Sage Journals: Discover world-class research

Abstract

Despite recent advances in the treatment of ovarian cancer, a large majority of women with this diagnosis will die from recurrence of their disease. Targeted therapies, in the form of monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly altered the management of many solid tumors and hematologic malignancies. No such agents have been approved by the US FDA for use in ovarian cancer, although Phase II data suggests excellent single-agent activity of some of these drugs. Antiangiogenic agents in combination with chemotherapy are being evaluated in Phase III clinical trials, both in the adjuvant setting and in recurrent platinum-sensitive disease. Poly-ADP-ribose polymerase inhibitors are promising agents in BRCA1/2-mutated breast and ovarian cancers. Ongoing clinical trials are exploring the anti-tumor effect of poly-ADP-ribose polymerase inhibitors administered as single agents and in combination with chemotherapy. Many other new drugs are in earlier grades of development. In this article, we review the state of the art in targeted therapies for ovarian cancer and identify future directions for their development in the management of this often devastating disease.

Keywords

ovarian cancer targeted agents

Ovarian cancer is the leading cause of death among malignancies of the female reproductive system throughout the developed world and the fifth most common cause of cancer-related mortality among women in the USA [1]. Although progress has been made in the treatment of ovarian cancer leading to improved overall survival (OS) rates compared with historic rates, 5-year survivals remain poor with only 46% of patients living beyond that time point [2]. This is due, in part, to a lack of accurate screening and early detection methods, resulting in a majority of ovarian cancers being diagnosed at advanced grades. The limited availability of effective systemic therapy and the development of chemotherapy-resistant disease also contribute to the poor survival figures. Only 20% of patients present with early-grade disease [2]. These patients have an excellent prognosis with a 5-year survival rate exceeding 80% [3].

The optimal postsurgical chemotherapeutic approach for patients with epithelial ovarian, fallopian tube or primary peritoneal cancer includes chemotherapy with a platinum-taxane doublet [4 –6]. The addition of a third cytotoxic agent to the standard carboplatin/paclitaxel combination fails to improve the OS [7]. Three randomized trials have demonstrated superiority of the combination of intraperitoneal (ip.) and intravenous (iv.) chemotherapy over iv. chemotherapy alone [8 –10]; however, challenges posed by its delivery and concerns over increased toxicity have resulted in the failure of this approach to gain widespread acceptance [11]. Disease relapse in ovarian cancer remains a common and ominous development, with median survivals of only 12–24 months following recurrence [12].

Improved understanding of tumor biology, cell signaling pathways and tumorigenesis has led to new insights into cancer therapy. The development of more effective systemic treatment strategies promises to substantially improve the poor prognosis for women with advanced ovarian cancer. Targeted agents have been successfully incorporated into the standard management algorithms for many tumor types. In this article, we will discuss the major advancements in targeted therapies for ovarian cancer and identify potential future directions of this broad category of anticancer treatments.

Targeting angiogenesis

Angiogenesis, the process of new blood vessel formation, is essential to sustainable tumor growth and metastasis, and is an important target in the treatment of gynecologic malignancies [13,14]. VEGF is a major contributor to angiogenesis. VEGF-A is the most important member of this subfamily of growth factors, which also includes VEGF-B, VEGF-C, VEGF-D, VEGF-E and PlGF [13].

Preclinical and in vitro data suggest a relationship between VEGF expression and gynecologic malignancies. Elevations in serum VEGF levels have been shown to be predictive of ovarian malignancy compared with benign masses [15]. In patients with ovarian cancer, elevated serum VEGF levels have been shown to predict for poor-prognosis features including ascites, more advanced grade, higher histologic grade and decreased OS [16 –19].

Anti-VEGF therapy

Clinical experience with single-agent bevacizumab

Bevacizumab is a humanized monoclonal antibody that inhibits VEGF and has shown promising activity in early-Phase clinical trials in ovarian cancer (Table 1). However, unexpectedly high rates of gastrointestinal perforation (GIP) in advanced-grade, heavily pretreated patients are prompting increased caution and identification of risk factors associated with bevacizumab administration.

Table 1.

Clinical trials of angiogenesis targets in ovarian cancer.

