u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132

available at www.sciencedirect.com

journal homepage: www.updateoncancer.com

Development of novel agents for ovarian cancer

B.T. Hennessy ∗ , M. Markman

Departments of Gynecology Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center,
1515 Holcombe Boulevard, Houston, TX 77030, USA

a r t i c l e i n f o a b s t r a c t

Keywords: Epithelial ovarian cancer, the fourth leading cause of cancer deaths in American women,
Ovarian is a devastating disease. Although the combined intraperitoneal and intravenous adminis-
Cancer tration of first-line chemotherapy does produce some improvement in patient outcomes
Molecular in comparison with intravenous administration alone, the results of completed clinical
Genomic trials suggest that a plateau has been reached in the benefits that can be achieved with
Chemotherapy cytotoxic chemotherapy alone in ovarian cancer. Epithelial ovarian cancer is currently clas-
Novel sified by surgical and histologic criteria. However, the predictive value of this classification
Targeted is limited. Moreover, the complexity of the different subtypes of ovarian cancer presents
Therapy challenges to our understanding of the origin and pathogenesis of this disease. The sequen-
tial acquisition of molecular anomalies as occurs in colorectal carcinogenesis has not been
described for ovarian cancer. However, increasing evidence indicates that multiple genetic
and epigenetic events contribute to epithelial ovarian carcinogenesis. These events include
aberrations in the expression of patterning genes, genomic instability, and resultant chro-
mosomal changes, and may be triggered by excessive exposure of surface epithelial cells
to autocrine/paracrine stimulation by sex steroids and other growth factors. As the dis-
ease progresses, activation of kinase pathways and continued abnormal autocrine/paracrine
stimulation contribute to genomic instability and chemoresistance but also identify novel
potential targets for therapeutic intervention. Although the list of genomic and other aber-
rations in ovarian cancer is daunting, a systems approach and the integration of therapies
targeting multiple component ‘driver’ genes of important genetic aberrations has potential
in treatment and for potentiation of cytotoxic chemotherapy efficacy.
© 2009 Elsevier Ltd. All rights reserved.

1. Introduction ment therapy, a family history of ovarian and/or breast cancer,

Epithelial ovarian cancer is the fourth leading cause of can-
cer deaths in American women [1]. Although referred to as
epithelial ovarian cancer, neoplasms with similar morphology
and behavior can also arise from endometriosis, endosalp-
ingiosis, the fallopian tube and peritoneum. The disease is
currently thought to arise from the ovarian surface epithelium
(OSE). Risk factors include increasing age, estrogen replace-
and nulliparity, whereas the oral contraceptive pill (OCP)
decreases risk. Consistent with an association with ovula-
tion and endocrine factors, 40–60% of ovarian cancers express
estrogen receptor (ER)␣ , although only a minor proportion of
patients, usually those possessing low-grade tumors, respond
to endocrine manipulation [2]. Loss of ER␤ and progesterone
receptor expression may be important events leading to ovar-
ian carcinogenesis.

∗
Corresponding author at: Departments of Gynecology Medical Oncology and Systems Biology, CPB6.3444, The University of Texas MD
Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: +1 713 563 1792; fax: +1 713 745 1541.
E-mail address: bhennessy@mdanderson.org (B.T. Hennessy).
1872-115X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.uct.2009.02.001
120 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132

Table 1 – Conventional staging of ovarian cancer.

Stage Description

1 Tumor limited to ovary or ovaries

A One ovary involved
B Both ovaries involved
C Tumor limited to ovary or ovaries with ascites, positive peritoneal washings, surface involvement, or rupture present
2 Ovarian tumor with pelvic extension
3 Tumor involving the upper abdomen or lymph nodes
4 Distant organ involvement (includes a malignant pleural effusion and parenchymal involvement of liver or spleen)

Three interrelated theories have been proposed to explain
the epidemiologic data associated with susceptibility to ovar-
ian cancer [3]. The incessant ovulation hypothesis postulates
that repetitive wounding and cell proliferation in postovu-
latory repair of the OSE result in a stepwise accumulation
of genomic abnormalities. Ovarian epithelial inclusion cysts
occur as a result and may increase the risk of carcino-
genesis by trapping cells in an environment of aberrant
autocrine/paracrine stimulation by growth factors including
hormones, phospholipids, and vascular endothelial growth
factor (VEGF), which activate intracellular processes such as
kinase signaling. The gonadotropin theory postulates that
surges of pituitary gonadotrophins at ovulation and persis-
tent high levels following menopause stimulate OSE cells,
resulting in accumulation of genetic changes and carcinogen-
esis. The third theory suggests a role for inflammation and
changes in redox potential in the setting of ovulation and
OSE repair and may account for the increased risk of ovarian
cancer associated with talc/asbestos exposure, endometriosis,
pelvic inflammatory disease, and mumps infection [4]. Since
the inflammation-like setting in which ovulation occurs is
cyclooxygenase 2 (COX2)-dependent, this provides support for
exploration of the chemopreventive and therapeutic potential
of COX2 inhibitors in ovarian cancer. However, while chemo-
prevention and screening remain extremely attractive, the low
prevalence of ovarian cancer in the general population reduces
enthusiasm for such approaches. Most current efforts that
attempt to improve patient outcomes thus focus on therapy
for women with established ovarian cancer.
Table 1 shows epithelial ovarian cancer staging and Fig. 1
represents current treatment guidelines. The majority of
patients present with advanced (stage III/IV) high-grade dis-
ease and, as a result, most of these patients ultimately relapse
and die from ovarian cancer within 5 years of diagnosis despite
an improved median survival associated with standard first-
line therapy (paclitaxel or docetaxel/carboplatin combination

Fig. 1 – Simplified schema of current NCCN treatment guidelines for epithelial ovarian cancer. Cytoreductive surgery
generally consists of a total abdominal hysterectomy, salpingo-oophorectomy, and omentectomy. Unilateral
salpingo-oophorectomy for those desiring fertility preservation may be considered in patients with stage 1A or 1C disease
of any grade (*). Generally, adjuvant taxane/carboplatin-based chemotherapy is recommended in patients following
debulking of grade 3 stage 1A/B tumors or of any stage IC-IV tumors. With grade 2 stage 1A/B disease, observation may also
be an appropriate option (**). Although data regarding interval cytoreductive surgery during primary chemotherapy are
somewhat conflicting, most studies agree in terms of the benefit of an extensive attempt at surgical cytoreduction during
primary therapy. Several studies have also shown a survival advantage for intraperitoneal chemotherapy in patients with
advanced (stage III) ovarian cancer (***) although there has thus far been reticence to move this into standard of care.
 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132 121

