Methods
A PubMed search was performed using the keywords
novel biomarkers in ovarian cancer to prepare a comprehensive
literature review. Some 637 articles were observed
for the initial search. The results were filtered by
species, languages (English), article type, manuscripts
published in the past five years, and with free full text
and extracted miRNA and Long and non-coding RNA
publications. Three hundred fifty three associated papers
and 18 review articles appered after the filter process.
Additional searches and selection were performedusing
the keywords genetic markers in ovarian cancer, multidrug
resistance in ovarian cancer and prognostic markers
to supplement the information. Finally, 70 papers
were selected for inclusion in the manuscript following
a careful review of the abstracts. These papers consisted
of 3 meta-analyses, 8 reviews, and 57 original papers.
Serum and Tissue Markers in Ovarian Carcinoma
CA125: Early detection of ovarian cancer greatly increases
the chances for successful treatment. CA-125is
the most sensitive and used marker in the management
ofovarian cancerat every stage of the disease. CA-125 is
used at the time of diagnosis of the disease, to evaluate
the possibility of complete resection during surgery, to
estimate sensibility for adjuvant or neo-adjuvant chemotherapy,
and for diagnosis of recurrence. CA-125has
a diagnostic and therapeutic value and could be of help
during therapeutic evaluation, and could also be used
to estimate global and progression-free survival. Low
preoperative rates, half-life, and fast normalization of
CA-125 during adjuvant chemotherapy are correlated
with optimal surgery and better global and progression-
free survival. The normal range of CA-125 is a
strong predictive factor for disease recurrence, even if
its role in survival has not yet been determined. The
level of CA-125 and its dynamic interpretation is an
indispensable approach for the diagnosis, therapeutics,
and follow-up of ovarian cancer. Although serum CA-
125 is still a very important prognostic and predictive
factor for personalized care in ovarian carcinoma, CA-
125 exhibits poor sensitivity for detecting early disease
stages and low specificity to malignancy.
HE4: HE4 is a novel biomarker expressed in serous
ovarian carcinoma and can be measured in serum,
urine, and other body fluids using enzyme-linked immunosorbent
assays (ELISA).HE4 protein is frequently
overexpressed in serous and endometrioid histologic
types of ovarian cancer.[-] However, HE4 is not
specific for ovariancancer,HE4 expression has also
been found in other malignancies such as pulmonary
and endometrial adenocarcinomas.[,] It is reported
in the majority of published papers that serum HE4
sensitivity and specificity in gynaecologic diseases are
better than CA-125. The results of Molina et al. confirmed
these previous studies by clearly showing that
the use of HE4 may be important in the differential diagnosis
of ovarian cancers with other gynecologic conditions
including premenopausal women.[-] The
authors also remarked that HE4 had a better utility in
the differential diagnosis of ovarian cancer, and abnormal
levels were found in only one third of patients with
endometrial or endocervical cancer, and none with
squamouscervical cancer. By contrast, CA-125 is frequently
abnormal in all these malignancies. Molina et
al. concluded that HE4 was the tumor marker of choice
inovarian cancer, with a higher sensitivity, specificity,
and efficiency in early stages than CA-125.[]
Two markers have been Food and Drug Administration
(FDA) approved: cancer antigen125 (CA-125) in
1987 and more recently, human epididymis protein-4
(HE4) in 2008 with limited application of monitoring
disease recurrence and therapeutic response.[,-]
RECAF: RECAF is an alphafetoprotein receptor that
is a wide-spectrum oncofetal antigen with clinical potential
for cancer diagnosis, prognosis, and screening.