Target agent	Regimen/schedule	Design	n	Prior chemotherapy in n (%)	Platinum-resistant (%)	Response (%)	Median PFS (months)	Median OS (months)	Ref.
Bevacizumab	15 mg/kg every 21 days	Phase II	44	2 (52)	100	16	4.4	10.7	[20]
				3 (48)
Bevacizumab	15 mg/kg every 21 days	Phase II	62	1 (34)	58	21	4.7	17	[22]
				2 (66)
Bevacizumab	10 mg/kg every 14 days	Phase II	70	1–3	40	24	7.2	16.9	[27]
	Cyclophosphamide: 50 mg daily
Bevacizumab	10 mg/kg days 1 and 15 every 28 days	Phase II	22	1–2	100	22	N/A	N/A	[28]
	Topotecan: 4 mg/m² days 1, 8, 15 every 28 days
Bevacizumab	2 mg/kg weekly, 3 weeks on, one week off	Phase II	22	>1	N/A	36	>6 months	N/A	[29]
	PLD: 10 mg/m² weekly, 3 weeks on, 1 week off
Bevacizumab	15 mg/kg every 3 weeks, cycles 2–7	Phase II	24	>3	100	N/A	N/A	N/A	[30]
	PLD: 30 mg/m² every 3 weeks
Bevacizumab	15 mg/kg every 21 days, cycles 2–6	Phase II	20	0	0	80†	N/A	N/A	[31]
	Paclitaxel: 175 mg/m²
	Carboplatin: AUC = 5
Bevacizumab	15 mg/kg every 21 days with chemotherapy and in maintenance period (12 months)	Phase II	110	0	0	62	70% 1-year PFS	N/A	[32]
	Oxaliplatin: 85 mg/m²
	Docetaxel: 75 mg/m²
Bevacizumab	15 mg/kg every 3 weeks, cycles 2–6	Phase II	39	0	0	N/A	N/A	N/A	[33]
	Paclitaxel: iv. – 135 mg/m² day 1; ip. – 60 mg/m² day 8
	Cisplatin: ip. – 75 mg/m² day 2
Bevacizumab	15 mg/kg every 3 weeks, cycles 2–6	Phase II	22	0	0	N/A	N/A	N/A	[34]
Aflibercept	2 or 4 mg/kg every 14 days	Randomized, multicenter Phase II	162	2–3	(0 platinum-sensitive)	11	N/A	N/A	[37]
Cediranib (AZD2171)	30 mg/day‡	Phase II	47	0 (41)	57	17§	5.2	N/A	[42]
				1 (48)
				2 (11)
Cediranib (AZD2171)	30 mg/day‡	Multicenter	60	1	57	41	4.1	11.9	[43]
	Phase II
Sunitinib	50 mg daily for 4 of 6 weeks	Phase II	16	1–2	N/A	13	N/A	N/A	[47]
CA4P	CA4P: 63 mg/m² every 21 days, Paclitaxel: 175 mg/m²	Phase II	34¶	N/A	100	32#	N/A	N/A	[51]
	Carboplatin: AUC = 5
BIBF 1120	250 mg twice daily	Randomized	44††	N/A	N/A	N/A	4.8	N/A	[52]
	Phase II

†

By CA 125 normalization.

‡

Reduced from starting dose of 45 mg/day.

Derived from intent-to-treat analysis, n = 47.

Data available on 34 patients, total n = 44.

By GCIG criteria.

††

84 patients randomized to either BIBF 1120 or placebo with 44 receiving study drug.

AUC: Area under the curve; ip.: Intraperitoneal; iv.: Intravenous; OS: Overall survival; PFS: Progression-free survival; PLD: Pegylated liposomal doxorubicin.

Two Phase II clinical trials with single-agent bevacizumab have been conducted in ovarian cancer. In an industry-sponsored Phase II trial of 44 patients with platinum-refractory epithelial ovarian cancer (EOC) or peritoneal serous carcinoma, bevacizumab, 15 mg/kg every 21 days, has demonstrated a response rate of 15.9% and a median OS of 10.7 months [20]. This trial was closed prematurely because of a high rate of GIP (11%) compared with previous experience in other tumor types (1.5–2.4%) [21]. Analysis of the toxicity data from this trial suggested that incidences of GIP were seen primarily in more heavily pretreated patients (those receiving more than two prior regimens), in platinum-refractory EOC and in patients who demonstrated radiographic evidence of bowel wall thickening or bowel obstruction. This study also reported an unexpected rate of arterial thromboembolic events. Other bevacizumab-related complications such as grade 3 or 4 hypertension, proteinuria, bleeding, wound healing complications and venous thromboembolic events were seen at the anticipated rates.

