(2021). Correlation of imaging and plasma based biomarkers to predict response to
bevacizumab in epithelial ovarian cancer (EOC). Gynecol. Oncol. 161, 382–388. doi:10.
1016/j.ygyno.2021.02.032
Burbridge, M. F., Bossard, C. J., Saunier, C., Fejes, I., Bruno, A., Leonce, S., et al.
(2013). S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong
preclinical activity alone and in association with bevacizumab. Mol. Cancer Ther. 12,
1749–1762. doi:10.1158/1535-7163.MCT-13-0075
Burger, R. A., Brady, M. F., Bookman, M. A., Fleming, G. F., Monk, B. J., Huang, H.,
et al. (2011). Incorporation of bevacizumab in the primary treatment of ovarian cancer.
N. Engl. J. Med. 365, 2473–2483. doi:10.1056/nejmoa1104390
Burger, R. A. (2011). Overview of anti-angiogenic agents in development for
ovarian cancer. Gynecol. Oncol. 121, 230–238. doi:10.1016/j.ygyno.2010.11.035
Burger, R. A., Sill, M. W., Monk, B. J., Greer, B. E., and Sorosky, J. I. (2007). Phase II
trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary
peritoneal cancer: A gynecologic oncology group study. J. Clin. Oncol. 25, 5165–5171.
doi:10.1200/JCO.2007.11.5345
Byron,S.A.,Gartside,M.G.,Wellens,C.L.,Goodfellow,P.J.,Birrer,M.J.,
Campbell, I. G., et al. (2010). FGFR2 mutations are rare across histologic
subtypes of ovarian cancer. Gynecol. Oncol. 117, 125–129. doi:10.1016/j.
ygyno.2009.12.002
Califano, D., Gallo, D., Rampioni Vinciguerra, G. L., De Cecio, R., Arenare, L.,
Signoriello, S., et al. (2021). Evaluation of angiogenesis-related genes as prognostic
biomarkers of bevacizumab treated ovarian cancer patients: Results from the phase IV
mito16a/ManGO OV-2 translational study. Cancers (Basel) 13, 5152. doi:10.3390/
cancers13205152
Campbell, N. E., Greenaway, J., Henkin, J., Moorehead, R. A., and Petrik, J. (2010).
The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of
cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer. Neoplasia 12,
275–283. doi:10.1593/neo.91880
Campos, S. M., Penson, R. T., Matulonis, U., Horowitz, N. S., Whalen, C., Pereira, L.,
et al. (2013). A phase II trial of Sunitinib malate in recurrent and refractory ovarian,
fallopian tube and peritoneal carcinoma. Gynecol. Oncol. 128, 215–220. doi:10.1016/j.
ygyno.2012.07.126
Cannistra, S. A., Matulonis, U. A., Penson, R. T., Hambleton, J., Dupont, J., Mackey,
H., et al. (2007). Phase II study of bevacizumab in patients with platinum-resistant
ovarian cancer or peritoneal serous cancer. J. Clin. Oncol. 25, 5180–5186. doi:10.1200/
JCO.2007.12.0782
Cantanhede, I. G., and de Oliveira, J. R. M. (2017). PDGF family expression in
glioblastoma multiforme: Data compilation from ivy glioblastoma atlas project
database. Sci. Rep. 7, 15271. doi:10.1038/s41598-017-15045-w
Cao, Y. (2013). Multifarious functions of PDGFs and PDGFRs in tumor growth and
metastasis. Trends Mol. Med. 19, 460–473. doi:10.1016/j.molmed.2013.05.002
Carmeliet, P., and Jain, R. K. (2011). Molecular mechanisms and clinical applications
of angiogenesis. Nature 473, 298–307. doi:10.1038/nature10144
Carmeliet, P., and Jain, R. K. (2011). Principles and mechanisms of vessel
normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10,
417–427. doi:10.1038/nrd3455
Casanovas, O., Hicklin, D. J., Bergers, G., and Hanahan, D. (2005). Drug resistance by
evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet
tumors. Cancer Cell 8, 299–309. doi:10.1016/j.ccr.2005.09.005
Chae, S. S., Kamoun, W. S., Farrar, C. T., Kirkpatrick, N. D., Niemeyer, E., de Graaf, A.
M., et al. (2010). Angiopoietin-2 interferes with anti-VEGFR2-induced vessel
normalization and survival benefit in mice bearing gliomas. Clin. Cancer Res. 16,
3618–3627. doi:10.1158/1078-0432.CCR-09-3073
Chan, J. K., Brady, W., Monk, B. J., Brown, J., Shahin, M. S., Rose, P. G., et al. (2018). A
phase II evaluation of sunitinib in the treatment of persistent or recurrent clear cell
ovarian carcinoma: An NRG Oncology/Gynecologic Oncology Group Study (GOG-
254). Gynecol. Oncol. 150, 247–252. doi:10.1016/j.ygyno.2018.05.029
Chekerov, R., Hilpert, F., Mahner, S., El-Balat, A., Harter, P., De Gregorio, N., et al.
(2018). Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant
ovarian cancer (TRIAS): A multicentre, randomised, double-blind, placebo-controlled,
phase 2 trial. Lancet Oncol. 19, 1247–1258. doi:10.1016/s1470-2045(18)30372-3
Cheng, N., Brantley, D., Fang, W. B., Liu, H., Fanslow, W., Cerretti, D. P., et al. (2003).
Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors.
Neoplasia 5, 445–456. doi:10.1016/s1476-5586(03)80047-7
Chiron, M., Bagley, R. G., Pollard, J., Mankoo, P. K., Henry, C., Vincent, L., et al.
(2014). Differential antitumor activity of aflibercept and bevacizumab in patient-
derived xenograft models of colorectal cancer. Mol. Cancer Ther. 13, 1636–1644.
doi:10.1158/1535-7163.MCT-13-0753
Cloughesy, T., Finocchiaro, G., Belda-Iniesta, C., Recht, L., Brandes, A. A., Pineda, E.,
et al. (2017). Randomized, double-blind, placebo-controlled, multicenter phase II study
of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with
recurrent glioblastoma: Efficacy, safety, and hepatocyte growth factor and O(6)-
methylguanine-DNA methyltransferase biomarker analyses. J. Clin. Oncol. 35,
343–351. doi:10.1200/JCO.2015.64.7685
Coleman,R.L.,Brady,M.F.,Herzog,T.J.,Sabbatini,P.,Armstrong,D.K.,Walker,J.L.,
et al. (2017). Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary
cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG oncology/gynecologic
oncology group study GOG-0213): A multicentre, open-label, randomised, phase 3 trial.
Lancet Oncol. 18, 779–791. doi:10.1016/S1470-2045(17)30279-6
Collinson, F., Hutchinson, M., Craven, R. A., Cairns, D. A., Zougman, A., Wind, T. C.,
et al. (2013). Predicting response to bevacizumab in ovarian cancer: A panel of potential
biomarkers informing treatment selection. Clin. Cancer Res. 19, 5227–5239. doi:10.
1158/1078-0432.CCR-13-0489
Colombo,N.,Tomao,F.,BenedettiPanici,P.,Nicoletto,M.O.,Tognon,G.,
Bologna, A., et al. (2022). Randomized phase II trial of weekly paclitaxel vs.
cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant
high-grade epithelial ovarian cancer. Gynecol. Oncol. 164, 505–513. doi:10.1016/j.
ygyno.2022.01.015
Cortez,A.J.,Tudrej,P.,Kujawa,K.A.,andLisowska,K.M.(2018).Advancesinovarian
cancer therapy. Cancer Chemother. Pharmacol. 81, 17–38. doi:10.1007/s00280-017-3501-8
Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., et al. (2003).
Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity.
Nat. Med. 9, 562–567. doi:10.1038/nm863
Davidson, B. A., and Secord, A. A. (2014). Profile of pazopanib and its potential in the
treatment of epithelial ovarian cancer. Int. J. Womens Health 6, 289–300. doi:10.2147/
IJWH.S49781
De Falco, S. (2012). The discovery of placenta growth factor and its biological activity.
Exp. Mol. Med. 44, 1–9. doi:10.3858/emm.2012.44.1.025
Delgado, V. M., Nugnes, L. G., Colombo, L. L., Troncoso, M. F., Fernandez, M. M.,
Malchiodi, E. L., et al. (2011). Modulation of endothelial cell migration and
angiogenesis: A novel function for the "tandem-repeat" lectin galectin-8. FASEB J.
25, 242–254. doi:10.1096/fj.09-144907
Dewangan, J., Srivastava, S., Mishra, S., Divakar, A., Kumar, S., and Rath, S. K. (2019).