Tcherkassova et al. reported that serum RECAF was detected
in elevated levels in patients ovarian cancer when
compared with normal individuals. They also showed
that the level of RECAF protein was higher in stage III/
IV than stage I/II. Both RECAF and CA-125 were able
to discriminate between healthy patients and those with
cancer. More importantly, RECAF had beter performace
to detect early-stage disease. Moreover, the specificity
of the RECAF test was high at early and late stages of
ovarian cancer, whereas the sensitivity of CA-125 was
lower in earlier stages than in advance disease. Using
the combination of RECAF and CA-125 serum values
provides the specificity and the sensitivity necessary to
screen for ovarian cancer, especially at early stages.[]
Osteopontin (OPN): Osteopontin, a soluble protein
present in all body fluids related to adhesion and
extracellular matrix interactions, affects multiple cellular
functions, includingin flammation, angiogenesis, and tumor metastasis. Alternative splicing and posttranslational
modificationsof OPN result in a variable
molecular weight of 41 to 75kd. Higher tissue mRNA
and proteinlevel of OPN were reported in borderline
tumors compared with ovarian adenocarcinomas,
whereas Kim et al. reported on higher OPN tissue expression
in OC and borderline tumors compared with
benign tumors and normal tissue, as well as higher serum
levels in ovarian cancer patients compared with
healthy subjects and patients with benign ovarian
disease or other gynecologic cancers.[,] The use
of serum OPN in combination with leptin, prolactin,
and insulin-like growth factor II as a diagnostic test for
ovarian cancer was associated with 95% sensitivity and
specificity.[] It is suggested that CA-125 and macrophage
inhibitory factor were added to the panel by this
group.[] As serum marker, 95% sensitivity and specificity
for OPN were similarly observed in combination
with CA-125 and kallikrein 10.[]OPN level rose earlier
compared with CA-125 marker in patients with recurrent
disease.[] Osteopontin expression was more
frequent in effusions from patients with high-grade
tumors, but was significantly associated with better debulking
at primary surgery and complete response to
chemotherapy at diagnosis. Unexpectedly, Davidson et
al. showed that the presence of OPN in ovarian cancer
cells in effusions was associated with less aggressive
clinical course. OPN is frequently expressed in ovarian
carcinoma effusions, but its presence is associated with
less aggressive clinical course.[]
Netrin-1: Netrin-1 (NTN1) is a diffusible lamininrelated
protein that has been shown to play a major
role in the developing nervous system.[,] NTN1 is
aberrantly overexpressed in the majority of malignant
ovarian tumors but not in benign tumors. Moreover,
high NTN1 expression was correlated with both tumor
stage and grade. The differences in NTN1 expression
upon progression to malignancy canbe used safely in
malignant tumors, because NTN1 is barely expressed in
normal and benign tissues. Lack of expression in normal/
benign tissue is a desired but rare feature of cancer
biomarkers. Therefore, Papanastasiou et al. suggested
that NTN1 expression could possibly be used asa biomarker
to distinguish benign from malignant ovariantumors.[] NTN1 expression should also be evaluated
in larger prospective studies as a promising candidate
biomarker to distinguish early-stage ovarian cancer.
Nidogen-2 (Nid2): The nidogen family consists
of two isoforms, nidogen-1 and nidogen-2, which
are ubiquitous basement membrane (BM) proteins in
mammals that are broadly expressed in various tissues. Nidogens have an important role in BM formation as
integrating elements for BM assembly.[,]
Kuk C et al. showed that nidogen-2 was elevated
in the serum of patients with ovarian carcinoma as
compared with patients with benign gynecologic diseases
and healthy controls. ROC curve analysis demonstrated
that nidogen-2 had potential diagnostic value.
Spearman correlation showed that nidogen-2 correlates
highly with CA-125. Similar to CA-125, level of serum
nidogen-2 is more frequently elevated in serous adenocarcinoma
compared with other histotypes and latestage
of disease. It is reported that there was close correlation
between nidogen 2 and CA-125 and these two
markers mimic each other, therefore nidogen-2 could
not be an additional marker for ovarian cancer.[]
Kallikrens: The human kallikrein-related peptidase
family is a family of serine proteases, which has
been identified onhuman chromosome 19q13.[]
The family consists of 15 genes, of which 12 (KLK2,
KLK3, KLK4, KLK5,KLK6, KLK7, KLK8, KLK10,
KLK11, KLK13, KLK14, and KLK15) appear to be
overexpressed in ovarian cancer. It has been shown that
mRNA expression of KLK6 and KLK13 increased in
ovarian cancer compared with normal ovarian tissues.
