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Biology of ovarian cancer and

Symposium Paper
Future Oncology
trabectedin mechanism of action
Isabelle Ray-Coquard
Medical Oncology, Centre Léon Bérard, Lyon, France n Tel: +33 478 782 888
n isabelle.ray-coquard@lyon.unicancer.fr

More than 50% of patients with ovarian cancer have genetic alterations in the
homologous repair pathway. Trabectedin appears to induce damage more
readily in tumor cells with defects in the homologous repair system. Moreover,
trabectedin inhibits monocyte differentiation into tumor-associated macrophages
and inhibits the production of inflammatory mediators such as IL-6. In patients
with platinum-sensitive, relapsed ovarian cancer, trabectedin plus pegylated
liposomal doxorubicin was associated with a trend towards improved overall
survival by extending the platinum-free interval. These clinical effects could
possibly be attributed to actions of trabectedin on the tumor microenvironment
(e.g., a reduction of IL-6). Thus, trabectedin is an agent with mechanisms of
action especially appropriate for targeting key processes in the biology of
ovarian cancer.

Biology of ovarian cancer drivers of carcinogenesis. Important information

Despite improved screening strategies, only 20%
of ovarian cancers are diagnosed early, while they
are still limited to the ovaries (i.e., at stage 1) [1].
Epithelial ovarian carcinoma is a particularly
lethal malignancy without a highly curative
chemotherapy [2]. Novel treatments, especially
in patients with advanced disease or who are
in relapse, are urgently needed. However, the
condition continues to pose major challenges for
medical oncologists, since more than one type
of ovarian cancer exists.
Ovarian cancers are heterogeneous at the
cellular and molecular levels, and have multiple
genetic and epigenetic abnormalities. Some
pathophysiologic understanding is evident,
for example, in the case of high-grade serous
ovarian carcinoma, which is associated
with TP53 mutation and loss of function
in 60–80% of familial and sporadic cases.
Pathogenetic information is also available
concerning the role of cortical inclusion cysts
in cystadenoma, borderline cystadenoma and
cystadenocarcinoma (low-grade serous ovarian
carcinoma). Nonetheless, from the cellular
biology viewpoint, consideration of epithelial
ovarian carcinoma in two categories is far
too simplistic, as the major sources of genetic
damage are often unclear [1].
From the molecular biology viewpoint,
various genetic drivers exist in different patient
subgroups: for example, KRAS mutation in
about BRCA alterations is provided by the
Cancer Genome Atlas project, which obtained
DNA sequence data from 316 tumor samples
from patients with high-grade serous ovarian
carcinoma [3]. A third of tumor samples showed
evidence of alterations in the BRCA system.
These alterations comprised germline mutations,
somatic mutations and epigenetic silencing via
hypermethylation [3]. Previous reports have
documented that up to 10–15% of ovarian
cancers are linked with germline mutations of
BRCA1 or BRCA2 [1].
BRCA mutations: improved responses to
trabectedin
The Cancer Genome Atlas project demonstrated,
in ana­lysis of the entire homologous repair (HR)
pathway, that 51% of patients with ovarian
cancer had genetic alterations in the HR system
[3]. It is known that DNA repair defects lead
to multifocal aggressive disease with faster
progression, and that lack of functional BRCA
genes leads to increased genomic instability
and disease progression [1]. Interestingly, recent
research revealed that somatic BRCA mutations
(versus no HR system abnormalities) were
associated with improved clinical responses to
trabectedin in patients with soft tissue sarcoma Keywords
[4,5]. In tumor samples from 113 trabectedin-
n cancer genetics
treated patients with advanced soft tissue n homologous repair pathway
sarcoma, and regarding BRCA1, patients with n ovarian cancer

patients with mucinous disease; or PIK3CA
mutation in clear-cell carcinoma (Ta ble  1).
However, most patients with ovarian cancer have
high-grade serous carcinoma, where p53 and
BRCA profiles are the most important genetic
at least one allele of the most common AAAG n trabectedin
n tumor microenvironment
haplotype, versus patients without an AAAG
allele, had significantly greater progression-
free survival (PFS; median: 5.6 vs 2.5 months;
p = 0.03) and overall survival (OS; median: 14.1 part of

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 Symposium Paper Ray-Coquard

Table 1. Molecular pathology of epithelial ovarian cancer.