Salinomycin inhibits breast cancer progression via targeting HIF-1α/VEGF mediated
tumor angiogenesis in vitro and in vivo.Biochem. Pharmacol. 164, 326–335. doi:10.
1016/j.bcp.2019.04.026
Dewhirst, M. W., and Ashcraft, K. A. (2016). Implications of increase in vascular
permeability in tumors by VEGF: A commentary on the pioneering work of harold
Dvorak. Cancer Res. 76, 3118–3120. doi:10.1158/0008-5472.CAN-16-1292
Dewhirst,M.W.,Ong,E.T.,Braun,R.D.,Smith,B.,Klitzman,B.,Evans,S.M.,etal.(1999).
Quantification of longitudinal tissue pO2 gradients in window chamber tumours: Impact on
tumour hypoxia. Br. J. Cancer 79, 1717–1722. doi:10.1038/sj.bjc.6690273
Dewhirst, M. W., and Secomb, T. W. (2017). Transport of drugs from blood vessels to
tumour tissue. Nat. Rev. Cancer 17, 738–750. doi:10.1038/nrc.2017.93
Dhanabal, M., Jeffers, M., LaRochelle, W. J., and Lichenstein, H. S. (2005).
Angioarrestin: A unique angiopoietin-related protein with anti-angiogenic
properties. Biochem. Biophys. Res. Commun. 333, 308–315. doi:10.1016/j.bbrc.2005.
05.134
Disis, M. L., Taylor, M. H., Kelly, K., Beck, J. T., Gordon, M., Moore, K. M., et al.
(2019). Efficacy and safety of avelumab for patients with recurrent or refractory ovarian
cancer: Phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol. 5, 393–401.
doi:10.1001/jamaoncol.2018.6258
Frontiers in Pharmacology frontiersin.org16
Mei et al. 10.3389/fphar.2023.1147717
Dobrzanski, P., Hunter, K., Jones-Bolin, S., Chang, H., Robinson, C., Pritchard, S.,
et al. (2004). Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist.
Cancer Res. 64, 910–919. doi:10.1158/0008-5472.can-3430-2
Dogra, S., Neelakantan, D., Patel, M. M., Griesel, B., Olson, A., and Woo, S. (2021).
Adipokine apelin/APJ pathway promotes peritoneal dissemination of ovarian cancer
cells by regulating lipid metabolism. Mol. Cancer Res. 19, 1534–1545. doi:10.1158/1541-
7786.MCR-20-0991
du Bois, A., Floquet, A., Kim, J. W., Rau, J., del Campo, J. M., Friedlander, M., et al.
(2014). Incorporation of pazopanib in maintenance therapy of ovarian cancer. J. Clin.
Oncol. 32, 3374–3382. doi:10.1200/JCO.2014.55.7348
du Bois, A., Kristensen, G., Ray-Coquard, I., Reuss, A., Pignata, S., Colombo, N., et al.
(2016). Standard first-line chemotherapy with or without nintedanib for advanced
ovarian cancer (AGO-OVAR 12): A randomised, double-blind, placebo-controlled
phase 3 trial. Lancet Oncol. 17, 78–89. doi:10.1016/s1470-2045(15)00366-6
du Bois, A., Vergote, I., Wimberger, P., Ray-Coquard, I., Harter, P., Curtis, L. B., et al.
(2012). Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women
with newly diagnosed, untreated, gynaecologic tumours: A phase I/II trial of the AGO
study group. Br. J. Cancer 106, 629–632. doi:10.1038/bjc.2011.608
Ellis, L. M., and Hicklin, D. J. (2008). Pathways mediating resistance to vascular
endothelial growth factor-targeted therapy. Clin. Cancer Res. 14, 6371–6375. doi:10.
1158/1078-0432.CCR-07-5287
Elyashiv, O., Ledermann, J., Parmar, G., Farrelly, L., Counsell, N., Feeney, A., et al.
(2021). ICON 9-an international phase III randomized study to evaluate the efficacy of
maintenance therapy with olaparib and cediranib or olaparib alone in patients with
relapsed platinum-sensitive ovarian cancer following a response to platinum-based
chemotherapy. Int. J. Gynecol. Cancer 31, 134–138. doi:10.1136/ijgc-2020-002073
Erber, R., Thurnher, A., Katsen, A. D., Groth, G., Kerger, H., Hammes, H. P., et al.
(2004). Combined inhibition of VEGF and PDGF signaling enforces tumor vessel
regression by interfering with pericyte-mediated endothelial cell survival mechanisms.
FASEB J. 18, 338–340. doi:10.1096/fj.03-0271fje
Fabbi, M., Costa, D., Russo, D., Arenare, L., Gaggero, G., Signoriello, S., et al. (2022).
Analysis of A Disintegrin and metalloprotease 17 (ADAM17) expression as a prognostic
marker in ovarian cancer patients undergoing first-line treatment plus bevacizumab.
Diagn. (Basel) 12, 2118. doi:10.3390/diagnostics12092118
Farolfi, A., Petrone, M., Scarpi, E., Galla, V., Greco, F., Casanova, C., et al. (2018).
Inflammatory indexes as prognostic and predictive factors in ovarian cancer treated
with chemotherapy alone or together with bevacizumab. A multicenter, retrospective
analysis by the MITO group (MITO 24). Oncol 13, 469–479. doi:10.1007/s11523-018-
0574-1
Feng, M., Yao, G., Yu, H., Qing, Y., and Wang, K. (2016). Tumor apelin, not serum
apelin, is associated with the clinical features and prognosis of gastric cancer. BMC
Cancer 16, 794. doi:10.1186/s12885-016-2815-y
Franco, M., Roswall, P., Cortez, E., Hanahan, D., and Pietras, K. (2011). Pericytes
promote endothelial cell survival through induction of autocrine VEGF-A signaling and
Bcl-w expression. Blood 118, 2906–2917. doi:10.1182/blood-2011-01-331694
Fuh, K. C., Secord, A. A., Bevis, K. S., Huh, W., ElNaggar, A., Blansit, K., et al. (2015).
Comparison of bevacizumab alone or with chemotherapy in recurrent ovarian cancer
patients. Gynecol. Oncol. 139, 413–418. doi:10.1016/j.ygyno.2015.06.041
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G., and Jain, R. K. (2018).
Enhancing cancer immunotherapy using antiangiogenics: Opportunities and
challenges. Nat. Rev. Clin. Oncol. 15, 325–340. doi:10.1038/nrclinonc.2018.29
Gao, J., Li, F., Liu, Z., Huang, M., Chen, H., Liao, G., et al. (2021). Multiple genetic
variants predict the progression-free survival of bevacizumab plus chemotherapy in
advanced ovarian cancer: A retrospective study. Med. Baltim. 100, e27130. doi:10.1097/
MD.0000000000027130
Garrido-Laguna, I., Krop, I., Burris, H. A., 3rd, Hamilton, E., Braiteh, F., Weise, A. M.,
et al. (2019). First-in-human, phase I study of PF-06647263, an anti-EFNA4
calicheamicin antibody-drug conjugate, in patients with advanced solid tumors. Int.
J. Cancer 145, 1798–1808. doi:10.1002/ijc.32154
Gavalas, N. G., Liontos, M., Trachana, S. P., Bagratuni, T., Arapinis, C., Liacos, C.,
et al. (2013). Angiogenesis-related pathways in the pathogenesis of ovarian cancer. Int.
J. Mol. Sci. 14, 15885–15909. doi:10.3390/ijms140815885
Georganaki, M., van Hooren, L., and Dimberg, A. (2018). Vascular targeting to
increase the efficiency of immune checkpoint blockade in cancer. Front. Immunol. 9,
3081. doi:10.3389/fimmu.2018.03081
Gerald, D., Chintharlapalli, S., Augustin, H. G., and Benjamin, L. E. (2013).
Angiopoietin-2: An attractive target for improved antiangiogenic tumor therapy.
Cancer Res. 73, 1649–1657. doi:10.1158/0008-5472.CAN-12-4697
Ghedini, G. C., Ronca, R., Presta, M., and Giacomini, A. (2018). Future applications of
FGF/FGFR inhibitors in cancer. Expert Rev. Anticancer Ther. 18, 861–872. doi:10.1080/
14737140.2018.1491795
González-Martín, A., Chung, H., Saada-Bouzid, E., Yanez, E., Senellart, H., Cassier, P.,
et al. (2020) Efficacy Saf. lenvatinib plus pembrolizumab patients previously Treat.
ovarian cancer multicohort phase 2 LEAP-005 study 30, 2. A1–A2.