High KLK6 or KLK13 expression in primary ovarian
tumors can significantly predict prognosis in terms of
recurrence-free survival and overall survival. All study
have suggested that KLK6 and KLK13 could be potential
biomarkers and therapeutic targets for treatment of
ovarian cancer in the future.[]
In another study, it was found that serum KLK6
and KLK10 had much lower overall sensitivities than
serum CA125, whereas serum KLK10 may have higher
specificity among these 3 markers.[] Magdolen et al.
showed that a high level of KLK5 protein is released
into serum and ascitic fluids in patients with ovarian
cancer, whereas KLK5 is very low in benign ovarian tumors.
Thus, it is suggested that elevated KLK5 levels in
serum and ascitic fluid could be used as a biomarker
for early detection as well as for disease management
in ovarian cancer.[] Furthermore, Bayani et al. demonstrated
that the KLK locus at 19q13.3/4 was subject
to high genomic instability and copy number heterogeneity,
mediated by structural rearrangements of19q.
Moreover, structural rearrangements on 19q are associated
with tumor grade, and may be associated with, or a
marker of the differential pathogenesis thereby distinguishing
low-grade and high-grade serous cancers.[]
Claudins: Claudins are tight junction proteins that
are involved in tight junction formation and function.
Previous studies have shown that Claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC)
along with Claudin-3 and Claudin-4. CLDN7 is elevated
in all major subtypes of ovarian cancer: serous, endometrioid,
clear cell and mucinous at both the mRNA
and protein levels. Claudin-7 could be functionally
involved in the invasion of ovarian carcinoma, but is
inversely correlated with migration. Claudin-7plays
important roles in a number of signaling pathwaysinvolved
in cancer, cellular growth, proliferation, and cell
cycle. Therefore, it will be important for ovarian carcinogenesis
and have significant potential in diagnostic
and therapeutic applications. Thus, futher research is
needed to discoverits diagnostic and therapeutic potential.[]
Folate Receptor Alpha (FR?): The folate receptor
a (FRa), a 38?40 kDa molecule, is a well characterized
member of the folate receptor (FR) family. FRa is
anchored to cell membranes through a glycosylphosphatidylinositol
moiety and transports folates via an
endocytic process.[] FRa expression has limited
distribution in normal tissue, including few epithelia,
predominantly in the lung, kidney, and choroid plexus,
but is overexpressed in a spectrum of solid tumors,
including ovarian cancer, non-small cell lung cancer,
breast cancer, kidney cancer, and in high-grade osteosarcoma.[-] Thus, it has been suggested as a
promising molecule as a biomarker for ovarian carcinoma.
Functional intact FRa is elevated in ovarian carcinomain
comparison with healthy controls. FRa levels
should be researched in larger cohorts uncluding those
with early-stage ovarian cancerto testify as to whether
FRa is a feasible marker for ovarian cancer.[]
Genetic and Epigenetic Markers in Ovarian
Carcinoma
HYL-1 (Hyaluronidase-1): Mammalian hyaluronidases
are endo-N-acetylhexosaminidases that hydrolyze
the glycosaminoglycan hyaluronan. The gene
family has 6?7 different genes which are about 40%
identity among each others.[,] Allelic imbalance
of three members of the gene family (HYAL1, HYAL2
and HYAL3) has been shown in tumors and stroma tissues
of ovarian cancers.[] It was shown that HYAL1
mRNA levels are inversely correlated with those of ER?