A similar Gynecologic Oncology Group (GOG) study utilizing the same schedule of single-agent bevacizumab in persistent or recurrent EOC and primary peritoneal cancer showed promising clinical activity without the GIP complications reported in the previous clinical trial [22]. GOG 170-D enrolled patients with both platinum-sensitive and platinum-resistant disease who had received two or fewer previous chemotherapy regimens. A RR of 21% and a median OS of 17 months were reported in 62 patients treated on this study. Expected toxicities were seen; however, no GIP was observed. The differences in the complication rates reported by these two studies might be explained by differences in eligibility. The industry trial included only women with primary or secondary platinum-resistant disease who had a higher number of prior regimens (half of the study population had received three prior regimens). The GOG study enrolled both platinum-sensitive and platinum-resistant patients and allowed up to two prior regimens.

A recent meta-analysis suggests that bevacizumab remains a significant risk factor in the development of GIP in cancer treatment, occurring in 0.9% of treated patients with a mortality rate of 22% [23]. The rate of GIP may be as high as 4.8% in ovarian cancer [24] and continued vigilance is recommended when incorporating bevacizumab into future clinical trials in ovarian cancer. A small series of 13 patients with recurrent ovarian and fallopian tube cancer combining bevacizumab with the EGFR inhibitor, erlotinib reported an increased rate (15%) of bowel perforations [25].

Bevacizumab in combination with chemotherapy

When added to chemotherapy, bevacizumab has demonstrated improved outcomes and tolerability in both metastatic colorectal cancer and non-small-cell lung cancer [21,26]. Phase II trials of bevacizumab in combination with chemotherapy in recurrent ovarian cancer have shown encouraging clinical activity and acceptable toxicity profiles.

The combination of bevacizumab and low-dose metronomic oral cyclophosphamide in 70 patients with EOC who received 1–3 previous lines of chemotherapy showed a RR of 24% and a median OS of 16.9 months [27]. Four episodes of GIP (6%) were observed, but no predictive factors were identified.

A Phase II trial of weekly topotecan and bevacizumab in 22 patients with platinum-refractory ovarian or primary peritoneal cancer showed similar results, with a partial response (PR) rate of 22% and stable disease (SD) in 28% of patients [28]. Study participation was limited to patients who had previously received a maximum of two chemotherapy regimens. No patients discontinued the study owing to treatment-related toxicity and no bowel perforations were observed.

Small trials of bevacizumab in combination with pegylated liposomal doxorubicin (PLD) have also been recently reported. In a trial of 22 patients with recurrent ovarian cancer previously treated with chemotherapy receiving weekly PLD and bevacizumab, a complete response (CR) rate of 9% and a PR rate of 27% were reported [29]. GIP was observed in one patient and hypertension was reported as being manageable. Preliminary toxicity data from another Phase II study of PLD and bevacizumab in platinum-resistant ovarian cancer also suggest that this doublet is well-tolerated [30].

Bevacizumab in combination with first-line chemotherapy

The combination of carboplatin and paclitaxel plus bevacizumab as a first-line strategy was reported in a trial of 20 patients with advanced grade epithelial ovarian cancer, following cytoreductive surgery [31]. Bevacizumab was administered with cycles two through to six. The overall RR, defined by normalization of CA-125 levels, was observed in 80% of patients with 30% showing CRs and 50% showing PRs. No GIP or wound complications were observed, and grade 3 hypertension was observed in only 10% of the study subjects. More recently, the preliminary results of a Phase II study of a novel chemotherapeutic regimen of oxaliplatin and docetaxel plus bevacizumab followed by maintenance bevacizumab every 3 weeks for a total of 12 months of therapy after debulking surgery for ovarian, primary peritoneal or fallopian tube cancer has been reported [32]. A total of 110 subjects were included in the toxicity analysis; 55 patients had measurable disease and 61% of patients were optimally debulked. The CR rate was 32.8% and the PR rate was 29.1% with a 1-year progression-free survival (PFS) estimated at 70.1%. One episode (1%) of GIP was reported and 9% of patients experienced grade 3 or 4 hypertension.

Data are also emerging from trials of bevacizumab and ip. chemotherapy regimens in the setting of first-line therapy for optimally debulked patients with ovarian or primary peritoneal cancer. In a Phase II study of 39 women with optimally debulked grade II or III ovarian cancer, patients received iv. and ip. paclitaxel, ip. cisplatin and iv. bevacizumab as first-line therapy [33]. This was followed by the continuation of bevacizumab every 3 weeks for 17 treatments. This regimen appears to be feasible and appropriate for further study. One patient (2.5%) died following dehiscence of a colonic anastamosis and three episodes (8%) of grade 3 small bowel obstructions were noted. Another Phase II trial (n = 22) of iv. bevacizumab, iv. paclitaxel and ip. cisplatin followed by bevacizumab consolidation in optimally debulked ovarian cancer reported no additional acute toxicities related to bevacizumab [34].