Greenberg, J. I., Shields, D. J., Barillas, S. G., Acevedo, L. M., Murphy, E., Huang, J.,
et al. (2008). A role for VEGF as a negative regulator of pericyte function and vessel
maturation. Nature 456, 809–813. doi:10.1038/nature07424
Grossfeld, G. D., Ginsberg, D. A., Stein, J. P., Bochner, B. H., Esrig, D., Groshen, S.,
et al. (1997). Thrombospondin-1 expression in bladder cancer: Association with
p53 alterations, tumor angiogenesis, and tumor progression. J. Natl. Cancer Inst. 89,
219–227. doi:10.1093/jnci/89.3.219
Hainsworth, J. D., Thompson, D. S., Bismayer, J. A., Gian, V. G., Merritt, W. M.,
Whorf, R. C., et al. (2015). Paclitaxel/carboplatin with or without sorafenib in the first-
line treatment of patients with stage III/IV epithelial ovarian cancer: A randomized
phase II study of the sarah cannon research Institute. Cancer Med. 4, 673–681. doi:10.
1002/cam4.376
Hall, M. R., Dehbi, H. M., Banerjee, S., Lord, R., Clamp, A., Ledermann, J. A., et al.
(2020). A phase II randomised, placebo-controlled trial of low dose (metronomic)
cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or
primary peritoneal cancer. Gynecol. Oncol. 159, 692–698. doi:10.1016/j.ygyno.2020.
09.048
Halvorsen, A. R., Kristensen, G., Embleton, A., Adusei, C., Barretina-Ginesta, M. P.,
Beale, P., et al. (2017). Evaluation of prognostic and predictive significance of circulating
MicroRNAs in ovarian cancer patients. Dis. Markers 2017, 3098542, doi:10.1155/2017/
3098542
Hamanishi, J., Mandai, M., Ikeda, T., Minami, M., Kawaguchi, A., Murayama, T., et al.
(2015). Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with
platinum-resistant ovarian cancer. J. Clin. Oncol. 33, 4015–4022. doi:10.1200/JCO.2015.
62.3397
Hamanishi, J., Takeshima, N., Katsumata, N., Ushijima, K., Kimura, T., Takeuchi, S.,
et al. (2021). Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for
patients with platinum-resistant ovarian cancer: Open-label, randomized trial in Japan
(NINJA). J. Clin. Oncol. 39, 3671–3681. doi:10.1200/JCO.21.00334
Han, L., Dong, Z., Qiao, Y., Kristensen, G. B., Holm, R., Nesland, J. M., et al. (2005).
The clinical significance of EphA2 and Ephrin A-1 in epithelial ovarian carcinomas.
Gynecol. Oncol. 99, 278–286. doi:10.1016/j.ygyno.2005.06.036
Haunschild, C. E., and Tewari, K. S. (2020). Bevacizumab use in the frontline,
maintenance and recurrent settings for ovarian cancer. Future Oncol. 16, 225–246.
doi:10.2217/fon-2019-0042
Heldin, C. H. (2013). Targeting the PDGF signaling pathway in tumor treatment. Cell
Commun. Signal 11, 97. doi:10.1186/1478-811X-11-97
Heldin, C. H., and Westermark, B. (1999). Mechanism of action and in vivo role of
platelet-derived growth factor. Physiol. Rev. 79, 1283–1316. doi:10.1152/physrev.1999.
79.4.1283
Heo, K., Kim, Y. H., Sung, H. J., Li, H. Y., Yoo, C. W., Kim, J. Y., et al. (2012). Hypoxia-
induced up-regulation of apelin is associated with a poor prognosis in oral squamous
cell carcinoma patients. Oral Oncol. 48, 500–506. doi:10.1016/j.oraloncology.2011.
12.015
Herath, N. I., Spanevello, M. D., Sabesan, S., Newton, T., Cummings, M., Duffy, S.,
et al. (2006). Over-expression of Eph and ephrin genes in advanced ovarian cancer:
Ephrin gene expression correlates with shortened survival. BMC Cancer 6, 144. doi:10.
1186/1471-2407-6-144
Herzog, T. J., Scambia, G., Kim, B. G., Lhomme, C., Markowska, J., Ray-Coquard, I.,
et al. (2013). A randomized phase II trial of maintenance therapy with Sorafenib in
front-line ovarian carcinoma. Gynecol. Oncol. 130, 25–30. doi:10.1016/j.ygyno.2013.
04.011
Hirte, H., Lheureux, S., Fleming, G. F., Sugimoto, A., Morgan, R., Biagi, J., et al. (2015).
A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian
tube cancer: A trial of the princess margaret, chicago and California phase II consortia.
Gynecol. Oncol. 138, 55–61. doi:10.1016/j.ygyno.2015.04.009
Hoffmann, M., Fiedor, E., and Ptak, A. (2017). Bisphenol A and its derivatives
tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and
secretion in ovarian cancer cells through a peroxisome proliferator-activated
receptor gamma-dependent mechanism. Toxicol. Lett. 269, 15–22. doi:10.1016/j.
toxlet.2017.01.006
Huang, D., Ding, Y., Zhou, M., Rini, B. I., Petillo, D., Qian, C. N., et al. (2010).
Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell
carcinoma. Cancer Res. 70, 1063–1071. doi:10.1158/0008-5472.CAN-09-3965
Huang, J., Soffer, S. Z., Kim, E. S., McCrudden, K. W., Huang, J., New, T., et al. (2004).
Vascular remodeling marks tumors that recur during chronic suppression of
angiogenesis. Mol. Cancer Res. 2, 36–42. doi:10.1158/1541-7786.36.2.1
Huang, Y., Chen, X., Dikov, M. M., Novitskiy, S. V., Mosse, C. A., Yang, L., et al.
(2007). Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis
associated with elevated levels of VEGF. Blood 110, 624–631. doi:10.1182/blood-
2007-01-065714
Huinen, Z. R., Huijbers, E. J. M., van Beijnum, J. R., Nowak-Sliwinska, P., and
Griffioen, A. W. (2021). Anti-angiogenic agents - overcoming tumour endothelial cell
anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol. 18, 527–540.
doi:10.1038/s41571-021-00496-y
Frontiers in Pharmacology frontiersin.org17
Mei et al. 10.3389/fphar.2023.1147717
Jeanne, A., Sarazin, T., Charle, M., Moali, C., Fichel, C., Boulagnon-Rombi, C., et al.
(2021). Targeting ovarian carcinoma with TSP-1:CD47 antagonist TAX2 activate s anti-
tumor immunity. Cancers (Basel) 13, 5019. doi:10.3390/cancers13195019
Jiang, B. H., and Liu, L. Z. (2009). PI3K/PTEN signaling in angiogenesis and
tumorigenesis. Adv. Cancer Res. 102, 19–65. doi:10.1016/S0065-230X(09)02002-8
Jin, C., Yuan, M., Bu, H., and Jin, C. (2022). Antiangiogenic strategies in epithelial
ovarian cancer: Mechanism, resistance, and combination therapy. J. Oncol. 2022,
4880355. doi:10.1155/2022/4880355
Jing, Y., Lu, H., Wu, K., Subramanian, I. V., and Ramakrishnan, S. (2011). Inhibition
of ovarian cancer by RGD-P125A-endostatin-Fc fusion proteins. Int. J. Cancer 129,
751–761. doi:10.1002/ijc.25932
Kalin, R. E., Kretz, M. P., Meyer, A. M., Kispert, A., Heppner, F. L., and Brandli, A. W.
(2007). Paracrine and autocrine mechanisms of apelin signaling govern embryonic and
tumor angiogenesis. Dev. Biol. 305, 599–614. doi:10.1016/j.ydbio.2007.03.004
Katoh, M. (2016). Therapeutics targeting FGF signaling network in human diseases.
Trends Pharmacol. Sci. 37, 1081–1096. doi:10.1016/j.tips.2016.10.003
Khalique, S., and Banerjee, S. (2017). Nintedanib in ovarian cancer. Expert Opin.
Investig. Drugs 26, 1073–1081. doi:10.1080/13543784.2017.1353599
Khan, K. A., and Kerbel, R. S. (2018). Improving immunotherapy outcomes with anti-
angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol. 15, 310–324. doi:10.1038/
nrclinonc.2018.9
Kim, B. J., Kim, D., Kim, J. H., Kim, H. S., and Jang, H. J. (2021). The efficacy and
safety of onartuzumab in patients with solid cancers: A meta-analysis of randomized
trials. Indian J. Cancer 58, 232–240. doi:10.4103/ijc.IJC_797_18
Kloepper, J., Riedemann, L., Amoozgar, Z., Seano, G., Susek, K., Yu, V., et al. (2016).
Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to
anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl. Acad. Sci. U. S. A.