specifically in clear cell and mucinous ovarian cancertissue
samples, suggesting a role for ER? in regulating
HYAL1 gene expression in ovarian cancer. It was suggested
that levels of hyaluronidase expression may vary
depending on tumor type and on aggressive tumor behavior
and the expression of HYAL-1 in ovarian cancer tissue samples representing four different histopathological
subtypes. Elevated levels of this enzyme has
been demonstrated in clear cell and mucinous ovarian
cancer, but not in serous or endometrioid cancer. It was
also demonstrated that levels of HYAL1 mRNA in clear
cell and mucinous ovarian cancers were inversely correlated
with those of ER?. It was thought that HYAL-1
might play a role in tumor proliferation and cell cycle
progression in ERnegative clear cell and mucinous
ovarian cancer. Helena et al. proposed hyaluronidase-1
as a potential target/biomarker for clear cell and mucinous
ovarian cancer, especially in tumors with low ER?
levels or Er?-negative ovarian cancer.[]
Myofibrillogenesis regulator 1 (MR1): MR-1 is a
protein with 142 amino acid residues located on chromosomes
2q35.[-] MR-1 may promote cancer cell
proliferation by binding to specific proteins such as eukaryon
initiation factor 3, which is highly associated
with the regulation of tumor cell growth and invasion.
[64] Expression of MR-1 is increased both in mRNA
and protein levels in tumor tissues from patients with
ovarian cancer with serous papillary histology compared
with benign control tissues. Knockdown of
MR-1 expression inhibits cell adhesion and invasion,
and anti-cancer drugs decrease the expression levels
of MR-1 in cancer cells. Thus, MR-1 may be a novel
biologic marker and potential therapeutic target for
the treatment of ovarian cancer. It could also be used
to monitor the effect of anti-cancer therapies. Further
studies are needed to clarify whether MR-1 is an early
diagnostic marker for ovarian cancer and to develop its
full therapeutic potential.[]
Lysosome-associated protein transmembrane-4
beta (LAMPM4B): LAPTM4B is a novel tumor-associated
gene, which was first cloned in hepatocellular
carcinomas (HCCs).[,] LAPTM4B is highly
overexpressed in ovaries and the uterus.[] Yin et
al. initially shown the association between LAPTM4B
expression and metastasis of epitelial ovarian carcinoma.
They found that the sensitivity and specificity
of LAPTM4B overexpression was 48.7% and 90.9% for
intraperitoneal metastasis, and 73.8%% and 71.1% for
lymph node metastasis, respectively.[] According
the results, the authors suggested that LAPTM4B overexpression
may be a novel predictor of epithelial ovarian
carcinoma metastasis and an important potential
biomarker for early diagnosis of ovarian carcinoma.
Opioid-binding protein/cell adhesion moleculelike
gene (OPCML): OPCML, a recently-identified
tumorsuppressor, is frequently inactivated by allele
loss and CpG island promoter methylation in epithelial ovarian cancer. Genetic analysis revealed that OPCML
was frequently inactivated somatically in epithelial
ovarian cancer via allele loss and CpG island methylation,
although inactivation mutation of OPCML is
rare. Gene expression studies further demonstrated
that OPCML expression was completely abolished in
more than 80% of primary ovarian tumors as well as
ovarian cancer cells.
IFFO1-M: Campan et al. investigated serum DNA
of patients with ovarian carcinoma usingthe Illumina
Infinium platform to analyze the DNA methylation
status of more than 27.000 CpG islands. They identified
one marker called IFFO1-M (IFFO1 promoter methylation),
which is frequently methylatedin ovarian tumors
and that is rarely detected in the blood of the normal
population.[] It is thought that IFFO1-M will be
a blood-based candidate marker for sensitive detection
of ovarian cancer after future validation stages of the
marker development process.