Ovarian cancer type Precursor Molecular features
Low-grade serous carcinoma Cystadenoma–borderline tumor–carcinoma Mutations in KRAS or BRAF, or both
sequence
High-grade serous carcinoma De novo in epithelial inclusion cysts TP53 mutation and BRCA1 dysfunction;
PIK3CA amplification (25–40%)
Low-grade endometrioid carcinoma Endometriosis and endometrial-like Mutations in CTNNB1 (b-catenin gene) and
hyperplasia† PTEN with microsatellite instability
High-grade endometrioid carcinoma Epithelial inclusion glands or cysts TP53 mutation and BRCA1 dysfunction;
PIK3CA mutation
Mucinous carcinoma Cystadenoma–borderline tumor–carcinoma Mutations in KRAS; possible TP53 mutation
sequence associated with transition from borderline
tumor to carcinoma
Clear-cell carcinoma Possibly endometriosis PTEN mutation/loss of heterozygosity; PIK3CA
mutation
PIK3CA is the gene at chromosome 3q26 that specifically encodes the p110a subunit of the PI3K protein.
†
Endometriosis and adjacent low-grade endometrioid carcinoma have common genetic events such as loss of heterozygosity at the same loci of the same allele
(e.g., PTEN). Conversely, high-grade and poorly differentiated endometrioid carcinomas are similar to high-grade serous carcinomas.
Data from [3].

Adipocytes
Fibroblasts Macrophages

CCL2, LIF,
IL-1β, TGFβ1, IL-6, IL-8,
thrombin, IL-6,
MMP2, HGF, FAP, CCL2,
IL-8, IL-10, CSF-1,
α-SMA, CLIC4, TIMP-1,
CCL18, CCR2,
uPA, LPA, CXCL12 FABP4,
CXCR2, FXII,
adiponectin
TNF-α
Extracellular matrix Mesothelial cells

α5β1 integrin
ITGβ1,
TG2, α5β3,
HA, versican
CXCL12, TGF-β,
Cancer cells
IL-6, BMPs

VEGF, IL-8,
GRO-α, CCL2,
Endothelial cells Mesenchymal
CXCR1/2
stem cells

Figure 1. The tumor microenvironment in ovarian cancer.

a-SMA: a-smooth muscle actin; CCL: Chemokine (C–C motif) ligand; CCR: C–C chemokine receptor;
CXCL: CXC chemokine ligand; CXCR: CXC chemokine receptor; FXII: Factor XII; GRO-a: Growth-
regulated oncogene-a; HA: Hyaluronic acid; ITGb1: Integrin-b1; LIF: Leukocyte infiltration factor;
LPA: Lysophosphatidic acid; TIMP-1: Tissue inhibitor of MMP-1; uPA: Urokinase-type plasminogen
activator.
Adapted from [13] .

12 Future Oncol. (2013) 9(12 Suppl. 1) future science group

 Biology of ovarian cancer & trabectedin mechanism of action Symposium Paper

Table 2. Microenvironment-targeted drugs in ovarian cancer.

Drug Phase of Type Target; MoA Effect on Study results
clinical microenvironment
development
Bevacizumab III mAb Binds all isoforms of Angiogenesis Prolonged PFS
VEGF-A
Etanercept I p75 TNF TNF-a blocker Inhibits actions of Lower IL-6 and CCL2 levels; six
receptor TNF-a of 30 patients (20%) with
fusion protein prolonged disease stabilization
Infliximab I mAb Binds to TNF-a with high Lower levels of Lower IL-17, CXCL12, TNF-a and
affinity proinflammatory IL-6 levels
cytokines
Sibrotuzumab I mAb Binds to FAP Targets major One of 20 patients (5%) with
constituents of tumor colorectal cancer had stable
stroma disease for 2 years
Siltuximab II mAb Neutralizes IL-6 Inhibits functional Lower proangiogenic factors;
activity of IL-6 seven of 20 patients (35%) had
disease stabilization
Trabectedin III Tetrahydro­ Binds to DNA minor Inhibits monocyte-to- Together with PLD, improved
isoquinoline groove, prevents cell cycle macrophage PFS and overall responses in
alkaloid completion; causes differentiation; lower patients with platinum-free
apoptosis protumoral cytokines interval >6 months
Volociximab II mAb Binds a5b1 integrins Blocks attachment of No complete and partial
cancer cells to the responses
mesothelium
CCL2: Chemokine (C–C motif) ligand-2; CXCL12: CXC chemokine ligand-12; mAb: Monoclonal antibody; MoA: Mechanism of action; PFS: Progression-free survival;
PLD: Pegylated liposomal doxorubicin.
Adapted from [13].

vs 5.4 months; p = 0.0095) [4]. This suggests that levels of IL-6, which correlates with disease
trabectedin induces direct DNA damage more status [10,11]. A high serum level of IL-6 is also
readily in tumor cells with, rather than without, associated with a worse prognosis in ovarian
defects in the HR system. cancer patients [12].