113, 4476–4481. doi:10.1073/pnas.1525360113
Krusche, B., Ottone, C., Clements, M. P., Johnstone, E. R., Goetsch, K., Lieven, H.,
et al. (2016). EphrinB2 drives perivascular invasion and proliferation of glioblastoma
stem-like cells. Elife 5, e14845. doi:10.7554/eLife.14845
Lacquaniti, A., Altavilla, G., Picone, A., Donato, V., Chirico, V., Mondello, P., et al.
(2015). Apelin beyond kidney failure and hyponatremia: A useful biomarker for cancer
disease progression evaluation. Clin. Exp. Med. 15, 97–105. doi:10.1007/s10238-014-
0272-y
Lamalice, L., Le Boeuf, F., and Huot, J. (2007). Endothelial cell migration during
angiogenesis. Circ. Res. 100, 782–794. doi:10.1161/01.RES.0000259593.07661.1e
Langenkamp, E., Zhang, L., Lugano, R., Huang, H., Elhassan, T. E., Georganaki, M.,
et al. (2015). Elevated expression of the C-type lectin CD93 in the glioblastoma
vasculature regulates cytoskeletal rearrangements that enhance vessel function and
reduce host survival. Cancer Res. 75, 4504–4516. doi:10.1158/0008-5472.CAN-14-3636
Lassus, H., Sihto, H., Leminen, A., Nordling, S., Joensuu, H., Nupponen, N. N., et al.
(2004). Genetic alterations and protein expression of KIT and PDGFRA in serous
ovarian carcinoma. Br. J. Cancer 91, 2048–2055. doi:10.1038/sj.bjc.6602252
Ledermann, J. A., Embleton, A. C., Raja, F., Perren, T. J., Jayson, G. C., Rustin, G. J. S.,
et al. (2016). Cediranib in patients with relapsed platinum-sensitive ovarian cancer
(ICON6): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet 387,
1066–1074. doi:10.1016/S0140-6736(15)01167-8
Ledermann, J. A., Embleton-Thirsk, A. C., Perren, T. J., Jayson, G. C., Rustin, G. J. S.,
Kaye, S. B., et al. (2021). Cediranib in addition to chemotherapy for women with
relapsed platinum-sensitive ovarian cancer (ICON6): Overall survival results of a phase
III randomised trial. ESMO Open 6, 100043. doi:10.1016/j.esmoop.2020.100043
Ledermann, J. A., Hackshaw, A., Kaye, S., Jayson, G., Gabra, H., McNeish, I., et al.
(2011). Randomized phase II placebo-controlled trial of maintenance therapy using the
oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian
cancer. J. Clin. Oncol. 29, 3798–3804. doi:10.1200/JCO.2010.33.5208
Lee, C. K., Lee, M. E., Lee, W. S., Kim, J. M., Park, K. H., Kim, T. S., et al. (2015).
Dovitinib (TKI258), a multi-target angiokinase inhibitor, is effective regardless of KRAS
or BRAF mutation status in colorectal cancer. Am. J. Cancer Res. 5, 72–86.
Lee, J. M., Annunziata, C. M., Hays, J. L., Cao, L., Choyke, P., Yu, M., et al. (2020).
Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or
without prior-bevacizumab treatment. Gynecol. Oncol. 159, 88–94. doi:10.1016/j.ygyno.
2020.07.031
Lee, J. M., Sarosy, G. A., Annunziata, C. M., Azad, N., Minasian, L., Kotz, H., et al.
(2010). Combination therapy: Intermittent sorafenib with bevacizumab yields activity
and decreased toxicity. Br. J. Cancer 102, 495–499. doi:10.1038/sj.bjc.6605514
Lengyel, E. (2010). Ovarian cancer development and metastasis. Am. J. Pathol. 177,
1053–1064. doi:10.2353/ajpath.2010.100105
Leone Roberti Maggiore, U., Valenzano Menada, M., Venturini, P. L., and Ferrero, S.
(2013). The potential of sunitinib as a therapy in ovarian cancer. Expert Opin. Investig.
Drugs 22, 1671–1686. doi:10.1517/13543784.2013.841138
Levitzki, A. (2004). PDGF receptor kinase inhibitors for the treatment of PDGF driven
diseases. Cytokine Growth Factor Rev. 15, 229–235. doi:10.1016/j.cytogfr.2004.03.010
Lheureux, S., Oaknin, A., Garg, S., Bruce, J. P., Madariaga, A., Dhani, N. C., et al.
(2020). Evolve: A multicenter open-label single-arm clinical and translational
phase II trial of cediranib plus olaparib for ovarian cancer after PARP inhibition
progression. Clin. Cancer Res. 26, 4206–4215. doi:10.1158/1078-0432.CCR-19-
4121
Li, J., Zhi, X., Sun, Y., Chen, M., and Yao, L. (2022). The PDGF family is associated
with activated tumor stroma and poor prognosis in ovarian cancer. Dis. Markers 2022,
5940049. doi:10.1155/2022/5940049
Lisle, J. E., Mertens-Walker, I., Rutkowski, R., Herington, A. C., and Stephenson, S. A.
(2013). Eph receptors and their ligands: Promising molecular biomarkers and
therapeutic targets in prostate cancer. Biochim. Biophys. Acta 1835, 243–257. doi:10.
1016/j.bbcan.2013.01.003
Liu, J. F., Barry, W. T., Birrer, M., Lee, J. M., Buckanovich, R. J., Fleming, G. F., et al.
(2014). Combination cediranib and olaparib versus olaparib alone for women with
recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol.
15, 1207–1214. doi:10.1016/S1470-2045(14)70391-2
Liu, J. F., Barry, W. T., Birrer, M., Lee, J. M., Buckanovich, R. J., Fleming, G. F., et al.
(2019). Overall survival and updated progression-free survival outcomes in a
randomized phase II study of combination cediranib and olaparib versus olaparib in
relapsed platinum-sensitive ovarian cancer. Ann. Oncol. 30, 551–557. doi:10.1093/
annonc/mdz018
Liu, J. F., Brady, M. F., Matulonis, U. A., Miller, A., Kohn, E. C., Swisher, E. M., et al.
(2022). Olaparib with or without cediranib versus platinum-based chemotherapy in
recurrent platinum-sensitive ovarian cancer (NRG-GY004): A randomized, open-label,
phase III trial. J. Clin. Oncol. 40, 2138–2147. doi:10.1200/jco.21.02011
Liu, J. F., Gordon, M., Veneris, J., Braiteh, F., Balmanoukian, A., Eder, J. P., et al.
(2019). Safety, clinical activity and biomarker assessments of atezolizumab from a Phase
I study in advanced/recurrent ovarian and uterine cancers. Gynecol. Oncol. 154,
314–322. doi:10.1016/j.ygyno.2019.05.021
Liu, J. F., Herold, C., Gray, K. P., Penson, R. T., Horowitz, N., Konstantinopoulos, P.
A., et al. (2019). Assessment of combined nivolumab and bevacizumab in relapsed
ovarian cancer: A phase 2 clinical trial. JAMA Oncol. 5, 1731–1738. doi:10.1001/
jamaoncol.2019.3343
Liu, X., Xu, Y., Jin, Q., Wang, W., Zhang, S., Wang, X., et al. (2016). EphA8 is a
prognostic marker for epithelial ovarian cancer. Oncotarget 7, 20801–20809. doi:10.
18632/oncotarget.8018
Liu, Y., Luo, Y., Cai, M., Shen, P., Li, J., Chen, H., et al. (2021). Anti-angiogenic
therapy in ovarian cancer: Current situation and prospects. Indian J. Med. Res. 154,
680–690. doi:10.4103/ijmr.IJMR_1160_19
Lopes-Coelho, F., Martins, F., Pereira, S. A., and Serpa, J. (2021). Anti-angiogenic
therapy: Current challenges and future perspectives. Int. J. Mol. Sci. 22, 3765. doi:10.
3390/ijms22073765
Lorusso, D., Marchetti, C., Conte, C., Giudice, E., Bolomini, G., Vertechy, L., et al.
(2020). Bevacizumab as maintenance treatment in BRCA mutated patients with
advanced ovarian cancer: A large, retrospective, multicenter case-control study.
Gynecol. Oncol. 159, 95–100. doi:10.1016/j.ygyno.2020.07.022
Lu, C., Shahzad, M. M., Moreno-Smith, M., Lin, Y. G., Jennings, N. B., Allen, J. K.,
et al. (2010). Targeting pericytes with a PDGF-B aptamer in human ovarian carcinoma
models. Cancer Biol. Ther. 9, 176–182. doi:10.4161/cbt.9.3.10635
Lu, C., Thaker, P. H., Lin, Y. G., Spannuth, W., Landen, C. N., Merritt, W. M., et al.