miRNAs: MicroRNAs (miRNAs), a recently-discovered
class of regulatory RNAs, are frequently deregulated
in carcinogenesis. In ovarian tumorigenesis,
numerous miRNAs have been found altered and some
of these genes may represent ideal targets for diagnosis,
prognosis, and treatment.[]
EAG CHANNELS: Asher et al. demostrated for the
first time that high expression of Eag potassium channels
in patients with ovarian cancer was significantly associated
with poor survival. There was also a significant
association of Eag staining with high tumor grade and
presence of residual disease. Proliferation of SK-OV-3
cells was significantly inhibited after treatment with
voltage gated K+ channel blockers. Therefore, this novel
finding demonstrates a role for Eag as a prognostic
marker for survival in patients with ovarian cancer.[]
Molecular Markers in Hereditary Ovarian
Carcinoma
Hereditary Breast and OvarianCancer Syndrome
(HBOC): HBCO is associated with a significantly increased
risk for breast and ovarian cancer compared
with that of the general population. Mutations in
BRCA1 and BRCA2 account for 80?90% of HBOCcases.
Hereditary breast-ovarian cancer syndromeis characterized
by early-onset breast and ovarian cancers,
bilateral breast cancer, both breast and ovarian cancer
in the same person, and male breast cancer. Cancer in
families that have the syndrome is seen in several generations.
Both BRCA1 and BRCA2 genes have a tumor
suppressor function and both are inherited as autosomal dominant with incomplete penetrance. Both genes
play integral roles in genomic stability and integrity, cell
cycle control, apoptosis, and DNA repair. The lifetime
risk of developing ovarian cancer is about 20%?50% in
patients carrying BRCA mutations.[] Some 85% of
female breast cancer and 40% of ovarian cancer is associated
with BRCA1 syndrome, whereas male breast
cancer and 20% of ovarian cancer is associated with
BRCA2 syndrome. BRCA-associated ovarian cancers
are characterized by higher patient survival rates and a
better response to platinum-based chemotherapy.[]
The median survival time is 53.4 months for BRCA
carriers versus 37.8 months fornon carrriers.[]
Hereditary Nonpolyposis Colon Carcinoma
(HNPCC) syndrome: HNPCC, also known Lynch II
syndrome, is an autosomal dominant disorder characterized
by an increased predilection for right colon
cancer (without polyps) and endometrial-ovarian cancer
(serous and endometrioid variants). Lynch II syndrome
is characterized by germ-line mutations of DNA
mismatch repair genes hMLH1, hMSH2, hMSH6 and
PMS2. To date, most germline mutations have been
identified in the MSH2 or MLH1 genes. Altered mismatch
repair genes lead to microsatellite instability and
inactivation of genes that the control cell cycle and DNA
repair. Women with HNPCC syndrome have a lifetime
risk of about 12% for developing ovarian cancer.[]
Tools for Risk Estimation of Ovarian Cancer
CA-125 isa frequently used marker for initial diagnosis
in ovarian cancer. However, the performance of CA-
125 varies depending onthe cut-off selected, and the
patient population, with sensitivities ranging from 29?
100%. CA-125 gives many false positives in a wide variety
of normal, benign, andother malignancies, leading
to low specificity.[,,] To improve the performance
of CA-125, retrospective studies have reported
using serial CA-125 measurements combined with other
markers and te results wereinterpreted using a Risk
of Ovarian Cancer Algorithm (ROCA). Many other
risk assesment strategies have sought to combine CA-
125 with additional markers.[,<8r0>] The OvaCheckH
test includes a CA-125 test with seven other markers
and has 81.1% sensitivity and 85.4% specificity.[]
However, the test performance needs to be validated.
The Risk of Ovarian Malignancy Algorithm (ROMA)
combines measurements of both CA-125 and HE4.[]
The Risk ofMalignancy Index (RMI) was designed to
improve specificity by combining CA-125 with an imaging
score and menopausal status.[] Unfortunately, risk estimation tools, ROMA and RMI do not appear to
increase performance significantly over CA-125 alone.