The tumor microenvironment in ovarian Treatment strategies targeted at the

cancer
The tumor microenvironment interacts in a
continuous crosstalk with tumor cells, leading
to tumor survival and progression (Figure 1) [6].
Human cells from the tumor microenvironment,
such as mesothelial cells and macrophages,
secrete chemokines or cytokines (e.g., chemokine
[C–C motif] ligand-2 [CCL2] and IL-6), and
produce an inflammatory cell network that
regulates tumor growth [7]. Tumor-associated
macrophages (TAMs) form a particularly
important part of this regulatory network,
and in the ovarian cancer microenvironment,
TAMs increase invasiveness and promote tumor
proliferation by two mechanisms: suppressive
inflammatory signals mediated by IL-6 and
IL-10; and angiogenesis mediated by PIGF,
PDGF, VEGF and matrix metalloproteinases.
A paracrine and autocrine loop exists between
both mechanisms [8,9]. For instance, serous fluid
from ovarian cancer patients contains high
tumor microenvironment
The aforementioned preclinical and clinical
findings surrounding the role of the tumor
microenvironment in ovaria n ca ncer
pathogenesis have led to the development of
microenvironment-targeted treatment strategies.
Recently, Musrap and Diamandis reviewed
the effectiveness of such strategies in ovarian
cancer (Table 2) [13]. Bevacizumab, for example,
has been shown to prolong PFS; and early-
phase inhibitors of TNF (e.g., etanercept and
infliximab) or IL-6 (e.g., siltuximab) have been
shown to reduce levels of proinflammatory
cytokines or proangiogenic factors and stabilize
disease in patients with platinum-resistant
ovarian cancer [13]. Trabectedin inhibits
monocyte differentiation into TAMs, and has
also been shown to inhibit ex vivo production
of inflammatory mediators (e.g., CCL2 and
IL-6; Figure 2) by monocytes, TAMs and ovarian
cancer cells [8].

future science group www.futuremedicine.com 13

 Symposium Paper Ray-Coquard

Tumor proliferation Trabectedin Angiogenesis

HO
NH OCH3
CH3O HO CH3
O
+ AcO O S H
H3C
N CH3
N
O
O OH
+
IL-6 VEGF
IL-8
↓ Apoptosis New vessel
↑ Proliferation formation

Matrix remodelling Immune suppression

IL-6 Naive
Treg
PTX3 CCL2
Th2

Deposition and
Th1
degradation

Figure 2. Trabectedin inhibits ex vivo production of inflammatory and angiogenic

mediators by monocytes, tumor-associated macrophages and ovarian cancer cells.
CCL2: Chemokine (C–C motif) ligand-2; Th1: T-helper type 1 lymphocyte; Th2: T-helper type 2
lymphocyte; Treg: Regulatory T cell.
Adapted with permission from [8] .

Trabectedin targets the tumor with platinum-sensitive versus platinum-resistant

microenvironment
To date, in the clinical setting, there are no clear
data confirming that the effects of trabectedin
on the tumor microenvironment represent
the major effects of the compound. However,
in a randomized Phase II study, del Campo
and coworkers reported that trabectedin
had promising activity in 107 patients with
platinum-sensitive, relapsed ovarian cancer; the
objective response rate (ORR) was 35.8–38.9%
[14]. Pooled data from three Phase II trials, in
which trabectedin monotherapy was evaluated
in a total of almost 300 patients with refractory/
recurrent ovarian cancer who had received
one or two lines of previous platinum-based
therapy, have also been evaluated [15]. The ORR
to trabectedin was markedly greater in patients
disease (33–46 vs 5–9%), irrespective of whether
trabectedin was administered as second- or third-
line therapy (Table  3). In all four trabectedin
subgroups (i.e., regardless of platinum resistance
and line of trabectedin therapy), the rate of
disease stabilization was similar (39–48%) [15].
Potentially, the effects of trabectedin on the
tumor microenvironment might help to explain
these similar rates of stable disease.
Thus, trabectedin can be considered a
cytotoxic compound that induces tumor
shrinkage, as evident from pooled Phase II data
as single-agent therapy in relapsed advanced
ovarian cancer: the complete response rate was
documented as 10.7%, and the partial response
rate as 25.7%. Trabectedin can also be regarded
as a multitargeted therapy capable of targeting

Table 3. Trabectedin efficacy in Phase II clinical trials in patients with refractory/recurrent ovarian cancer.
Tumor response Line of trabectedin therapy
Second-line (n = 199) Third-line or greater (n = 95)
Platinum-resistant Platinum-sensitive Platinum-resistant Platinum-sensitive
disease (n = 67) disease (n = 132) disease (n = 40) disease (n = 55)
ORR (%; CR + PR); 9 33 5 46
95% CI 3.4–18.5 24.7–41.3 0.6–16.9 32.0–59.4
SD (%) 40 39 48 40
CR: Complete response; ORR: Objective response rate; PR: Partial response; SD: Stable disease.
Data from [15].