Ongoing Phase III trials of bevacizumab in ovarian cancer

The encouraging results of these Phase II clinical trials have prompted the GOG to initiate Phase III trials of bevacizumab in combination with chemotherapy both in first-line treatment (GOG 218 and GOG 252) and in recurrent platinum-sensitive disease (GOG 213) (Table 2). These trials aim to determine the benefit of bevacizumab in combination with iv. (GOG 218) and ip. chemotherapy (GOG 252). The primary objective of both trials is PFS. GOG 218, which closed to accrual in June 2009, was also designed to examine the potential role of maintenance bevacizumab. Bevacizumab 15 mg/kg is administered every 3 weeks in both studies, with maintenance bevacizumab continuing for an additional 48 weeks. The chemotherapy used in GOG 218 consists of the standard regimen of carboplatin and paclitaxel iv. given every 3 weeks. Although the study has yet to be officially presented, preliminary reports suggest a PFS benefit at 1 year in the group of patients receiving maintenance bevacizumab compared with chemotherapy alone [201]. GOG 252 is a three-arm trial comparing novel versus standard regimens of iv. paclitaxel, and ip. cisplatin versus ip. carboplatin versus iv. carboplatin–paclitaxel with the addition of bevacizumab to all three trial arms. Bevacizumab 15 mg/kg is administered every 3 weeks, both concurrently and as maintenance therapy. The continued use of bevacizumab in GOG 252 will be contingent on the results of GOG 218.

Table 2.

Bevacizumab Phase III trial summary.

Study	Eligibility	Regimens	Primary end point	Secondary end point(s)
GOG 213†	Platinum-sensitive recurrent ovarian or primary peritoneal carcinoma	Carboplatin + paclitaxel	OS	PFS, toxicity
		vs
		Carboplatin + paclitaxel + bevacizumab (15 mg/kg) + maintenance bevacizumab
GOG 218	Optimally or suboptimally debulked grade III/IV ovarian cancer	Carboplatin + paclitaxel + placebo followed by maintenance placebo for a total of 15 months	PFS	OS
		vs
		Carboplatin + paclitaxel + bevacizumab (15 mg/kg) followed by maintenance placebo
		vs
		Carboplatin + paclitaxel + bevacizumab (15 mg/kg) followed by maintenance bevacizumab (15 mg/kg)
GOG 252	Optimally or suboptimally debulked grade II-IV ovarian, primary peritoneal or fallopian tube carcinoma	iv. carboplatin (AUC = 6) + iv. paclitaxel (80 mg/m² days 1, 8, 15) + bevacizumab (15 mg/kg) followed by maintenance bevacizumab	PFS	OS, toxicity, QOL
		vs
		ip. carboplatin (AUC = 6) + iv. paclitaxel (80 mg/m² days 1, 8, 15) + bevacizumab (15 mg/kg) followed by maintenance bevacizumab
		vs
		iv. paclitaxel (135 mg/m² day 1) + ip. cisplatin (75 mg/m² day 2) + ip. paclitaxel (60 mg/m² day 8) + bevacizumab (15 mg/kg) followed by maintenance bevacizumab
ICON7	Grade IIB-IV ovarian cancer and poor-risk grade I	Carboplatin (AUC = 6) + paclitaxel (175 mg/m²)	PFS	OS
		vs
		Carboplatin (AUC = 6) + paclitaxel (175 mg/m²) + bevacizumab (7.5 mg/kg) + maintenance bevacizumab
OCEANS trial	Platinum-sensitive recurrent ovarian, primary peritoneal or fallopian tube carcinoma	Carboplatin (AUC = 4) + gemcitabine (1000 mg/m² days 1, 8) + placebo iv.	PFS	Response, OS, toxicity, GI perforation
		vs
		Carboplatin (AUC = 4) + gemcitabine (1000 mg/m² days 1, 8) + bevacizumab (15 mg/kg)

†

Patients determined not to be candidates for secondary cytoreductive surgery will be randomized to receive carboplatin plus paclitaxel chemotherapy or the same chemotherapy plus bevacizumab.