[,] Another multimarker test, OvPlexTM, which
combines CA-125 with C-reactive protein, serum amyloid
A (SAA), interleukin 6 (IL-6), andIL-8, was shown
to have 94.1% sensitivity and 93.1% specificity.[83] The
test had biases whereby the case and control samples
were not from the same population. Another test, Ova-
SureTM, combines leptin, prolactin, osteopontin, insulin-
like growth factor II, and macrophage inhibitory
factorwith CA-125. The test"ssensitivity and specificity
were 95.3% and 99.4%, respectively.[] However,
there are multiple concerns about thestudy design and
validation population.[,] One of the newest serum-
based tests is the OVA1 test, which was approved
in 2011. The key purpose of this test was to identify
ovarian cancer risk in women who presented with an
adnexal mass and were planning surgery.[,] The
test measures transthyretin, apolipoprotein AI, transferrin,
and ?2 microglobulin combined with CA-125.
The performance of OVA1 depends on the source of
the surgicalpatient population and the menopausal status
of the patient.[,] A new marker was identified
by Yip et al. that was capable of discriminating between
samples drawn from women with benign ovarian conditions
and those from women with ovarian cancer. In
their study, a preliminary multivariate analysis, using a
logistic regression model on the nine most informative
biomarkers appeared to have significantly improved
performance over OVA1 biomarkers.[]
Novel Therapeutics in Ovarian Carcinoma
TRAP1: TRAP1 (TNF receptor-associated protein 1) is
a mitochondrial heath shock protein 75 that has antioxidant
and antiapoptotic functions.[,] It is evident
that mitochondrial defects and dysfunctions of oxidative
phosphorylation and energy production inovarian
cancercells are directly related to their resistanceto
platinum drugs. Landriscina et al. demostrated for the
fist time that TRAP1 is upregulated in osterosarcoma.
[] mRNA expression of TRAP1 is increased in tumor
cells resistant to 5-fluorouracil and platin derivatives.[] Resistance to platinum-based chemotherapy
(CDDP) is the major obstacle to successful treatment
of ovarian cancer. High level of TRAP1 expression is
showned estrogen receptor-positive and CDDP-resistant
ovarian carcinomas. Therefore, TRAP1 could be
a prognostic marker predicting drug resistance and a
therapeutic target to protectagainst drug resistance forpatients
with ovarian cancer. Also, the fact that expression levels of TRAP1 proteins in ovarian cancers are
estrogen regulated could helpto identify patients who
would benefit from endocrine therapy.
Folate Receptor ? inhibitor: Folate receptor ? expression
is highly restricted in normal adult tissues but
upregulated in a wide range of human cancer types,
including epithelial ovarian cancer. Farletuzumab, a
humanized monoclonal antibody against folate receptor
? has shown antitumor activity and favorable toxicityin
preclinical evaluation. In aphase I study, Farletuzumab
administered as an i.v. infusion at doses of
12.5 to 400 mg/m2 was generally safe and well tolerated
in the management of heavily pretreated patients with
epithelial ovarian cancer. Farletuzumab will be an altenative
agent in patients with platinum-sensitive and
platinum-resistant epithelial ovarian cancer.
K+ Channel Blockers: Eag and HERG K+channels
are overexpressed in ovarian cancer and high Eag
staining is associated with significantly poorer survival,
which identifes Eag as a putative prognostic marker.
Asher et al. demostrated that K+channel blockers
could be used to inhibit proliferating ovarian cancer
cells as a therapeutic.
Antiangiogenic agents, VEGFR inhibitors: Cediranib
is an oral tyrosine kinase inhibitor of VEGFR1, 2,
and 3, and c-Kit, which interacts with the ATP-binding
site within kinase domainof the receptor.[,] Cediranib
is an effective moleculefor the prevention of tumor
progression by inhibiting VEGFR-2 activity and
angiogenesis, and concomitantly inhibiting VEGFR-3
activity and lymphangiogenesis. Therefore, Cediranib
has been shown to be an active drug in recurrent
ovarian cancer. A phaseIII randomized study (ICON6)
on patients with ovarian, fallopian tube, and primary
peritoneal carcinoma isongoing with three different
combination therapies. Moreover, another phase
I/II trial is ongoing for VEGF Trap, which is afusion
protein that combines the Fc region of IgG1 withdomain
two of VEGFR1, and domain three of VEGFR2
(VEGFR?1R2) in combination with Docetaxel in patients
with recurrent ovarian cancer, primary peritoneal
cancer, and fallopian tube cancer.