Table 2 – Current concepts regarding the origins and molecular pathology of ovarian cancer. PIK3CA is the gene at
chromosome 3q26 which specifically encodes the p110␣ subunit of phosphatidylinositol-3-kinase (PI3K) [25].
Histology Precursor Molecular features

Low-grade serous carcinoma Cystadenoma-borderline Mutations in K-ras and/or b-raf

tumor-carcinoma sequence
High-grade serous carcinoma ‘De novo’ in epithelial inclusion cysts p53 mutation and BRCA1 dysfunction
(usually promoter methylation)
PIK3CA amplification (25–40%)
Low-grade endometrioid Endometriosis and endometrial-like Mutations in CTNNB1 (␤-catenin gene) and
carcinoma hyperplasiaa PTEN with microsatellite instability
High-grade endometrioid Epithelial inclusion glands/cysts p53 mutation and BRCA1 dysfunction
carcinoma (usually promoter methylation)
PIK3CA mutation
Mucinous carcinoma Cystadenoma-borderline Mutations in K-ras; ? p53 mutation
tumor-carcinoma sequence associated with transition from borderline
tumor to carcinoma
Clear cell carcinoma ?endometriosis ?PTEN mutation/loss of heterozygosity
PIK3CA mutation

The statement following the ? is controversial and not conclusively shown to date.
a
Endometriosis and adjacent low-grade endometrioid carcinoma share common genetic events such as loss of heterozygosity at the same loci
involving the same allele (e.g. PTEN). In contrast, high-grade and poorly differentiated endometrioid carcinomas are similar to high-grade
serous carcinomas.