14 Future Oncol. (2013) 9(12 Suppl. 1) future science group

 Biology of ovarian cancer & trabectedin mechanism of action
immune cells in the tumor microenvironment,
as evident from relatively high reported rates
of disease stabilization or tumor dormancy in
pooled Phase II data [15].
Evidence is available corroborating tumor
stabilization and prolonged clinical benefit for
trabectedin in patients with soft tissue sarcoma.
For instance, despite a low ORR, Le Cesne and
colleagues reported pooled Phase II data that
demonstrated a median OS of 10.3 months,
with 29.3% of patients surviving for more than
2 years [16]. More recently, Monk et al. reported
similar findings for trabectedin in patients
with uterine leiomyosarcoma: median PFS was
5.8 months and OS was >26.1 months. The
researchers compared their data with those from
other studies in uterine leiomyosarcoma, and
documented that median PFS with trabectedin
appeared greater than that for various other
cytotoxic agents (e.g., gemcitabine and
ifosfamide; Figure 3) [17].
Trabectedin may reduce IL-6 levels
Coward and Kulbe recently reviewed the role
of IL-6 in gynecologic malignancies and,
importantly, in ovarian cancer [18]. IL-6 induces
proliferation, survival, migration and invasion
of tumor cells, and also has key functions
in angiogenesis, and in TAM and T-cell
differentiation [18]. In addition, IL-6 appears to
have a critical role in mediating the development of
resistance to platinum (e.g., cisplatin) and taxanes
(e.g., paclitaxel) via overexpression of multidrug
VP-16 2.1
Topotecan 1.8
Paclitaxel 1.6
PLD 2.1
Ifosfamide 2.8
Trabectedin
Gemcitabine† 2.9
0 1 2 3
Median PFS (months)
Figure 3. Progression-free survival for various cytotoxic agents in uterine leiomyosarcoma.
†
In previously treated patients.
PFS: Progression-free survival; PLD: Pegylated liposomal doxorubicin.
Data from [17] .
future science group
Symposium Paper
resistance-related genes (e.g., MDR1 and GSTpi)
and inhibition of proapoptotic proteins (e.g.,
Bcl-2 and Bcl-3) [19,20]. Disease recurrence clearly
poses a major therapeutic challenge when ovarian
cancer cells acquire resistance to chemotherapies
[21]; however, preclinical data have emerged
demonstrating that IL-6 blockade significantly
sensitizes platinum-resistant ovarian cancer cells
to cisplatin [19].
In the OVA-301 study in platinum-
sensitive, relapsed ovarian cancer, trabectedin
plus pegylated liposomal doxorubicin was
associated with a trend towards improved OS
versus pegylated liposomal doxorubicin alone
(median: 18.8 vs 9.9 months; p = 0.0513;
Figure 4). Furthermore, the combination schedule
appeared to extend the platinum-free interval,
potentially allowing the next platinum treatment
to be more active and providing extra time for
patients to recover from previous platinum-
induced toxicities [22]. These clinical effects could
perhaps be attributed to actions of trabectedin on
the tumor microenvironment, and in particular
to a reduction of endogenous and exogenous
IL-6 levels permitting reversal of resistance to
platinum. However, whether a nonplatinum
schedule definitively prolongs platinum-free
interval, and improves sensitivity to subsequent
lines of platinum therapy, requires clarification
through further research in prospective clinical
trials. The ongoing, Phase III, INOVATYON
study is expected to provide important
information in this regard [22].
5.8
4 5 6 7
www.futuremedicine.com 15
 Symposium Paper Ray-Coquard

1.0
HR: 0.64 (95% CI: 0.41–1.01)
0.9 p = 0.0513
0.8

Cumulative probability
0.7
0.6
0.5
0.4
0.3
0.2
PLD; median: 9.9 months
0.1
Trabectedin + PLD; median: 18.8 months
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)

Figure 4. Trabectedin plus pegylated liposomal doxorubicin versus pegylated liposomal

doxorubicin alone improves overall survival in patients with platinum-sensitive, relapsed
ovarian cancer, results from the OVA-301 study.
HR: Hazard ratio; PLD: Pegylated liposomal doxorubicin.
Reproduced with permission from [22] .

Conclusion Financial & competing interests disclosure

DNA instability in tumor cells and immune
signals from the microenvironment are
associated with the genesis and progression of
ovarian cancer. Significantly, trabectedin has
been found to induce direct DNA damage in
tumor cells and to inhibit immune signals from
the tumor microenvironment. Trabectedin can
therefore be considered a particularly important
cytotoxic agent with mechanisms of action that
make it especially appropriate for targeting key
processes in the biology of ovarian cancer.
The author has no relevant affiliations or financial
involvement with any organization or entity with a
financial interest in or financial conflict with the
subject matter or materials discussed in the manu-
script. This includes employment, consultancies,
honoraria, stock ownership or options, expert testi-
mony, grants or patents received or pending, or
royalties.
Editorial assistance was provided by Content Ed
Net, with funding from PharmaMar, Madrid,
Spain.

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17