(2008). Impact of vessel maturation on antiangiogenic therapy in ovarian cancer. Am.
J. Obstet. Gynecol. 198, 477–e9. ; discussion 477 e479-410. doi:10.1016/j.ajog.2007.
12.028
Lu, K. V., Chang, J. P., Parachoniak, C. A., Pandik a, M. M., Aghi, M. K., Meyronet, D.,
et al. (2012). VEGF inhibits tumor cell invasion and mesenchymal transition through a
MET/VEGFR2 complex. Cancer Cell 22, 21–35. doi:10.1016/j.ccr.2012.05.037
Madsen, C. V., Steffensen, K. D., Olsen, D. A., Waldstrom, M., Smerdel, M., Adimi, P.,
et al. (2012). Serial measurements of serum PDGF-AA, PDGF-BB, FGF2, and VEGF in
multiresistant ovarian cancer patients treated with bevacizumab. J. Ovarian Res. 5, 23.
doi:10.1186/1757-2215-5-23
Mansouri, A., McGregor, N., Dunn, R., Dobbie, S., Holmes, J., Collins, L., et al. (2021).
Randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in
patients with platinum-resistant ovarian cancer (OCTOVA): A study protocol.
BMJ Open 11, e041463. doi:10.1136/bmjopen-2020-041463
Maroto, P., Porta, C., Capdevila, J., Apolo, A. B., Viteri, S., Rodriguez-Antona, C., et al.
(2022). Cabozantinib for the treatment of solid tumors: A systematic review. Ther. Adv.
Med. Oncol. 14, 17588359221107112. doi:10.1177/17588359221107112
Marth, C., Vergote, I., Scambia, G., Oberaigner, W., Clamp, A., Berger, R., et al.
(2017). ENGOT-ov-6/TRINOVA-2: Randomised, double-blind, phase 3 study of
pegylated liposomal doxorubicin plus trebananib or placebo in women with
recurrent partially platinum-sensitive or resistant ovarian cancer. Eur. J. Cancer 70,
111–121. doi:10.1016/j.ejca.2016.09.004
Martinez-Bosch, N., and Navarro, P. (2020). Galectins in the tumor
microenvironment: Focus on galectin-1. Adv. Exp. Med. Biol. 1259, 17–38. doi:10.
1007/978-3-030-43093-1_2
Frontiers in Pharmacology frontiersin.org18
Mei et al. 10.3389/fphar.2023.1147717
Matei, D., Graeber, T. G., Baldwin, R. L., Karlan, B. Y., Rao, J., and Chang, D. D.
(2002). Gene expression in epithelial ovarian carcinoma. Oncogene 21, 6289–6298.
doi:10.1038/sj.onc.1205785
Mellman, I., Coukos, G., and Dranoff, G. (2011). Cancer immunotherapy comes of
age. Nature 480, 480–489. doi:10.1038/nature10673
Merritt, W. M., Nick, A. M., Carroll, A. R., Lu, C., Matsuo, K., Dumble, M., et al.
(2010). Bridging the gap between cytotoxic and biologic therapy with metronomic
topotecan and pazopanib in ovarian cancer. Mol. Cancer Ther. 9, 985–995. doi:10.1158/
1535-7163.MCT-09-0967
Mielczarek-Palacz, A., Kondera-Anasz, Z., Smycz-Kubanska, M., Englisz, A., Janusz,
A., Krolewska-Daszczynska, P., et al. (2022). The role of galectins-1, 3, 7, 8 and 9 as
potential diagnostic and therapeutic markers in ovarian cancer (Review). Mol. Med.
Rep. 25, 166. doi:10.3892/mmr.2022.12682
Mitra, A. K., Sawada, K., Tiwari, P., Mui, K., Gwin, K., and Lengyel, E. (2011). Ligand-
independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian
cancer invasion and metastasis. Oncogene 30, 1566–1576. doi:10.1038/onc.2010.532
Monk, B. J., Han, E., Josephs-Cowan, C. A., Pugmire, G., and Burger, R. A. (2006).
Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic
regimens in advanced refractory epithelial ovarian cancer. Gynecol. Oncol. 102,
140–144. doi:10.1016/j.ygyno.2006.05.006
Monk, B. J., Minion, L. E., and Coleman, R. L. (2016). Anti-angiogenic agents in
ovarian cancer: Past, present, and future. Ann. Oncol. 27 (1), i33–i39. doi:10.1093/
annonc/mdw093
Monk, B. J., Poveda, A., Vergote, I., Raspagliesi, F., Fujiwara, K., Bae, D. S., et al.
(2014). Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer
(TRINOVA-1): A randomised, multicentre, double-blind, placebo-controlled phase
3 trial. Lancet Oncol. 15, 799–808. doi:10.1016/S1470-2045(14)70244-X
Monk, B. J., Poveda, A., Vergote, I., Raspagliesi, F., Fujiwara, K., Bae, D. S., et al.
(2016). Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent
ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-
free survival-2. Gynecol. Oncol. 143, 27–34. doi:10.1016/j.ygyno.2016.07.112
Moroney, J. W., Powderly, J., Lieu, C. H., Bendell, J. C., Eckhardt, S. G., Chang, C. W.,
et al. (2020). Safety and clinical activity of atezolizumab plus bevacizumab in patients
with ovarian cancer: A phase Ib study. Clin. Cancer Res. 26, 5631–5637. doi:10.1158/
1078-0432.CCR-20-0477
Motz, G. T., and Coukos, G. (2011). The parallel lives of angiogenesis and
immunosuppression: Cancer and other tales. Nat. Rev. Immunol. 11, 702–711.
doi:10.1038/nri3064
Nagy, J. A., and Dvorak, H. F. (2012). Heterogeneity of the tumor vasculature: The
need for new tumor blood vessel type-specific targets. Clin. Exp. Metastasis 29, 657–662.
doi:10.1007/s10585-012-9500-6
Ng, C. S., Zhang, Z., Lee, S. I., Marques, H. S., Burgers, K., Su, F., et al. (2017). CT
perfusion as an early biomarker of treatment efficacy in advanced ovarian cancer: An
ACRIN and GOG study. Clin. Cancer Res. 23, 3684–3691. doi:10.1158/1078-0432.CCR-
16-1859
Nishio, S., Matsumoto, K., Takehara, K., Kawamura, N., Haseg awa, K., Takeshima, N.,
et al. (2020). Pembrolizumab monotherapy in Japanese patients with advanced ovarian
cancer: Subgroup analysis from the KEYNOTE-100. Cancer Sci. 111, 1324–1332. doi:10.
1111/cas.14340
Nixon, A., Liu, J., Xiong, N., Hurwitz, H. I., Lyu, J., Liu, Y., et al. (2021). Blood-based
biomarkers in patients with platinum-sensitive and resistant ovarian cancer treated with
olaparib and cediranib: Results from the UM9825 trial. Gynecol. Oncol. 162, S99. doi:10.
1016/s0090-8258(21)00831-3
Norden, A. D., Schiff, D., Ahluwalia, M. S., Lesser, G. J., Nayak, L., Lee, E. Q., et al.
(2015). Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent
high-grade gliomas. J. Neurooncol. 121, 297–302. doi:10.1007/s11060-014-1631-y
Noren, N. K., Lu, M., Freeman, A. L., Koolpe, M., and Pasquale, E. B. (2004). Interplay
between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc.
Natl. Acad. Sci. U. S. A. 101, 5583–5588. doi:10.1073/pnas.0401381101
Numnum, T. M., Rocconi, R. P., Whitworth, J., and Barnes, M. N. (2006). The use of
bevacizumab to palliate symptomatic ascites in patients with refractory ovarian
carcinoma. Gynecol. Oncol. 102, 425–428. doi:10.1016/j.ygyno.2006.05.018
Ogawa, K., Pasqualini, R., Lindberg, R. A., Kain, R., Freeman, A. L., and Pasquale, E. B.
(2000). The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor
neovascularization. Oncogene 19, 6043–6052. doi:10.1038/sj.onc.1204004
Ostman, A. (2017). PDGF receptors in tumor stroma: Biological effects and
associations with prognosis and response to treatment. Adv. Drug Deliv. Rev. 121,
117–123. doi:10.1016/j.addr.2017.09.022
Oyama, T., Ran, S., Ishida, T., Nadaf, S., Kerr, L., Carbone, D. P., et al. (1998). Vascular
endothelial growth factor affects dendritic cell maturation through the inhibition of
nuclear factor-kappa B activation in hemopoietic progenitor cells. J. Immunol. 160,
1224–1232. doi:10.4049/jimmunol.160.3.1224
Papa,A.,Zaccarelli,E.,Caruso,D.,Vici,P.,BenedettiPanici,P.,andTomao,F.
