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4 Journal of Oncology

ovarian cancer was conducted. Five partial responses in a

sample size of 45 patients (11%) were reported.

5. Epidermal Growth Factor Inhibitors

In addition to the VEGF inhibitors, the epidermal growth

factor receptor (EGFR) has emerged as an attractive target

[47–49]. The activation of EGFR signaling pathways is

known to increase proliferation, angiogenesis, and decrease

apoptosis. Several strategies that target the EGFR in gyne-

cologic cancers have included monoclonal antibodies [1–3],

(trastuzumab, pertuzumab, EMD7200) and tyrosine kinases

inhibitors [4–6] (geﬁtinib, erlotinib, lapatinib and CI-1033).

Bookman and colleagues [1, 50] reported a response rate of

7% in a phase II trial of ovarian cancer patients treated with

trastuzumab. Kaye et al. [51], Amler et al. [52], and Makhija

et al. [53] in independent studies examined pertuzumab, a

humanized recombinant monoclonal antibody that inhibits

the dimerization of HER2 with EGFR, HER 3, and HER4,

in patients with ovarian cancer. As a single agent there

were only modest responses. Gordan et al. [54] recently

published the clinical activity of pertuzumab in advanced

ovarian cancer. There were ﬁve partial responses (response

rate 4.3%), eight patients (6.8%) with stable disease lasting

at least 6 months, and 10 patients with CA-125 reduction

of at least 50%. Median progression-free survival (PFS) was

6.6 weeks. Twenty eight percent of the tumor biopsies were

pHER2+ by ELISA. Of note the progression free survival for

pHER2+ patients was 20.9 weeks (n

= 8) versus 5.8 weeks for

pHER2

−.

Several studies are ongoing. The EORTC have recently

completed a trial investigating erlotinib as maintenance

therapy following ﬁrst-line chemotherapy in patients with

ovarian cancer (NCT00263822). A phase II open label

trial of erlotinib and bevacizumab is being conducted by

Alberts et al. in patients with advanced ovarian cancer

(NCT00696670).

Unlike other disciplines there is lack of data in the

gynecological literature on who, if any, will beneﬁt from

EGFR inhibitors. Schilder et al. [55] reported that in a sample

size of 55 ovarian cancer patients 3.6% had mutations in

the EGFR tyrosine kinase domain and that the mutation

correlated with a response to geﬁtinib. Exploratory analyses

in the pertuzumab studies [51–53] suggested that patients

with platinum resistant disease and low levels of HER3

mRNA might beneﬁt from pertuzumab. An additional study

by Tanner et al. [56] demonstrated an inﬂuence of HER 3

expression on the survival of patients with ovarian cancer.

Selection of ovarian cancer patients with EGFR ampli-

ﬁcations, increased pHER2, and low expression of HER 3

ratios may represent the selected few that may respond to

EGFR inhibitors.

6. Combination Therapy with EGFR and

VEGF Inhibitors

EGFR activation has been reported to promote VEGF [57]

secretion. Several clinical studies are exploring the combi-

nation of EGFR inhibitors and VEGF inhibitors. Nimeiri

et al. [12] investigated the clinical activity and safety of

bevacizumab and erlotinib patients with recurrent ovarian,

primary peritoneal, and fallopian tube cancer. In this study

patients were heavily pretreated. Two patients had a fatal

bowel perforation.

Currently investigators at the Harvard Cancer Center

are conducting a randomized phase II trial of Beva-

cizumab or Bevacizumab and Erlotinib as First Line

Consolidation Chemotherapy after Carboplatin, Paclitaxel,

and Bevacizumab (CTA) Induction Therapy for Newly

Diagnosed Advanced Ovarian, Fallopian Tube and Primary

Peritoneal Cancer & Papillary Serous Mullerian Tumors

(NCT00520013) [20].

7. Platelet Derived Growth Factor Inhibitors

Platelet-derived growth factor (PDGF) a prototype for

understanding the function of growth factors and receptor

tyrosine kinases (TK) [58] induces cell growth and sur-

vival, transformation, migration, vascular permeability, and

wound healing [59]. PDGF receptor (PDGFR) activation

in cancer occurs as a consequence of gene ampliﬁcation,

chromosomal rearrangements, or activating mutations [60–

62]. PDGFR activation is critical to tumor initiation in

addition to functioning as a mediator of connective tissue

stroma [63].

PDGFR has been shown in 50–80% of ovarian tumors

[63]. Several agents that target the PDGFR have been studied.

These include imatinib mesylate [63–66], sorafenib, [17, 26],

sunitinib [25], dasatinib [67], 3G3 [68], and CDP 860 [69].

Imatinib mesylate is a selective Abl, c-Kit, and PDGFR

inhibitor. Three phase II clinical trials [64, 70, 71] in patients

with ovarian cancer failed to demonstrate clinical beneﬁt.

The GOG (170 M) is currently studying dasatinib in

a Phase II Evaluation of Dasatinib in the Treatment of

Persistent or Recurrent Epithelial Ovarian, Fallopian Tube,

or Primary Peritoneal Carcinoma

BIBF1120 [72] is a novel agent. It is a triple angiok-

inase inhibitor that targets the VEGFR, PDGRF, and the

ﬁbroblast growth factor receptor (FGFR). Sustained pathway

inhibition is a distinct feature of this agent. Ledermann et

al. [73] recently conducted a randomized phase II placebo-

controlled trial using maintenance therapy to evaluate the

vascular targeting agent BIBF 1120 following treatment of

relapsed ovarian cancer. The 36-week PFS rate for BIBF 1120

was 15.6% and 2.9% for placebo. The authors concluded

that maintenance BIBF 1120 could delay disease progression

in ovarian cancer patients who had previously responded to

chemotherapy.

8. Folate Receptor Inhibitors

Folic acid is an essential vitamin and of importance for

one-carbon transfer processes medicated by enzyme systems

involved in DNA synthesis [74]. Increased expression of

α-FR has been described in various tumor tissues, including

ovarian, endometrial, and breast cancer [75]. While the

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