chemotherapy and surgical debulking) [5]. Although the
combined intraperitoneal and intravenous administration
of first-line chemotherapy does produce some improve-
ment in patient outcomes in comparison with intravenous
administration alone at the expense of increased toxicity
[6], the incorporation of additional cytotoxic chemotherapy
drugs into first-line treatment has not resulted in signifi-
cant improvements in patient outcomes in comparison with
paclitaxel/carboplatin therapy alone [7]. This suggests that a
plateau has been reached in the benefits that can be achieved
with cytotoxic chemotherapy alone in ovarian cancer. Thus,
although novel chemotherapy drugs (e.g. epothilones and hali-
chondrins, both novel microtubule inhibitors and karenitecin,
a camptothecin analogue) and formulations (e.g. nanopar-
ticle albumin-bound (nab)-paclitaxel (Abraxane® ), liposomal
lurtotecan (OSI-211) and antibody-drug conjugates such as
cBR96-doxorubicin that delivers doxorubicin to tumor tissues
expressing the Lewis-y (Ley ) antigen) are being evaluated (Clin-
icalTrials.gov) [8], most enthusiasm and efforts to improve
treatment are moving towards novel targeted therapies.
Therefore, the bulk of this review will focus on the current and
future development of novel targeted therapeutic approaches
in ovarian cancer. To date, novel inhibitors such as epidermal
growth factor receptor (EGFR) family inhibitors or inhibitors of
Kit have not had a major impact on the treatment of women
with ovarian cancer likely because EGFR and Kit gene aber-
rations, which are associated with responsiveness to these
targeted therapies in other tumor types, are rare in epithe-
lial ovarian cancer [9]. More enthusiasm surrounds the use
of inhibitors of VEGF signaling such as the monoclonal anti-
body bevacizumab (Avastin® ); indeed, bevacizumab is now
being assessed in randomized phase III trials in women with
newly diagnosed ovarian cancer [10,11]. To advance the devel-
opment of novel agents for the treatment of ovarian cancer,
an in depth and improved understanding of the molecular
biology of the disease is required so that rational molecu-
lar targets can be identified and exploited. Further, epithelial
ovarian cancer is a heterogeneous disease and its clinical and
cellular biology have implications for the molecular pathogen-
esis of specific tumors (Table 2) and thus for novel potential
targets and therapies that will likely prove useful in patient
therapy. These novel therapies may have their greatest impact
on patient outcomes when used in combination with cytotoxic
chemotherapy drugs such as paclitaxel and carboplatin.
2. Pathogenesis of ovarian cancer
2.1. Clinical and cellular biology
The cellular and clinical biology of ovarian cancers have impli-
cations for patient outcomes after current standard therapies
[12–17]. Epithelial ovarian neoplasms are classified based on
their histologic appearance into serous, mucinous, endometri-
oid, and, less commonly, clear cell, transitional, squamous,
mixed, and undifferentiated types. The serous subtype is
most common. In a series of more than 8000 cases pub-
lished between 1982 and 1986, mucinous and endometrioid
carcinomas were found to be associated with a relatively
favorable prognosis, serous carcinomas less so, and undif-
ferentiated carcinoma was the most aggressive subtype of
ovarian carcinoma [12,18]. The data regarding clear cell (or
“mesonephroid”) carcinoma appeared somewhat conflicting,
with about half of reviewed publications placing it in a rel-
atively favorable category and the other half finding it to be
associated with an unfavorable prognosis [13]. These discrep-
ancies may be due in part to the fact that, although clear cell
carcinoma is inherently aggressive, it is frequently detected
at Stage I. The histopathologic grade of epithelial ovarian
carcinoma is also important to tumor behavior and has con-
sistently been found to be of prognostic significance [12,13]. In
virtually all published series’, histopathologic subtype had a
less significant impact on prognosis than either clinicopatho-
logic stage or histopathologic grade [12,13]. Emerging data now
122 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132
suggest that low- and high-grade carcinomas of the ovary
develop along different pathogenetic pathways, particularly
with serous carcinomas, and that low-grade carcinomas and
tumors of low malignant potential may emerge along a sim-
ilar developmental sequence of molecular changes [19–22].
The molecular heterogeneity associated with ovarian can-
cers of different grades and subtypes will be discussed in
detail below as it has profound implications for the design
of novel therapies. For example, many experts feel that grade
is an unreliable criterion on which to base a therapy decision
presently but this is likely to change as novel therapies that
target specific molecular anomalies are introduced. Currently,
the mitogen activated protein kinase (MAPK) kinase (MEK)
inhibitor AZD6244 is being evaluated specifically in the treat-
ment of women with low-grade ovarian cancer by the United
States (U.S.) National Cancer Institute (NCI-ClinicalTrials.gov)
(see below).
2.2. Molecular biology
An in-depth and improved understanding of the molecular
biology of epithelial ovarian cancer is likely to efficiently facil-
itate the identification of targets and the development of novel
agents for ovarian cancer treatment. Current understand-
ing of the molecular complexity of ovarian cancer suggests
that novel treatment strategies likely need to focus on more
than single molecules or targets. Like many solid tumors,
epithelial ovarian cancer has a high degree of chromoso-
mal instability, and both total and regional instability are
associated with tumor grade and altered patient outcomes
[23]. Ovarian carcinogenesis is thought to evolve through
the multistep acquisition of genomic and epigenetic aberra-
tions that initially deregulate normal cell growth control and
subsequently result in autonomous proliferation and other
“hallmark” features of malignancy [24]. Although there are
only a few “hallmarks”, many genomic aberrations act in con-
cert to contribute to the carcinogenesis process. Indeed, it is
known that aberrations in single oncogenes frequently result
in senescence or oncogene-induced cell death. Combined with
the evidence for multiple different non-overlapping defects in
cancer cells, this suggests a major degree of complexity. An
improved understanding of the underlying genomic aberra-
tions that drive epithelial ovarian cancer and how they disrupt
protein function leading to tumorigenesis is needed to design
optimal therapy strategies. Thus, a comprehensive character-
ization of genomic anomalies in epithelial ovarian cancer is
a useful first step in studies that attempt to advance under-
standing of ovarian carcinogenesis and thereby to discover
promising new targets and agents for therapy.
The selection of epithelial ovarian cancer as one of three
tumor types for extensive characterization as part of the
cancer genome atlas (TCGA) project offers an incredible oppor-
tunity to extend our understanding of this disease. Although
mutations frequently affect only a limited number of genes
in epithelial ovarian cancer, chromosomal copy number aber-
rations typically involve large numbers of genes and further
investigative techniques are required to determine a more
limited list of those target genes that act as ‘key drivers’ of
carcinogenesis. For example, in breast cancer, the HER2-neu
oncogene is believed to be a ‘key driver’ of the HER2-neu ampli-
con on chromosome 17q, although multiple other nearby
genes are frequently co-amplified with HER2-neu. Whether
these co-amplified genes are “innocent” passengers or act
cooperatively with HER2-neu remains unknown. Theoreti-
cally, genes selected for mutation as well as ‘key drivers’ of
chromosomal copy number alterations are most important to
the carcinogenesis process and represent the best potential
targets for novel therapies because of ‘oncogene addiction’
[24]. Study of the transcriptional and proteomic effects of
aberrant genes in ovarian cancer is thus essential to deter-
mining their importance to the carcinogenesis process and to
exploring the antitumor efficacy and proteomic effects of ther-
apies designed to specifically target the protein products of
these aberrant genes. Further, as there are too many candidate
genes for systematic analysis of all potential drivers at areas of
genomic abnormality, maintaining focus specifically on those
genomic changes that correlate with patient outcomes is an
imperfect filter but one that nonetheless allows us to focus
on genes that are most likely to provide effective treatment
targets.
2.3. Mutations
Genomic mutations are felt to play a frequent and key
role in the pathogenesis of multiple forms of cancer. High
prevalence mutations (>5%) have been found in only a lim-
ited number of genes in epithelial ovarian cancer, occur
in most cases in a histologic subtype- and grade-specific
fashion (Table 2) and identify genes whose functional per-
turbation likely plays a key role in ovarian carcinogenesis.
These genes include p53, CTNNB1, PTEN (all inactivated), K-
ras and PIK3CA (the gene that encodes the p110␣ protein
subunit of the phosphatidylinositol-3-kinase (PI3K) protein)
(both activated) [25–29]. Activating AKT1 mutations also occur
but at a frequency of under 5% [28]. Although p53 is a tumor
suppressor gene, due to the dominant negative activity of
mutant p53 protein, p53 function can be lost with a single
genetic event. Further, germline mutations of BRCA1, BRCA2,
and the hereditary non-polyposis coli (Lynch syndrome II)
genes, all associated with DNA repair processes, are asso-
ciated with a markedly increased risk of epithelial ovarian
cancer and account for 13.2% of all ovarian cancers [30]. Hered-
itary BRCA1/2-related ovarian cancers tend to occur at an
earlier age than sporadic tumors, possibly by predisposing to
genomic instability, and as compared with sporadic ovarian
tumors are more commonly high-grade serous tumors with
p53 dysfunction [31]. Although BRCA1 and BRCA2 are rarely
mutated by sporadic mutation in ovarian cancers, these genes
can also be silenced by methylation. Indeed, transcriptional
profiles demonstrate similar changes in sporadic and BRCA1-
associated tumors suggesting that BRCA1 function may be
compromised in most ovarian cancers. As poly (ADP-ribose)
polymerase 1 (PARP) inhibitors may be selectively active in
cancer patients with aberrations in BRCA1 and BRCA2 (see
below), this likely has clinical significance.
Novel high-throughput approaches to sequencing of spe-
cific functional groups of genes (e.g. the kinome) have not
thus far revealed other commonly mutated genes in ovarian
cancer but have probed only limited parts of the genome [32].
These approaches have, however, identified a large number of
 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132
“rare” events that may act coordinately during tumorigenesis.
Thus, high-throughput sequencing [33] by the Sanger Cen-
ter (www.sanger.ac.uk) and as proposed by TCGA in epithelial
ovarian cancer will likely identify a large number of low
frequency mutations. A systems biology approach with path-
way or network analyses may demonstrate that these “rare”
mutations result in coordinate aberrations in common critical
processes.
It is possible by ectopically manipulating genes in the ovar-
ian surface epithelial (OSE) cells of mice to induce a very
poorly differentiated form of ovarian cancer by combining p53
loss with activation/overexpression of two of three oncogenes
(myc, K-ras, and AKT1) [34,35]. In mice that are deficient for
both p53 and BRCA1, myc alone is sufficient to induce trans-