(2016). Targeting angiogenesis in endometrial cancer - new agents for tailored
treatments. Expert Opin. Investig. Drugs 25, 31–49. doi:10.1517/13543784.2016.
1116517
Papadopoulos, N., and Lennartsson, J. (2018). The PDGF/PDGFR pathway as a drug
target. Mol. Asp. Med. 62, 75–88. doi:10.1016/j.mam.2017.11.007
Patch, A. M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J.,
Fereday, S., et al. (2015). Whole-genome characterization of chemoresistant ovarian
cancer. Nature 521, 489–494. doi:10.1038/nature14410
Pennington, K. P., and Swisher, E. M. (2012). Hereditary ovarian cancer: Beyond the
usual suspects. Gynecol. Oncol. 124, 347–353. doi:10.1016/j.ygyno.2011.12.415
Perren, T. J., Swart, A. M., Pfisterer, J., Ledermann, J. A., Pujade-Lauraine, E.,
Kristensen, G., et al. (2011). A phase 3 trial of bevacizumab in ovarian cancer. N.
Engl. J. Med. 365, 2484–2496. doi:10.1056/nejmoa1103799
Peterson, T. E., Kirkpatrick, N. D., Huang, Y., Farrar, C. T., Marijt, K. A., Kloepper, J.,
et al. (2016). Dual inhibition of Ang-2 and VEGF receptors normalizes tumor
vasculature and prolongs survival in glioblastoma by altering macrophages. Proc.
Natl. Acad. Sci. U. S. A. 113, 4470–4475. doi:10.1073/pnas.1525349113
Pietras, K., Pahler, J., Bergers, G., and Hanahan, D. (2008). Functions of paracrine
PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological
targeting. PLoS Med. 5, e19. doi:10.1371/journal.pmed.0050019
Pignata, S., Lorusso, D., Joly, F., Gallo, C., Colombo, N., Sessa, C., et al. (2021).
Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-
based doublet alone in patients with platinum-sensitive ovarian cancer: A randomised,
phase 3 trial. Lancet Oncol. 22, 267–276. doi:10.1016/S1470-2045(20)30637-9
Plummer, R., Madi, A., Jeffels, M., Richly, H., Nokay, B., Rubin, S., et al. (2013). A
Phase I study of pazopanib in combination with gemcitabine in patients with advanced
solid tumors. Cancer Chemother. Pharmacol. 71, 93–101. doi:10.1007/s00280-012-
1982-z
Polcher, M., Eckhardt, M., Coch, C., Wolfgarten, M., Kubler, K., Hartmann, G., et al.
(2010). Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant
chemotherapy in patients with advanced ovarian cancer. Pharmacol 66, 203–207.
doi:10.1007/s00280-010-1276-2
Poluzzi, C., Iozzo, R. V., and Schaefer, L. (2016). Endostatin and endorepellin: A
common route of action for similar angiostatic cancer avengers. Adv. Drug Deliv. Rev.
97, 156–173. doi:10.1016/j.addr.2015.10.012
Poveda, A. M., Selle, F., Hilpert, F., Reuss, A., Savarese, A., Vergote, I., et al. (2015).
Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or
topotecan in platinum-resistant recurrent ovarian cancer: Analysis by chemotherapy
cohort of the randomized phase III AURELIA trial. J. Clin. Oncol. 33, 3836–3838. doi:10.
1200/JCO.2015.63.1408
Pranjol, M. Z. I., Zinovkin, D. A., Maskell, A. R. T., Stephens, L. J., Achinovich, S. L.,
Los, D. M., et al. (2019). Cathepsin L-induced galectin-1 may act as a proangiogenic
factor in the metastasis of high-grade serous carcinoma. J. Transl. Med. 17, 216. doi:10.
1186/s12967-019-1963-7
Presta, M., Dell’Era, P., Mitola, S., Moroni, E., Ronca, R., and Rusnati, M. (2005).
Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis.
Cytokine Growth Factor Rev. 16, 159–178. doi:10.1016/j.cytogfr.2005.01.004
Previs, R. A., Bevis, K. S., Huh, W., Tillmanns, T., Perry, L., Moore, K., et al. (2014). A
prognostic nomogram to predict overall survival in women with recurrent ovarian
cancer treated with bevacizumab and chemotherapy. Gynecol. Oncol. 132, 531–536.
doi:10.1016/j.ygyno.2014.01.036
Pujade-Lauraine, E., Fujiwara, K., Ledermann, J. A., Oza, A. M., Kristeleit, R., Ray-
Coquard, I. L., et al. (2021). Avelumab alone or in combination with chemotherapy
versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer
(JAVELIN ovarian 200): An open-label, three-arm, randomised, phase 3 study. Lancet
Oncol. 22, 1034–1046. doi:10.1016/s1470-2045(21)00216-3
Pujade-Lauraine, E., Hilpert, F., Weber, B., Reuss, A., Poveda, A., Kristensen, G., et al.
(2012). Aurelia: A randomized phase III trial evaluating bevacizumab (BEV) plus
chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer. OC) 30,
LBA5002.
Pujade-Lauraine, E., Hilpert, F., Weber, B., Reuss, A., Poveda, A., Kristensen, G., et al.
(2014). Bevacizumab combined with chemotherapy for platinum-resistant recurrent
ovarian cancer: The AURELIA open-label randomized phase III trial. J. Clin. Oncol. 32,
1302–1308. doi:10.1200/JCO.2013.51.4489
Ramasubbaiah, R., Perkins, S. M., Schilder, J., Whalen, C., Johnson, C. S., Callahan,
M., et al. (2011). Sorafenib in combination with weekly topotecan in recurrent ovarian
cancer, a phase I/II study of the Hoosier Oncology Group. Gynecol. Oncol. 123, 499–504.
doi:10.1016/j.ygyno.2011.08.033
Ray-Coquard, I., Cibula, D., Mirza, M. R., Reuss, A., Ricci, C., Colombo, N., et al.
(2020). Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-
controlled phase III trial of nintedanib combined with chemotherapy for newly
diagnosed advanced ovarian cancer. Int. J. Cancer 146, 439–448. doi:10.1002/ijc.32606
Reinthaller, A. (2016). Antiangiogenic therapies in ovarian cancer. Memo 9, 139–143.
doi:10.1007/s12254-016-0282-4
Reiss, Y., Knedla, A., Tal, A. O., Schmidt, M. H. H., Jugold, M., Kiessling, F., et al.
(2009). Switching of vascular phenotypes within a murine breast cancer model induced
by angiopoietin-2. J. Pathol. 217, 571–580. doi:10.1002/path.2484
Ribeiro, A. R. G., Salvadori, M. M., de Brot, L., Bovolin, G., Mantoan, H., Ilelis, F., et al.
(2021). Retrospective analysis of the role of cyclin E1 overexpression as a predictive
Frontiers in Pharmacology frontiersin.org19
Mei et al. 10.3389/fphar.2023.1147717
marker for the efficacy of bevacizumab in platinum-sensitive recurrent ovarian cancer.
Ecancermedicalscience 15, 1262. doi:10.3332/ecancer.2021.1262
Rigamonti, N., Kadioglu, E., Keklikoglou, I., Wyser Rmili, C., Leow, C. C., and De
Palma, M. (2014). Role of angiopoietin-2 in adaptive tumor resistance to VEGF
signaling blockade. Cell Rep. 8, 696–706. doi:10.1016/j.celrep.2014.06.059
Rini, B. I., Michaelson, M. D., Rosenberg, J. E., Bukowski, R. M., Sosman, J. A., Stadler,
W. M., et al. (2008). Antitumor activity and biomarker analysis of sunitinib in patients
with bevacizumab-refractory metastatic renal cell carcinoma. J. Clin. Oncol. 26,
3743–3748. doi:10.1200/JCO.2007.15.5416
Robelin, P., Tod, M., Colomban, O., Lachuer, J., Ray-Coquard, I., Rauglaudre, G., et al.
(2020). Comparative analysis of predictive values of the kinetics of 11 circulating
miRNAs and of CA125 in ovarian cancer during first line treatment (a GINECO study).
Gynecol. Oncol. 159, 256–263. doi:10.1016/j.ygyno.2020.07.021
Ronca, R., Giacomini, A., Rusnati, M., and Presta, M. (2015). The potential of
fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic
target in tumor angiogenesis. Expert Opin. Ther. Targets 19, 1361–1377. doi:10.1517/
14728222.2015.1062475
Ruscito, I., Gasparri, M. L., Marchetti, C., De Medici, C., Bracchi, C., Palaia, I., et al.
