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Journal of Oncology 5

Table 2: PDGF-targeted therapies in ovarian cancer.

clinical trial.gov ID

Therapeutic regimen

Study PI

NCT00913835

Doxil

± IMC 3G3 in platinum refractory or resistant EOC

W. McGuire

NCT00768144

Sunitinib in refractory/recurrent ovarian, fallopian tube, or peritoneal cancer

S. Campos

NCT00437372

Sunitinib and radiation therapy

A.Dicker

NCT00792545

Dasatinib + bevacizumab in surgically metastatic, or unresectable solid tumors

E. Kohn

NCT00672295

Dasatinib + paclitaxel + carboplatin in ovarian, fallopian tube, and peritoneal

cancer

A. Secord

NCT00436215

Sorafenib + bevacizumab in recurrent/refractory ovarian, fallopian tube, or

peritoneal cancer

E. Kohn

NCT00526799

Sorafenib + topotecan in platinum resistant EOC

D. Matei

NCT00390611

Paclitaxel + carboplatin

± sorafenib for ﬁrst-line therapy for EOC

J. Hainsworth

NCT00096200,

Sorafenib + paclitaxel + carboplatin in recurrent platinum-sensitive ovarian,

fallopian tube, or peritoneal cancer

V. von Gruenigan

NCT00510653

Gleevac study for patients with ovarian cancer

D. Gershenson

NCT00840450

Gleevac and paclitaxel with recurrent mullerian cancers

F. Mug gi a

function of α-FR in cancers is not fully understood,

folates are critical metabolites for nucleotide synthesis and

methylation reactions. Its overexpression might confer a

tumor growth advantage by increasing folate availability to

cancer cells [75]. Over 90% of nonmucinous ovarian cancers

overexpress α-FR [76]

Several strategies have been employed to target the

folate receptor. Some of these include the use of anti-α-FR

antibodies or folic acid conjugates. There has also been recent

research to show that α-FR may have a potential as a target for

immunotherapeutic approaches in ovarian cancer. α-FR is

a tumor-associated antigen that induces detectable immune

responses in 70% of patients with breast and ovarian cancer

[77]. The presence of endogenous immune reactivity raises

the possibility that the immune response could be further

enhanced by vaccines targeting the α-FR. Hernando et al.

[78] presented a case of a women with recurrent epithelial

ovarian cancer treated with a vaccination regimen created

with autologous dendritic cells engineered with mRNA-

encoded α-FR [78]. An initial contrast-enhanced CT of

the abdomen before vaccination had shown para-aortic

lymph node metastasis at the level of the left renal hilus

and lower abdominal aorta. Follow-up CT 16 months after

last vaccination depicted a more than 50% regression of

lymph node metastasis and a dramatic decrease in CA125

concentrations 4 weeks after the ﬁrst vaccination [78].

Farletuzumab (MORAb-003) is a monoclonal antibody

to α-FR that activates antibody-dependent cell-mediated

cytotoxicity and complement-mediated toxicity [79]. In a

recent Phase II trial of 54 patients [80]withplatinum-

sensitive relapsed disease patients who received combination

therapy exhibited a prolongation of their remission when

compared to their previous remission. Ongoing clinical

trials looking at Farletuzumab include a Phase III trial

comparing the eﬃcacy and safety of intravenous carboplatin

and taxanes with and without farletuzumab in subjects with

ﬁrst platinum-sensitive relapse, a Phase II trial examining

intravenous paclitaxel with and without farletuzumab in

patients with ﬁrst platinum-resistant or refractory relapse.

EC145 is a drug that is speciﬁcally designed to enter

cancer cells via the folate vitamin receptor (FR). Early

clinical evidence in a small number of phase I patients

suggests that EC145 may have antitumor eﬀect in women

with advanced ovarian cancer. Current independent studies

include a study of EC145 in patients with advanced ovarian

and endometrial cancers (NCT00507741) and a study in

patients with platinum resistant ovarian cancer with a

combination of Doxil and EC145 Combination Therapy

(NCT00722592).

9. Poly-ADP-Ribose Polymerase (PARP)

Inhibitors

Between 5 and 10% of all ovarian cancer cases are associated

with inheriting a mutation in the BRCA1 or BRCA2 gene

[81]. The lifetime risk of ovarian cancer for BRCA1 and

BRCA2 mutation carriers is estimated at 40–50% and 10–

20%, respectively. BRCA1 and BRCA2 are essential for the

repair of double strand DNA breaks (DSBs) and maintenance

of genomic stability [82].

Poly (ADP-ribose) polymerase (PARP) is a key nuclear

enzyme involved in the repair of DNA single-strand breaks

(SSBs) using the base excision repair pathway [83]. PARP-1

and PARP-2 are the only members of the PARP family known

to be activated by DNA damage, and PARP-1 has been best

characterized. PARP inhibition results in the accumulation of

DNA SSBs, which may lead to DSBs. Thus, the use of PARP

inhibitors in BRCA mutation carriers uses the concept of

synthetic lethality and hence can be described a therapeutic

exploitation.

In the ﬁrst human phase I clinical trial using Ola-

parib (AZD2281, KU-0059436; AstraZeneca) an oral small-

molecule PARP-1 inhibitor, toxicities included nausea, vom-

iting, anorexia, and fatigue. Eﬃcacy has been reported.

Olaparib has shown antitumor activity in BRCA-associated

ovarian cancer [84, 85]. Fifty patients were treated at various

doses, of which 41 were BRCA1 mutation carriers, eight were

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