formation and resultant cancers have increased sensitivity to
the DNA damaging agent cisplatin. Although the relevance of
these models to human ovarian cancer remains disputable,
they do have the potential to allow exploration for the role
of specific oncogenes in ovarian carcinogenesis and to allow
potential evaluation of targeted therapies. Further, OSE cells
provide potent reagents to determine mechanisms underlying
immortalization and transformation [36–38].
Mutations identify logical potential markers and tar-
gets to facilitate better treatment [24]. However, successful
targeting of the consequences of mutations in human ovar-
ian cancer treatment has not yet been achieved. Despite
promising preclinical and clinical data leading to an interna-
tional randomized phase II/III trial of p53 gene-therapy using
replication-deficient adenoviral vectors in combination with
first-line chemotherapy for epithelial ovarian cancer, no ben-
efit was shown [39]. However, there were multiple potential
problems including some that may have affected the success-
ful intratumoral delivery of p53. However, a number of novel
therapeutics targeting aberrations relevant to selected ovarian
cancer histiotypes such as mutations in PIK3CA are currently
entering clinical trials (e.g. the AKT inhibitor perifosine (Keryx
Pharmaceuticals, New York, NY) and the PI3K inhibitor SF1126
(Semafore Pharmaceuticals, Indianapolis, IN)). The successful
exploitation of genomic mutations for ovarian cancer therapy
will require not only effective delivery of the agent to tumor
cells but also a comprehensive understanding of the transcrip-
tional and functional proteomic effects of these mutations,
changes induced in response to in vitro and in vivo targeting
of the protein product of the mutant gene and its interaction
with other genomic changes.
2.4. Gene copy number aberrations
Genomic instability is thought to represent at least two dif-
ferent processes in ovarian carcinogenesis that occur at least
in part due to bridge-fusion-breakage that occurs at telomeric
crisis [24]. Of less importance are those genomic areas that
are destabilized as a result of the tumorigenesis process per
se. Likely more important are particular areas of the genome
that may be targeted and selected for amplification or deletion
specifically due to their functional importance for tumor ini-
tiation and progression. Although such aberrant areas of DNA
frequently carry multiple genes, it is presently thought that
only a limited number of the multiple genes are ‘key drivers’
of the process; these ‘key drivers’ are thought to be the most
123
critical markers and potential treatment targets. However, it
is not clear if each genomic aberration harbors a single “key
driver” or whether multiple genes within an aberrant region
may contribute to “cooperative carcinogenesis”.
Novel high throughput technologies such as comparative
genomic hybridization are capable of profiling copy number
changes across the entire genome in cancer [40–43] and have
become a conventional first step in the identification of poten-
tially important markers and targets in epithelial ovarian
cancer. Subsequent approaches to distinguishing candidate
‘drivers’ from other less important co-amplified or co-deleted
genes in areas of chromosomal copy number change have
focused on finding those aberrations that induce significant
changes in both RNA and protein levels and function and
result in alterations in the phenotypic behavior of manipu-
lated cells in vitro and/or in significant changes to patient
outcome [42]. These ‘drivers’ are susceptible to exploitation
through small molecule inhibition, antibody targeting, small
interfering (si)-RNA technology, or transfection and overex-
pression in the case of deleted genes.
Since inhibition of protein function is generally believed to
be more achievable than restoration of function, a perception
reinforced by the clinical failure in ovarian cancer to date to
exploit p53 loss and by the success in breast cancer of the
anti-HER2 monoclonal antibody trastuzumab, most studies
focus on areas of chromosomal gain (amplicons) rather than
on areas of deletion for identification of novel potential ther-
apy targets. Candidate ‘drivers’ at areas of copy number gain
that have been identified to date in ovarian cancer include the
small G protein RAB25 at 1q22, ecotropic viral integration site-
1 (EVI1), protein kinase C iota (PKCi), SnoN, BCL6, the initiation
factor eIF-5A2 and PIK3CA at 3q26.2, c-myc and PVT1 at 8q24.2,
remodeling and spacing factor 1 (rsf-1, HBXAP) and PAK1 at
11q13, HER2-neu at 17q12, AKT2 at 19q13.2 and ZNF217, BTAK
(Aurora Kinase), the tyrosine kinase BRK and EEF1A2 at 20q13.2
[41,44–51]. Some of these abnormalities are targetable with
novel agents that are currently undergoing preclinical or early
clinical assessment.
In addition to mutations and DNA copy number changes,
rearrangements, epigenetic changes and imprinting also
affect cellular function potentially identifying important
markers and therapy targets in ovarian cancer. Approximately
70 human genes are now known to be imprinted with only
one allele expressed at conception, during embryonic devel-
opment and in each normal adult cell. Several imprinted genes
including ARHI (NOEY2) and LOT1/ZAC function as tumor sup-
pressor genes, and these and other potential tumor suppres-
sors (e.g. RASSF1A, DLEC1, WWOX, HIC1, OVCA1 and OVCA2)
may be lost in ovarian cancer, either by epigenetic mecha-
nisms and/or deletions [52,53]. New comprehensive profiling
approaches to detect methylation patterns and to explore the
functional proteomic and other effects of imprinted genes are
likely to identify new candidates [54]. To date, however, clin-
ical studies have not yet begun to assess therapies that are
targeted to the majority of these aberrations.
2.5. Proteomic studies
Since DNA copy number, mutation, rearrangement and
methylation alterations ultimately act coordinately to alter
124 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132
critical cellular functions through changes at the protein level,
it is necessary to develop and implement functional pro-
teomics approaches that can assay post-translational and
other modifications of proteins. New mass spectroscopy plat-
forms and the efforts of the Clinical Proteome Analysis
Technology Consortium are providing new approaches and
opportunities. We have focused our efforts on development of
a novel, sensitive, moderate-throughput and quantitative pro-
teomic technology known as reverse phase tissue lysate array
(RPPA) [55,56]. RPPA is primarily a candidate gene approach
based on known proteins with high quality antibodies. It is
ideally suited to determine a ‘global’ proteomic view of sig-
naling changes induced by genomic aberrations as well as
pharmacodynamic signaling changes that occur in response
to the targeting of aberrant proteins [57]. The global functional
proteomic information derived from RPPA studies can thus
facilitate definition of optimal combination approaches that
will most effectively inhibit important signaling pathways in
ovarian and other cancers.
2.6. Histology-specific molecular changes in ovarian
cancer
Transcriptional profiling of ovarian cancers has revealed
marked differences in gene expression patterns between his-
tologic subtypes [58]. Further, as discussed, there are distinct
genomic aberrations that are clearly important to the patho-
genesis of specific histologic subtypes (Table 2). For example,
the importance of PTEN loss to endometrioid ovarian carcino-
genesis is supported by mouse models [59]. Together [25,29],
these observations provide considerable support to the long-
held notion that the different subtypes of epithelial ovarian
cancer should be regarded as separate disease entities with
distinct pathogenesis pathways and potential therapy targets.
Furthermore, genetic analysis indicates that cystadenomas,
borderline tumors and carcinomas do not represent a stepwise
progression for the serous subtype, although such a colorectal
cancer-type sequence may exist for mucinous tumors [29].
Although the different subtypes of epithelial ovarian
cancer (serous, endometrioid, mucinous) possess unique
molecular aberrations (Table 2), their morphologic features
resemble the specialized epithelia of the reproductive tract
that derive from the mullerian ducts and recent studies sug-
gest that they may all arise from a single OSE precursor cell
with the specific path of differentiation regulated by embry-
Table 3 – Important role for the homeobox genes HOXA7, A9, A10, and A11 in the morphologic heterogeneity of epithelial
ovarian cancers and their assumption of mullerian-like features [60].
Homeobox (HOX) gene Normally expressed ina
HOXA9 Fallopian tubes, endometrium,
endocervix
HOXA10 Endometrium, endocervix
HOXA11 Endocervix, lower uterine
segment
a
Little or no staining for HOX proteins is present in normal human ovarian surface epithelial cells.
onic pathways involving HOX genes [60]. These genes encode
transcription factors that control developmental patterning
along the anterior-posterior axis, and the temporal and spatial
expression of these genes is tightly coupled to their clustered
organization. HOX genes are not normally expressed in OSE
[60]. However, expression of HOXA9, HOXA10 and HOXA11 in
tumorigenic mouse OSE-derived cells has been demonstrated
to induce cells to differentiate along distinct mullerian lin-
eages, giving rise to tumors that exhibit morphologic features
that are characteristic of serous, endometrioid and mucinous
ovarian tumors, respectively (Table 3). HOXA7, a gene located
3 of HOXA9, has been additionally found to control the degree
of differentiation and grade of ovarian tumors [60]. Since sex
steroids regulate HOX expression throughout the menstrual
cycle in the adult, it is plausible that prolonged exposure of
OSE cells to these hormones in the adult female contributes
to inappropriate HOX activation, perhaps in the context of
epithelial inclusion cysts and excessive autocrine/paracrine
stimulation leading to proliferation and genomic instability.
3. Novel targets and approaches for ovarian
cancer therapy
3.1. Kinases: receptor tyrosine kinases
EGFR and HER2 are validated as important treatment targets
in cancers of the lung, head and neck, and breast, diseases
in which these receptors are frequently genomically abnor-
mal. However, they are less frequently genomically aberrant
in epithelial ovarian cancer. The prognostic significance of
HER2 in ovarian cancer is less clear than in breast can-
cer and responses to therapy with the monoclonal antibody
trastuzumab have been disappointing, probably due to the
low frequency of gene amplification [61]. In parallel, although
studies are attempting to exploit other membrane receptors
including EGFR and c-kit in ovarian cancer with tyrosine
kinase inhibitors such as gefitinib (inhibits EGFR) and imatinib
(inhibits c-kit), the rationale is frequently based on little mech-
anistic consideration other than protein (over)expression [9].
In the absence of frequent genomic aberrations of these recep-
tor tyrosine kinases in ovarian cancer and with conflicting
data regarding their prognostic significance, it may be that
therapies designed to specifically exploit them will not sig-
nificantly impact the outcome of ovarian cancer patients.
Epithelial ovarian Stable expression in
cancer expression transformed mouse OSE
cells induces formation of
Serous, endometrioid, Cystic, papillary tumors
mucinous resembling serous carcinomas
Mucinous, Glandular tumors resembling
endometrioid endometrioid carcinomas
Mucinous Tumors resembling mucinous
carcinomas
 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132 125