(2016). Cediranib in ovarian cancer: State of the art and future perspectives. Tumour
Biol. 37, 2833–2839. doi:10.1007/s13277-015-4781-4
Salgado, R., Benoy, I., Weytjens, R., Van Bockstaele, D., Van Marck, E., Huget, P., et al.
(2002). Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in
human cancer. Br. J. Cancer 87, 1437–1444. doi:10.1038/sj.bjc.6600655
Sallinen, H., Heikura, T., Koponen, J., Kosma, V. M., Heinonen, S., Yla-Herttuala, S.,
et al. (2014). Serum angiopoietin-2 and soluble VEGFR-2 levels predict malignancy of
ovarian neoplasm and poor prognosis in epithelial ovarian cancer. BMC Cancer 14, 696.
doi:10.1186/1471-2407-14-696
Sallinen, H., Heikura, T., Laidinen, S., Kosma, V. M., Heinonen, S., Yla-Herttuala, S.,
et al. (2010). Preoperative angiopoietin-2 serum levels: A marker of malignant potential
in ovarian neoplasms and poor prognosis in epithelial ovarian cancer. Int. J. Gynecol.
Cancer 20, 1498–1505. doi:10.1111/IGC.0b013e3181f936e3
Sawada, K., Radjabi, A. R., Shinomiya, N., Kistner, E., Kenny, H., Becker, A. R., et al.
(2007). c-Met overexpression is a prognostic factor in ovarian cancer and an effective
target for inhibition of peritoneal dissemination and invasion. Cancer Res. 67,
1670–1679. doi:10.1158/0008-5472.CAN-06-1147
Sawamiphak, S., Seidel, S., Essmann, C. L., Wilkinson, G. A., Pitulescu, M. E., Acker,
T., et al. (2010). Ephrin-B2 regulates VEGFR2 function in developmental and tumour
angiogenesis. Nature 465, 487–491. doi:10.1038/nature08995
Scharpfenecker, M., Fiedler, U., Reiss, Y., and Augustin, H. G. (2005). The Tie-2
ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine
loop mechanism. J. Cell Sci. 118, 771–780. doi:10.1242/jcs.01653
Schwandt, A., von Gruenigen, V. E., Wenham, R. M., Frasure, H., Eaton, S., Fusco, N.,
et al. (2014). Randomized phase II trial of sorafenib alone or in combination with
carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian,
peritoneal, or fallopian tube cancer. Invest. New Drugs 32, 729–738. doi:10.1007/s10637-
014-0078-5
Seaman, S., Stevens, J., Yang, M. Y., Logsdon, D., Graff-Cherry, C., and St Croix, B.
(2007). Genes that distinguish physiological and pathological angiogenesis. Cancer Cell
11, 539–554. doi:10.1016/j.ccr.2007.04.017
Secord, A. A., McCollum, M., Davidson, B. A., Broadwater, G., Squatrito, R.,
Havrilesky, L. J., et al. (2019). Phase II trial of nintedanib in patients with
bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer.
Gynecol. Oncol. 153, 555–561. doi:10.1016/j.ygyno.2019.03.246
Sharma, R., Valls, P. O., Inglese, M., Dubash, S., Chen, M., Gabra, H., et al. (2020).
[(18)F]Fluciclatide PET as a biomarker of response to combination therapy of
pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer. Eur.
J. Nucl. Med. Mol. Imaging 47, 1239–1251. doi:10.1007/s00259-019-04532-z
Shimada, C., Xu, R., Al-Alem, L., Stasenko, M., Spriggs, D. R., and Rueda, B. R. (2020).
Galectins and ovarian cancer. Cancers (Basel) 12 (6), 1421. doi:10.3390/
cancers12061421a
Shojaei, F., Lee, J. H., Simmons, B. H., Wong, A., Esparza, C. O., Plumlee, P. A., et al.
(2010). HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant
tumors. Cancer Res. 70, 10090–10100. doi:10.1158/0008-5472.CAN-10-0489
Song, Y., Fu, Y., Xie, Q., Zhu, B., Wang, J., and Zhang, B. (2020). Anti-angiogenic
agents in combination with immune checkpoint inhibitors: A promising strategy for
cancer treatment. Front. Immunol. 11, 1956. doi:10.3389/fimmu.2020.01956
Sorli, S. C., Le Gonidec, S., Knibiehler, B., and Audigier, Y. (2007). Apelin is a potent
activator of tumour neoangiogenesis. Oncogene 26, 7692–7699. doi:10.1038/sj.onc.
1210573
Sorli, S. C., van den Berghe, L., Masri, B., Knibiehler, B., and Audigier, Y. (2006).
Therapeutic potential of interfering with apelin signalling. Drug Discov. Today 11,
1100–1106. doi:10.1016/j.drudis.2006.10.011
Sostelly, A., and Mercier, F. (2019). Tumor size and overall survival in patients
with platinum-resistant ovarian cancer treated with chemotherapy and
bevacizumab. Clin. Med. Insights Oncol. 13, 1179554919852071. doi:10.1177/
1179554919852071
Spiliotaki, M., Markomanolaki, H., Mela, M., Mavroudis, D., Georgoulias, V., and
Agelaki, S. (2011). Targeting the insulin-like growth factor I receptor inhibits
proliferation and VEGF production of non-small cell lung cancer cells and
enhances paclitaxel-mediated anti-tumor effect. Lung Cancer 73, 158–165. doi:10.
1016/j.lungcan.2010.11.010
Steele, I. A., Edmondson, R. J., Bulmer, J. N., Bolger, B. S., Leung, H. Y., and Davies, B.
R. (2001). Induction of FGF receptor 2-IIIb expression and response to its ligands in
epithelial ovarian cancer. Oncogene 20, 5878–5887. doi:10.1038/sj.onc.1204755
Steffensen, K. D., Madsen, C. V., Andersen, R. F., Waldstrom, M., Adimi, P., and
Jakobsen, A. (2014). Prognostic importance of cell-free DNA in chemotherapy resistant
ovarian cancer treated with bevacizumab. Eur. J. Cancer 50, 2611–2618. doi:10.1016/j.
ejca.2014.06.022
Sun, S., Dong, H., Yan, T., Li, J., Liu, B., Shao, P., et al. (2020). Role of TSP-1 as
prognostic marker in various cancers: A systematic review and meta-analysis. BMC
Med. Genet. 21, 139. doi:10.1186/s12881-020-01073-3
Tait, C. R., and Jones, P. F. (2004). Angiopoietins in tumours: The angiogenic switch.
J. Pathol. 204, 1–10. doi:10.1002/path.1618
Takahashi, T., Yamaguchi, S., Chida, K., and Shibuya, M. (2001). A single
autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent
activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J.
20, 2768–2778. doi:10.1093/emboj/20.11.2768
Thurston, G., Rudge, J. S., Ioffe, E., Zhou, H., Ross, L., Croll, S. D., et al. (2000).
Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat. Med. 6,
460–463. doi:10.1038/74725
Tolkach, Y., Ellinger, J., Kremer, A., Esser, L., Muller, S. C., Stephan, C., et al. (2019).
Apelin and apelin receptor expression in renal cell carcinoma. Br. J. Cancer 120,
633–639. doi:10.1038/s41416-019-0396-7
Topalian, S. L., Taube, J. M., Anders, R. A., and Pardoll, D. M. (2016). Mechanism-
driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev.
Cancer 16, 275–287. doi:10.1038/nrc.2016.36
Troncoso, M. F., Ferragut, F., Bacigalupo, M. L., Cardenas Delgado, V. M., Nugnes, L.
G., Gentilini, L., et al. (2014). Galectin-8: A matricellular lectin with key roles in
angiogenesis. Glycobiology 24, 907–914. doi:10.1093/glycob/cwu054
Tuppurainen, L., Sallinen, H., Karvonen, A., Valkonen,E.,Laakso,H.,
Liimatainen, T., et al. (2017). Combined gene therapy using AdsVEGFR2 and
AdsTie2 with chemotherapy reduces the growth of human ovarian cancer and
formation of ascites in mice. Int. J. Gynecol. Cancer 27, 879–886. doi:10.1097/IGC.
0000000000000973
Turner, N., and Grose, R. (2010). Fibroblast growth factor signalling: From
development to cancer. Nat. Rev. Cancer 10, 116–129. doi:10.1038/nrc2780
Uhl, C., Markel, M., Broggini, T., Nieminen, M., Kremenetskaia, I., Vajkoczy, P., et al.
(2018). EphB4 mediates resistance to antiangiogenic therapy in experimental glioma.