PDGF inhibitors: PDGF magnifies the proliferation
of human ovarian surface epithelial cells and ovarian
cancercells.[,] High expression levels of PDGF
and PDGF? were found in73.3% and 35.6% of malignant
ovarian tumors, respectively.[] It was shown
that the elevated expression of PDGFR? is an independent
poor prognostic factor in patients with ovarian
cancer. Therefore, PDGF signaling pathways migth be
novel targets forovarian cancer therapy.
Tyrosine kinase inhibitors (EGFR): Pertuzumab,
a recombinant, humanized monoclonal antibody that
binds to HER2, induces activation ofantibody-dependent
cellular cytotoxicity without blocking the truncation
of HER2 with the difference of Trastuzumab.[]
Combination therapy of pertuzumab with gemcitabine
was assayed in a randomized phase II trial in 130 patients
with platinum-resistant ovarian, fallopian tube,
or primaryperitoneal cancer.[] An increased treatment
benefit was observed in the gemcitabine + pertuzumab
combination in patients with low HER3 mRNA
expression in their tumors. Therefore, pertuzumab
maybe effective in platinum-resistant ovarian cancer,
and low HER3 mRNA expression may predict a pertuzumab
clinicalbenefit.
PARP-1 inhibitors: The poly (ADP-ribose) polymerases
(PARPs) enzyme family has the most abundant
isoform playing a key role in the repair of DNAsingle-
strand breaks (SSBs) through the base excision
repair pathway. Olaparib (AZD2281), an oral smallmolecule
PARP inhibitor, was tested in BRCA-mutated
patients with ovarian, primary peritoneal, and fallopian
tube cancer.[,] In thestudy, 20 patients (40%)
responded to therapy. Currently, randomized trials of
olaparib and other PARP inhibitors in patients with
ovarian cancer are underway.
DNMTinhibitors: Azacytdine and 5-aza-2"-deoxycytidine
(decitabine) are approved to treat myelodysplastic
syndrome. Phase Iand IIclinical trials are ongoing
to examine treatment of ovarian cancer.[] A
phase Istudy has been completed recently of decitabine
combined with carboplatin in patients with recurrent
platinum-resistant ovarian carcinoma.[]
Cancer Testis Antigens (CTA): There are currently
nine Cancer Testis Antigens, SPAG9, OY-TES-1, Piwil2,
LAGE-1, NY-ESO-1, SSX, AKAP-3, SCP-1, and
Sp17. These antigens are the most suitable for a vaccine
of ovarian cancer and immunotherapy, although they
are not used in clinical practice now. Among these,
CTA, SPAG9, NY-ESO-1, Sp17, and AKAP-3 have
been examined in detail for diagostic and therapeutic
approaches. Phase I clinical trials have been completed
by Odunsi and Diefenbach et al. for the CTA NYESO-
1, which demonstrated thepotential for the vaccination
approach for advanced and high-risk ovarian
cancer.[,] In the study by Diefenbach et al.,[]
vaccination with the HLA-A0201-restrictedNY-ESO-
1b peptide was performed to patients at high risk for
ovarian cancer in first remission, following conventional
surgery and chemotherapy. No serious adverse
effects were seen after vaccinations. Concordantly, strong CD4 and CD8 positive T-cell responses indicatedthat
the NY-ESO-1-based vaccine was effective in
eliciting specific anti-tumoractivities. However, the authors
pointed out that ovarian tumor cells could escape
from the vaccine because there was a lack of NY-ESO-1
expression in recurrent tumors. The results based on
the NY-ESO-1 vaccine are very promising for ovarian
cancer clinical trials.