Table 4 – Epidermal growth factor receptor (EGFR)/HER2/phosphatidylinositol-3-kinase (PI3K) signaling pathway

abnormalities in ovarian cancer. PIK3CA—the gene encoding the catalytic p110␣ subunit of PI3K; p85 – the regulatory
subunit of PI3K.
Gene Genomic alteration in tumors Epithelial ovarian cancer subtype Alteration frequency in subtype

PIK3CA Amplification Prevalent in all high-grade epithelial 25–40%

ovarian cancers (mostly serous)
PIK3CA Activating mutations Serous epithelial ovarian tumors 2%
Endometrioid ovarian tumors 20%
Clear cell ovarian tumors 20%

PTEN Mutations Endometrioid ovarian tumors only (6–8% 50% (but rare in other subtypes)
of all epithelial ovarian tumors)
p85 Activating Mutations High-grade epithelial ovarian cancers Rare
AKT1 Activating mutations Not defined as of yet 2%
AKT2 Amplification High-grade epithelial ovarian cancers 5%
HER2 Amplification High-grade epithelial ovarian cancers 8%
EGFR Protein expression High-grade epithelial ovarian cancers 30–70%, although genomic
changes (amplification, mutation)
are rare

3.2. Kinases: PI3K/AKT signaling the treatment of borderline and low-grade ovarian tumors.
Although farnesyl transferase inhibitors and sorafenib were
Genomic aberrations commonly activate protein signal- originally developed to inhibit ras signaling, current interest
ing through the oncogenic PI3K/AKT pathway downstream resides with newer more specific inhibitors such as the MEK
from receptor tyrosine kinases in epithelial ovarian cancer inhibitor AZD6244 (AstraZeneca).
(Table 4) [44]. Given the evidence suggesting that cancer
cells with genomic anomalies activating PI3K/AKT signaling
are extremely sensitive to inhibitors of this signaling path- 3.4. Kinases: protein kinase C iota (PKCi)
way (‘oncogene addiction’) [28,44,62,63], PI3K/AKT pathway
PKCi is activated by K-ras and is also located near the peak of
inhibitors have exciting potential for ovarian cancer treat-
the 3q26.2 amplicon in high grade ovarian cancers. PKCi is a
ment. Indeed, the PI3K inhibitor LY294002 decreases ovarian
key catalytic regulator of the Par3-Par6-atypical PKC complex,
cancer cell proliferation and ascites formation and increases
a complex required for localization of E-cadherin to cell junc-
apoptosis induced by paclitaxel and other chemotherapies in
tions, for maintenance of tight and adherens junctions, and for
vitro and in vivo. Although this particular drug is not suitable
the establishment of epithelial cell polarity [65]. Many growth
to clinical development because of poor solubility and a short
factors are normally compartmentalized by tight junctions in
half life, several companies now have PI3K/AKT inhibitors
polarized cells. Loss of polarity is a feature of epithelial ovarian
in early phase clinical trials (SF1126, perifosine, XL147 from
cancer and allows growth factors and signaling complexes to
Exelixis (San Francisco, CA), BEZ235 from Novartis (East
interact aberrantly and to mediate autocrine cell activation.
Hanover, NJ)). Inhibitors of the PI3K/AKT pathway-related
Thus, deregulation of PKCi likely contributes to the patho-
G protein Rab25 [45] are also now available for preclinical
physiology of ovarian cancer. Our group has demonstrated
use. Because of its role in promoting cell survival under
that PKCi is a potential therapeutic target in human ovar-
stressful conditions, inhibition of the PI3K/AKT pathway may
ian tumors, being associated with proliferation and cyclin E
demonstrate greatest efficacy in combination with cytotoxic
induction. Strikingly, coordinate elevation of cyclin E and PKCi
chemotherapy.
identifies a population of patients with a particularly poor out-
come.
3.3. Kinases: Ras signaling