Angiogenesis 21, 873–881. doi:10.1007/s10456-018-9633-6
van Hinsbergh, V. W., and Koolwijk, P. (2008). Endothelial sprouting and
angiogenesis: Matrix metalloproteinases in the lead. Cardiovasc. Res. 78, 203–212.
doi:10.1093/cvr/cvm102
Varga, A., Piha-Paul, S., Ott, P. A., Mehnert, J. M., Berton-Rigaud, D., Morosky, A.,
et al. (2019). Pembrolizumab in patients with programmed death ligand 1-positive
advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecol. Oncol. 152, 243–250.
doi:10.1016/j.ygyno.2018.11.017
Vergote, I. B., Smith, D. C., Berger, R., Kurzrock, R., Vogelzang, N. J., Sella, A., et al.
(2017). A phase 2 randomised discontinuation trial of cabozantinib in patients with
ovarian carcinoma. Eur. J. Cancer 83, 229–236. doi:10.1016/j.ejca.2017.06.018
Vergote, I., du Bois, A., Floquet, A., Rau, J., Kim, J. W., Del Campo, J. M., et al. (2019).
Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib
versus placebo in women who have not progressed after first-line chemotherapy for
advanced ovarian cancer. Gynecol. Oncol. 155, 186–191. doi:10.1016/j.ygyno.2019.
08.024
Vergote, I., Scambia, G., O’Malley, D. M., Van Calster, B., Park, S. Y., Del Campo,
J. M., et al. (2019). Trebananib or placebo plus carboplatin and paclitaxel as first-line
treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): A
randomised, double-blind, phase 3 trial. Lancet Oncol. 20, 862–876. doi:10.1016/
S1470-2045(19)30178-0
Viallard, C., and Larrivee, B. (2017). Tumor angiogenesis and vascular normalization:
Alternative therapeutic targets. Angiogenesis 20, 409–426. doi:10.1007/s10456-017-
9562-9
Wang, J. Y., Sun, T., Zhao, X. L., Zhang, S. W., Zhang, D. F., Gu, Q., et al. (2008).
Functional significance of VEGF-a in human ovarian carcinoma: Role in vasculogenic
mimicry. Cancer Biol. Ther. 7, 758–766. doi:10.4161/cbt.7.5.5765
Wang, Y., Nakayama, M., Pitulescu, M. E., Schmidt, T. S., Bochenek, M. L.,
Sakakibara, A., et al. (2010). Ephrin-B2 controls VEGF-induced angiogenesis and
lymphangiogenesis. Nature 465, 483–486. doi:10.1038/nature09002
Wang, Y., Thai, T., Moore, K., Ding, K., McMeekin, S., Liu, H., et al. (2016).
Quantitative measurement of adiposity using CT images to predict the benefitof
bevacizumab-based chemotherapy in epithelial ovarian cancer patients. Oncol. Lett. 12,
680–686. doi:10.3892/ol.2016.4648
Frontiers in Pharmacology frontiersin.org20
Mei et al. 10.3389/fphar.2023.1147717
White, F. C., Benehacene, A., Scheele, J. S., and Kamps, M. (1997). VEGF mRNA is
stabilized by ras and tyrosine kinase oncogenes, as well as by UV radiation--evidence for
divergent stabilization pathways. Growth factors. 14, 199–212. doi:10.3109/
08977199709021520
Willett, C. G., Duda, D. G., di Tomaso, E., Boucher, Y., Ancukiewicz, M., Sahani, D.
V., et al. (2009). Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation
therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J. Clin.
Oncol. 27, 3020–3026. doi:10.1200/JCO.2008.21.1771
Wu, L., Chen, L., and Li, L. (2017). Apelin/APJ system: A novel promising therapy
target for pathological angiogenesis. Clin. Chim. Acta 466, 78–84. doi:10.1016/j.cca.
2016.12.023
Xie, Y., Su, N., Yang, J., Tan, Q., Huang, S., Jin, M., et al. (2020). FGF/FGFR signaling
in health and disease. Signal Transduct. Target Ther. 5, 181. doi:10.1038/s41392-020-
00222-7
Yu, P., Wilhelm, K., Dubrac, A., Tung, J. K., Alves, T. C., Fang, J. S., et al. (2017). FGF-
dependent metabolic control of vascular development. Nature 545, 224–228. doi:10.
1038/nature22322
Yuan, H. T., Khankin, E. V., Karumanchi, S. A., and Parikh, S. M. (2009).
Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium.
Mol. Cell. Biol. 29, 2011–2022. doi:10.1128/MCB.01472-08
Zhang, D., Huang, J., Sun, Y., and Guo, Q. (2019). Long-term progression-free
survival of apatinib monotherapy for relapsed ovarian cancer: A case report and
literature review. Onco Targets Ther. 12, 3635–3644. doi:10.2147/OTT.S198946
Zhang, L., Yang, N., Park, J. W., Katsaros, D., Fracchioli, S., Cao, G., et al. (2003).
Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host
endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian
cancer. Cancer Res. 63, 3403–3412.
Zhang, X., and Lawler, J. (2007). Thrombospondin-based antiangiogenic therapy.
Microvasc. Res. 74, 90–99. doi:10.1016/j.mvr.2007.04.007
Zhang, Y., Wang, H., Oliveira, R. H. M., Zhao, C., and Popel, A. S. (2022). Systems
biology of angiogenesis signaling: Computational models and omics. WIREs Mech. Dis.
14, e1550. doi:10.1002/wsbm.1550
Zhao, C., Isenberg, J. S., and Popel, A. S. (2018). Human expression patterns:
Qualitative and quantitative analysis of thrombospondin-1 under physiological and
pathological conditions. J. Cell. Mol. Med. 22, 2086–2097. doi:10.1111/jcmm.13565
Zhao, Y., and Adjei, A. A. (2015). Targeting angiogenesis in cancer therapy: Moving
beyond vascular endothelial growth factor. Oncologist 20, 660–673. doi:10.1634/
theoncologist.2014-0465
Zhou,Y.,Wu,C.,Lu,G.,Hu,Z.,Chen,Q.,andDu,X.(2020).FGF/FGFRsignalingpathway
involved resistance in various cancer types. J. Cancer 11, 2000–2007. doi:10.7150/jca.40531
Frontiers in Pharmacology frontiersin.org21
Mei et al. 10.3389/fphar.2023.1147717
Glossary
ABCB1 ATP binding cassette subfamily B member 1
ADAM17 a disintegrin and metalloprotease 17
AGP Alpha-1 acid glycoprotein
AKT protein kinase B
ANGPTs angiopoietins
APLN Apelin
APLNR G protein-coupled receptor APJ
BRCA breast cancer susceptibility gene
CA-125 cancer antigen 125
CAFs cancer associated fibroblasts
CBP carboplatin
CCNE1 cyclin E1
c-MET hepatocyte growth factor receptor
CTLA-4 cytotoxic T lymphocyte-associated protein 4
EC endothelial cell
EGFR epidermal growth factor receptor
EMA European Medicines Agency
EOC epithelial ovarian cancer
ERK extracellular signal-regulated kinase
FDA Food and Drug Administration
FGFs fibroblast growth factors
FLT4 fms-like tyrosine kinase-4
HER2 human epidermal growth factor receptor-2
HGF hepatocyte growth factor
HIF-1αhypoxia-inducible factor -1α
IGF-1 insulin-like growth factor 1
IL-6 interleukin 6
ICIs Immune checkpoint inhibitors
IP3 inositol 1,4,5-triphosphate
JAK Janus kinase
Lck lymphocyte-specific protein tyrosine kinase
Lyn tyrosine-protein kinase Lyn
MAPK mitogen-activated protein kinase
MMP-2 mitochondrial membrane potential-2
MSLN Mesothelin
MVD mevalonate diphosphate decarboxylase
NRP1 neuropilin 1; OC, ovarian cancer
OPN osteopontin
ORR overall response rate
OS overall survival
PARP poly (ADP-ribose) polymerase
PDGF platelet-derived growth factor
PD-1 programmed cell death protein
PFS progression-free survival
PI3K phosphatidylinositol 3-kinase
PLC phospsholipase-C
PLC-γPhospholipase C-γ
PLD pegylated liposomal doxorubicin
PlGF placental growth factor
Pt platinum
RTK receptor tyrosine kinases
RTKi receptor tyrosine kinase inhibitor
Src proto-oncogene tyrosine-protein kinase Src
STAT signal transducing activator of transcription
SUV standardized uptake value
TAMs tumor-associated macrophages
TAXOL paclitaxel
TFI treatment-free interval
TKI tyrosine kinase inhibitor
TPT topotecan
uPA urokinase plasminogen activator
VEGF vascular endothelial growth factor
YKL-40 Chitinase three like 1
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