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6 Journal of Oncology

Table 3: α-folate receptor inhibitors and ovarian cancer.

Clinical trial.gov ID Therapeutic regimen Study PI

NCT00722592 Doxil and EC145in platinum resistant EOC R. Messmann

NCT00738699 MORAb-003 in ﬁrst platinum resistant or refractory relapsed EOC D. Chakraborty

NCT00849667 MORAb-003 in platinum sensitive, ﬁrst relapse EOC D. Chakraborty

BRCA2 mutation carriers and one had a compelling family

history for BRCA mutation. Of the 46 patients with evaluable

disease, 41% reached either a complete or partial response.

Eleven percent had meaningful stabilization of disease for

4 months, giving a total clinical beneﬁt rate of 52%. The

median response duration was 30 weeks.

Recently reported were the results of a phase II trial of

the oral PARP inhibitor Olaparib (AZD 2281) in BRCA-

deﬁcient advanced ovarian cancer [86]. An international,

phase II study examined two cohorts of patients that received

oral olaparib in 28-day cycles, initially at the MTD, 400 mg

bid (33 pts), and subsequently at 100 mg bid (24 pts). The

conﬁrmed overall response rate was 33% at 400 mg bid dose

and 12.5% at 100 mg bid dose. Clinical beneﬁt rate (ORR

and/or conﬁrmed

≥50% decline in CA125) was 57.6% at

400 mg bid and 16.7% at 100 mg bd. Toxicity was mild.

Olaparib is currently being evaluated in randomized

Phase II trials in platinum-sensitive recurrent ovarian cancer,

and in known BRCA or high grade recurrent ovarian

cancer. It is also being compared with pegylated liposomal

doxorubicin in patients with BRCA mutated ovarian cancer

with a 0-12 month platinum-free interval (NCT00628251).

Other PARP inhibitors are also being evaluated in

BRCA mutation carriers with cancer, including AG0146999

(Pﬁzer) ABT888 (Abbott), BSI-201 (Bipar), INO-1001

(Inotek/Genentech), and MK4827 (Merck).

The use of PARP inhibitors might be extended to

sporadic ovarian cancers with homologous recombination

defects. These sporadic tumors seem to phenocopy BRCA1/2

deﬁcient tumors even though they do not possess the

germline mutations in either gene. This phenomenon is

called “BRCAness.” This can occur due to loss of heterozy-

gosity, hypermethlyation, and haploinsuﬃciency (inactiva-

tion of one BRCA allele), thereby, genetically silencing the

BRCA gene without an actual germline mutation. A recent

study suggests that over 50% of high-grade serous ovarian

cancer had loss of BRCA function, either by genetic or

epigenetic events [87]. A randomized placebo-controlled

trial of olaparib as a maintenance therapy in patients with

serous (sporadic) ovarian cancer at high risk for recurrence

is now underway.

10. Aurora Kinase Inhibitors

Aurora kinases are protein kinases that are important mitotic

regulators [88, 89]. They are central to many cellular

functions notably mitosis, centromere separation, as well as

mitotic spindle formation. Three aurora kinases (A, B, C)

exist. The activity of aurora kinase is cell cycle dependent and

active during the G2M phase of the cell cycle. Several inves-

tigators [88, 90, 91] have described the oncogenic potential

of these proteins. Aurora-A also phosphorylates the tumor

suppressor protein p53, resulting cell cycle progression [92].

Aurora A is overexpressed in 83% of human epithelial

ovarian carcinomas [93]. In addition, ampliﬁcation of

human chromosome 20q13.2, which contains Aurora-A,

frequently occurs in ovarian cancer [94]. Aurora kinase A has

been signiﬁcantly associated with tumor grade, FIGO stage,

and survival [93, 95].

Lin et al. [96] studied the role of MK-0457, a small

molecule pan-aurora kinase inhibitor in ovarian cancer cell

models. Two chemosensitive human ovarian cancer cell lines,

HeyA8 and SKOV3ip1, were used to study the eﬀects of

aurora kinase inhibition. Additionally two chemoresistant

cell lines (Hey A8-MDR and A2780-CP-20) were also

studied. Both cell lines showed that aurora kinase inhibition

alone signiﬁcantly reduced tumor burden. Combination

treatment with docetaxel resulted in signiﬁcantly improved

reduction in tumor growth beyond that aﬀorded by doc-

etaxel alone (P < or

= .03). Scharer et al. [97] also reported

that aurora kinase inhibitors synergize with paclitaxel to

induce apoptosis in ovarian cancer cells.

Manfredl et al. [98] reported the antitumor activity of

MLN8054, an orally active small molecule inhibitor of aurora

kinase. Growth of human tumor xenografts in nude mice was

dramatically inhibited after oral administration of MLN8054

in human tumor xenografts. MLN8054 induced mitotic

accumulation and apoptosis. Given these ﬁndings MLN8054

is currently being explored in the management of patients

with platinum-refractory or resistant epithelial, fallopian, or

primary peritoneal carcinoma (NCT00853307).

11. Hedgehog Pathway Inhibitors

Hedgehog signaling plays a role in many processes such as

cell diﬀerentiation, growth, and proliferation. This pathway

is active during embryonic development and remains active

in the adult where it is involved in the maintenance of stem

cell populations.

The Hedgehog family [99] has several proteins which

function as signaling molecules. These include Sonic

hedgehog (Shh), Indian hedgehog (Ihh), and Desert

hedgehog (Dhh). There are two receptors that are in-

volved in the Hedgehog pathway. PATCHED1 is a

hedgehog receptor. In the absence of a ligand PATCHED1

inhibits SMOOTHENED, a transmembrane G-coupled

protein. However, when the ligand binds PATCHED1,

SMOOTHENED suppression is relieved resulting in

transcription of the Hedgehog genes. PATCHED1 or

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