In the mouse ovary, K-ras activation in OSE cells in
combination with PTEN inactivation or TAG and hTERT-
immortalization induces the formation of high-grade cancers
[35,64]. In contrast, however, the K-ras gene is commonly acti-
vated by mutation in human low-grade serous ovarian tumors
and in 47% of mucinous lesions, with mutations being more
common in borderline tumors (27–60%) than in invasive (19%)
cancers; there is some evidence that mutations play a role in
the progression of the adenoma-borderline tumor-carcinoma
sequence in invasive mucinous and in borderline/low-grade
serous ovarian carcinomas [25,29]. Further, b-Raf mutations
have been identified in borderline and low-grade ovarian can-
cers. Thus, there is interest in exploring the clinical role
of drugs that inhibit signaling downstream from K-ras in
3.5. Kinases: Src
Src, a nonreceptor tyrosine kinase, is a key mediator for multi-
ple signaling pathways that regulate critical cellular functions
and is often aberrantly activated in ovarian carcinoma [66].
In vivo, Src inhibition by AP23994, an orally bioavailable ana-
logue of AP23846, significantly decreases tumor burden in
ovarian cancer xenografts both alone and in combination
therapy with docetaxel. Src inhibition also has potent antian-
giogenic effects and may be an attractive therapeutic approach
for patients with ovarian carcinoma. Src inhibitors such as
dasatinib (Bristol-Myers Squibb, New York, NY) and AZD0530
(AstraZeneca) are thus being evaluated in phase 2 clinical tri-
als.
126 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132
3.6. Kinases: signal transduction and activation of
transcription (STAT) signaling
STAT3 is phosphorylated by Janus kinase (JAK) and Src. Phos-
phorylated STAT3 forms dimers that can be translocated
to the nucleus, binding DNA and inducing transcription of
genes resulting in proliferation (cyclin D, c-myc, c-Fos), sur-
vival (Bcl-2, Bcl-XL, XIAP, Survivin) and angiogenesis. STAT3
can be activated by growth factor (EGFR) and cytokine recep-
tors (Interleukin-6R) or by direct interaction with Src or
Abl. Nuclear localization of phosphorylated STAT3 has been
observed in 71% of ovarian cancers and is associated with
decreased overall survival [67]. Autocrine and paracrine acti-
vation of STAT3 stimulates cell proliferation and motility in
vitro. JAK and STAT inhibitors have demonstrated antitumor
activity in ovarian cancer preclinical models [68,69].
3.7. PARP
PARP inhibitors such as AZD2281 (AstraZeneca) induce cancer-
specific synthetic lethality in homologous recombination
repair-defective cells, including BRCA1/2-mutant tumors [70].
In the expansion phase of a phase 1 clinical trial in women
with BRCA-deficient ovarian cancer, toxicities were mild and
14 of 32 patients, the majority of whom had platinum resis-
tant/refractory disease, achieved a partial response. Thus,
AZD2281 is well tolerated and demonstrates compelling
activity in patients with BRCA-deficient ovarian cancer. Com-
bination studies of PARP inhibitors with cytotoxic drugs are
now proceeding (ClinicalTrials.gov).
3.8. Autocrine signaling: phospholipids and cytokines
PKCi can also activate phospholipase D2 (PLD2), thus increas-
ing phospholipid release from the membrane [71]. In addition,
PLD1 may be located in the 3q26 amplicon in epithelial ovarian
cancer. Our group has also demonstrated that mRNA lev-
els of lipid phosphate phosphatase, an enzyme involved in
lysophospholipid degradation which markedly reduces ovar-
ian cancer growth when reintroduced into cells, is decreased
in the majority of ovarian cancers and cell lines [72]. Thus,
lysophospholipid levels are elevated in the ascitic fluid and
blood of ovarian cancer patients. Lysophosphatidic acid (LPA),
an autocrine/paracrine phospholipid growth factor synthe-
sized from lysophosphatidylcholine by lysophospholipase D
(autotaxin), is found at high concentrations in ascites and at
detectable levels in the plasma of most ovarian cancer patients
and is a potent inducer of cell proliferation, survival, resis-
tance to cisplatin, activation of proteases, invasiveness, VEGF
production, glycogen synthase kinase 3 (GSK-3) inhibition, IL-
6, and IL-8 transcription in ovarian cancer cells [73]. Indeed,
cytokines such as IL-6, IL-8, TNF␣, IL-1␣, CCL2, CXCL8 and M-
CSF and their receptors have all been implicated in ovarian
cancer growth and proliferation [74]. In addition, increased
levels of LPA receptors (LPA2 and LPA3) in ovarian cancer cells
contribute to growth and metastatic capability. Thus, LPA and
several cytokines represent highly valid autocrine targets in
ovarian cancer and a number of specific antagonists are cur-
rently in preclinical evaluation.
3.9. Autocrine signaling and angiogenesis: VEGF
VEGF production is increased in ovarian cancer cells as a result
of mechanisms including PI3K/AKT signaling activation and
LPA (auto)stimulation [75]. VEGF stimulates angiogenesis, acts
as an autocrine/paracrine growth factor through cancer cell
VEGF receptors, and is thought to be a major mediator of
ascites production. The STAT pathway may be particularly
important in mediating the effects of VEGF [75]. VEGF inhi-
bition reduces ascites formation in mouse models and the
ability of ovarian cancer cell lines to migrate in vitro [68].
The anti-VEGF antibody bevacizumab has produced exciting
antitumor activity in phase 2 clinical trials in women with
recurrent chemoresistant ovarian cancer both alone and in
combination with cytotoxic drugs such as oral cyclophos-
phamide [10,11,76]. Thus, it is currently being evaluated by
the GOG and other groups in phase III clinical trials in com-
bination with paclitaxel and carboplatin as first-line therapy
for women with epithelial ovarian cancer. Other inhibitors of
angiogenesis including VEGF Trap (AVE0005), small molecule
inhibitors of VEGF receptors (e.g. AZD2171/Cediranib (Astra
Zeneca)) and angiopoietin inhibitors (e.g. AMG386) are also
in clinical trials in ovarian cancer (ClinicalTrials.gov). Pre-
clinical data suggest that inhibitors of both VEGF receptors
and platelet-derived frowth factor receptor (PDGFR) may have
more antitumor activity than VEGF inhibitors alone [77].
3.10. Autocrine signaling: endothelins
The endothelin A peptides (ET-1, ET-2, and ET-3) are potent
mitogens for several human tumors. ET-1 and its ETA receptor
(ETAR) are overexpressed in primary and metastatic ovar-
ian cancers, providing the potential for autocrine stimulation
[78]. Interaction of ET-1 with ETAR activates a pertussis toxin-
insensitive G protein that stimulates phospholipase C gamma
activity, increases intracellullar calcium and activates PKC,
MAPK, and p125 focal adhesion kinase (FAK) phosphorylation.
Interaction with ET-1 also transactivates EGFR, stimulates pro-
liferation, blocks apoptosis, activates integrin-like kinase (ILK),
upregulates matrix metalloproteinases (MMPs), and increases
vascular endothelial growth factor (VEGF) expression enhanc-
ing angiogenesis. Clinical trials targeting endothelin signaling
in ovarian cancer are thus underway.
3.11. Adhesion and invasion of cancer cells
Normal OSE cells bind to laminin and collagen in the base-
ment membrane [79]. Adhesion to collagen appears to be
maintained in ovarian cancer cells. In cell culture, ovarian
cancer cell lines bind preferentially to type I collagen through
alpha2beta1 integrin. Alteration in adhesion to laminin may
be an important step in ovarian oncogenesis. The distinc-
tive pattern of metastasis to the peritoneal surface involves
binding of ovarian cancer cells to peritoneal mesothelial cells,
mediated by B1 integrin as well as CD44 and the mucin MUC16
(CA125) on the surface of ovarian cancer cells [80]. Mesothe-
lial cells express fibronectin, laminin and type IV collagen
that bind to integrins that contain the B1 subunit, hyaluronic
acid that binds to CD44 and mesothelin that binds to MUC16
(CA125) in 80% of ovarian cancers [81]. The expression of
 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132 127

multiple splice variant forms of CD44 occurs in ovarian can-
cer but the significance of this is unclear [82]. Anti-integrin,
anti-mesothelin and anti-CD44 antibodies as well as MUC16
knockdown can block the binding of ovarian cancer cells to
mesothelial cells and reduce invasion and the frequency of
peritoneal metastases [83,84]. Oregovomab, a murine mon-
oclonal antibody to CA125, is currently in Phase III testing
[85]. However, this antibody has recently been found not to
be effective as maintenance therapy after front-line treatment
of patients with advanced ovarian cancer [86]. The authors of
this phase III study concluded that future studies of this and
other tumor antigen-specific immunization strategies should
seek ways to augment induced immunity.
3.12. Gene therapy
Despite modest activity in preclinical models, adenovirus-
mediated gene therapy for ovarian cancer remains limited in
vivo by inefficient and nonspecific gene transfer, and phase III
studies were stopped early. Adenoviral targeting of mesothe-
lin, a cell surface glycoprotein which is overexpressed in
ovarian cancer but not in normal tissues except mesothelial
cells, makes it a candidate for transcriptional and transduc-
tional gene therapy targeting [87]. The NCI has supported an
ongoing Phase I/II study of intraperitoneal tgDCC-E1 and intra-
venous paclitaxel in platinum-resistant ovarian cancer at MD
Anderson Cancer Center (MDACC). The E1A gene, conveyed by
adenovirus Type 5, was shown to downregulate HER-2/neu and
increase cancer cell apoptosis in patients with ovarian cancer.
siRNAs incorporated into neutral liposomes are being
developed to facilitate delivery of siRNAs that can target virtu-
ally any oncogene to cancer cells in vivo. This technology has
already been used successfully in animal models [88] and will
soon be introduced into phase 1 clinical trials at MDACC.
3.13. Immune therapy approaches
Pemtumomab, a human milk fat globule membrane (HMFG),
is a 90Yttrium-radiolabeled murine IgG1 monoclonal anti-
body against polymorphic epithelial mucin, which is highly
expressed in ovarian cancer. Despite promising phase II stud-
ies [89], however, a phase III study (Study of Monoclonal
Antibody RadioimmunoTherapy [SMART]) using this agent
was closed after failing to meet superiority criteria. Current
agents being evaluated include the trifunctional anti-CD3
antibody catumaxomab, the investigational gene transfer
agent EGEN-001 (phIL-12-005/PPC) that contains the human
interleukin-12 gene in a special carrier system designed to
enter cancer cells, and MORAb-003 (farletuzumab), a human-
ized IgG1 antibody that targets over-expressed folate receptor

Fig. 2 – A systems approach to the integration of genomic and functional proteomic data for identification of rational
molecular strategies for the treatment of cancer. A comprehensive list of aberrant genes identified in chromosomal copy
number and sequence studies can be filtered using expression arrays and functional proteomic assays (e.g. reverse phase
protein array). The resultant targets are likely to represent important ‘drivers’ of oncogenesis and can be mapped using
network analysis approaches into interconnecting pathways. The latter can then be used for the design of rational therapy
approaches in individual patients (from ref. 94 with permission).
128 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132

alpha in ovarian cancer (ClinicalTrials.gov). MORAb-003 has
received orphan drug designation by the Food & Drug Admin-
istration (FDA) for ovarian cancer.
3.14. Cell cycle inhibitors and extracellular matrix
inhibitors
MMP inhibitors (MMPI) enjoyed a brief limelight with some
effect on decreasing CA125 when given to patients with ovar-
ian cancer and ascites. However, joint toxicities discouraged
further development [90]. A less toxic MMPI, BAY 12-9566, was
studied in Phase III both in small cell lung cancer and ovarian
cancer in combination with first-line chemotherapy. Unfortu-
nately, no additive effect could be documented.

Flavopiridol was the prototypic cyclin inhibitor, but its further
development was discontinued in favor of newer drugs [90].
Ispinesib selectively inhibits the mitotic motor protein kinesin
spindle protein (KSP) and phase II studies are underway
(ClinicalTrials.gov). Also under development are a telomerase
inhibitor, GRN163L (Geron Corporation) and N-cadherin antag-
onists (Adherex Technologies, Inc.).
3.15. DNA methylation and acetylation
Preclinical models have established the rationale for using
DNA demethylating agents including azacitidine to reverse
chemoresistance in ovarian cancer [91]. Indeed, a phase IIa
study of a sequential regimen using azacitidine with carbo-
platin in patients with platinum resistant epithelial ovarian

Fig. 3 – Our current working concept regarding the mechanisms of ovarian carcinogenesis. During the menstrual lifetime of
a female, ovarian surface epithelial (OSE) cell damage and repair occur with each ovulation to facilitate release of the ovum.
This happens under the control of local paracrine hormone and growth factor release from the ovarian follicle and corpus
luteum in addition to cycling levels of gonadotrophins. Prolonged and aberrant exposure of OSE cells to local growth factors
leads to a risk of genomic changes; this may be facilitated by ‘cell trapping’ within epithelial inclusion cysts. Hereditary
predisposition to genomic damage increases the risk of early-onset ovarian cancer as occurs, for example, in BRCA1
mutation carriers. Early genomic changes include the histology-specific aberrations such as p53 mutation and lead to loss
of growth control. Aberrant OSE cells acquire the ability to control their own growth in an autocrine fashion with activation
of kinase signaling pathways and begin to differentiate inappropriately under the possible influence of excessive and
inappropriate hormone and growth factor exposure. The nature and duration of exposure may control the exact pattern of
homeobox gene expression as in embryonic development. Increasing genomic instability then ensues with further
autocrine growth stimulation and kinase activation.
 u p d a t e o n c a n c e r t h e r a p e u t i c s 3 ( 2 0 0 9 ) 119–132
cancer conducted at MDACC has demonstrated the ability of
a hypomethylating agent to reverse platinum resistance [92].
4. Future directions
A systems approach to the comprehensive integration of
information derived from studies of gene copy number aber-
rations (CNA) and from other high-throughput technologies
has the potential to improve our understanding of ovarian
carcinogenesis and to facilitate the development of effec-
tive combinatorial therapies to rational targets. Although the
identification of the ‘drivers’ of genomic aberrations remains
challenging, it represents an important effort that should
improve our understanding of ovarian cancer pathophysiol-
ogy and lead to improved patient management. Our group and
others have validated potentially important ‘driver’ genes in
ovarian cancer genomic aberrations [41,44–51]. Such valida-
tion requires the demonstration of alterations at the DNA, RNA
and protein levels, functional effects on the phenotypic behav-
ior of ovarian tumor cells and an impact on patient outcomes,
all observations that support a critical role for genes in ovarian
carcinogenesis and as potential targets for novel therapies.
It is likely that multiple ‘drivers’ exist for most genomic
aberrations in ovarian cancer and that these ‘drivers’ func-
tion in concert with other abnormalities such as mutations
during the development and selection of CNA structure. Fur-
ther, given the number and complexity of CNAs in ovarian and
other solid tumors, it is also likely that ‘driver’ genes act in a
coordinate fashion both within and between amplicons to gov-
ern the natural history and therapy responsiveness of these
tumors. A recent study of glioblastoma proposed coordinate
high-resolution analysis of CNAs, mutations, methylation,
and transcriptional profiles with integration of these data into
functional pathways or networks as a very efficient approach
to identify drivers and potential targets [93].
The generation of comprehensive data integrating genomic
aberrations with the transcriptional and functional pro-
teomic effects of these aberrations unearths the possibility of
applying a systems approach to understanding the complex
molecular interactions that contribute to ovarian carcino-
genesis (Fig. 2) [94]. Indeed, recent studies have begun to
demonstrate that an integrated view of complex copy number
and sequence alterations in cancer can identify a limited num-
ber of pathways that could prove useful for cancer diagnosis
and therapy [93,95]. Such advances will allow the development
of novel therapy strategies in cancer that exploit global path-
way activation patterns rather than the function of individual
targets. Since the development of resistance to novel treat-
ments frequently involves reactivation of the pathway that
mediated the oncogenic effects of the inhibited target [96],
this approach may be less susceptible to the development of
resistance than current targeted therapy approaches.
Further advances in CGH and sequencing technologies as
well as in the comprehensive assessment of large numbers
of tumors have the potential to provide higher resolution of
genomic aberrations. Technological advances such as molec-
ular inversion probe (MIP) profiling are also beginning to allow
comprehensive study of the genome in formaldehyde-fixed
paraffin-embedded (FFPE) samples since this will facilitate the
129
interrogation of large numbers of stored cancer samples with
long term follow up data. Ultimately, an improved ability to
combine information from global genomic, transcriptional,
proteomic and functional technologies (Fig. 2) to identify and
characterize cooperating events between multiple genes and
genomic aberrations will be necessary to address the com-
plexity of ovarian tumorigenesis.
5. Conclusion
Ovarian cancers are complex malignancies with significant
chromosomal instability which partly occurs as a result of
aberrant autocrine/paracrine stimulation and activation of
kinase signaling pathways. Fig. 3 shows our current con-
cept regarding the mechanisms of ovarian carcinogenesis. An
understanding of the relationship between histology-specific
genetic aberrations and the regulation of tissue histogene-
sis by HOX gene control is vital to the development of novel
agents for ovarian cancer treatment. It appears that we have
reached a plateau in the benefits associated with cytotoxic
chemotherapy drugs in ovarian cancer. A comprehensive com-
pilation of aberrant events and processes in ovarian cancer
will increase understanding of pathophysiology and provide
novel therapy targets. Although the list of genomic aberra-
tions in ovarian cancer is daunting, a systems approach and
the integration of therapies targeting multiple component ‘tar-
get’ genes of important genetic aberrations has potential in
treatment and in the potentiation of chemotherapy efficacy.
Indeed, synchronous targeting of coamplified oncogenes in
the 3q26 amplicon may more profoundly inhibit ovarian tumor
proliferation than the targeting of single genes. In the future, it
will be vital that information from new high-throughput tech-
nologies be integrated in the determination and validation of
potentially important therapy targets. This will require shar-
ing of databases and development of coordinating consortia. It
will also be necessary to define the optimal route of adminis-
tration for novel therapies and how best to schedule them with
cytotoxic chemotherapy. Our covenant with ovarian cancer
patients demands that we develop a new paradigm to make
more efficient progress towards improved management of this
devastating disease.
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