AUC: Area under the curve; GI: Gastrointestinal; GOG: Gynecologic Oncology Group; ICON7: The seventh International Collaborative Ovarian Neoplasm study

ip.: Intraperitoneal; iv.: Intravenous; OCEANS: Ovarian Cancer Evaluation of Avastin and Safety; OS: Overall survival; PFS: Progression-free survival; QOL: Quality of life.

In platinum-sensitive recurrent ovarian or primary peritoneal carcinoma, GOG 213 will explore two principal hypotheses. First, this study has been designed to evaluate the role of secondary surgical cytoreduction in recurrent ovarian cancer; and second, it has been designed to determine the utility of adding bevacizumab to second-line carboplatin and paclitaxel to improve OS.

The seventh International Collaborative Ovarian Neoplasm (ICON7) study, comparing standard chemotherapy with and without bevacizumab, completed accrual of 1528 patients in February 2009. This large, international trial randomized high-risk early grade (FIGO grade I or IIA, clear cell or grade 3 carcinoma) and advanced grade (FIGO grade IIB or greater, all grades and all histological subtypes) ovarian cancer patients to receive standard carboplatin and paclitaxel versus chemotherapy plus bevacizumab at 7.5 mg/kg every 3 weeks for six cycles followed by maintenance bevacizumab for an additional 36 weeks. This study, along with GOG 218 and 252, promises to further define the role of first-line bevacizumab.

Another ongoing Phase III study will explore the combination of bevacizumab with carboplatin and gemcitabine (Ovarian Cancer Evaluation of Avastin and Safety-AVF4095s [OCEANS trial]).

Other targets in the VEGF pathway: VEGF trap

Other strategies to target the VEGF pathway include the administration of VEGF-trap, a fusion protein designed to bind VEGF-A. VEGF-trap binds and neutralizes all forms of VEGF-A as well as PlGF and has been shown to decrease tumor burden, inhibit ascites formation and initiate vascular remodeling in preclinical ovarian cancer models [35]. Preliminary results of a multicenter, randomized, Phase II study of VEGF-trap (aflibercept) given as a single agent at 2 or 4 mg/kg iv. every 14 days, were reported [36]. The study accrued 162 heavily pretreated patients including those with two or three previous chemotherapy regimens. Five patients (11%) achieved a PR. Serious adverse events included 4% of patients with hypertension and 2% with GIP. Final results are pending.

Inhibition of angiogenesis by small molecule kinase inhibitors

Several agents, including tyrosine kinase inhibitors of the VEGF pathway and multikinase inhibitors with VEGF inhibitory properties, have shown promise in early Phase studies in ovarian cancer.

Cediranib (AZD2171) is a potent orally bioavailable tyrosine kinase inhibitor (TKI) of VEGFR-2 (kinase insert domain receptor [KDR]) activity, an important mediator of VEGF-induced effects [37]. Phase I trials of cediranib showed evidence of clinical activity and tolerability at the maximally tolerated doses of 30 or 45 mg/day [38 –40].

A Phase II study of cediranib enrolling 47 patients with recurrent EOC demonstrated a clinical benefit rate (defined as CR, PR, SD >16 weeks or CA-125 nonprogression of greater than 16 weeks) of 30% [41]. The initial starting dose of 45 mg/day was decreased to 30 mg/day after the first 11 patients experienced increased toxicity. The adverse events reported on this study were similar to other TKIs of the VEGF pathway, including hypertension (46%), fatigue (24%) and diarrhea (13%). No bowel perforations were observed. The stated overall RR of 17% may be underestimated as this figure incorporated an intent-to-treat analysis. A total of 11 patients who were treated at 45 mg/day were censored from response analysis. The median PFS of 5.2 months was comparable to Phase II studies of bevacizumab in EOC [20,22] and the median OS has yet to be determined.

Another early trial of cediranib in relapsed or persistent ovarian cancer demonstrated that a daily dose of 30 mg was better tolerated than 45 mg/day [42]. Overall response and prolonged stable disease rates were 41 and 29% for platinum-sensitive and platinum-resistant disease respectively, suggesting potential activity. The median time to progression and median survivals were 4.1 and 11.9 months respectively with no significant differences between groups.

Pazopanib (Votrient®) is an orally bioavailable multitargeted receptor TKI of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α/β and c-kit approved by the FDA in October 2009 in the treatment of patients with advanced renal cell carcinoma. Early Phase II trial results of pazopanib in advanced, previously treated ovarian cancer showed activity as a single agent with response by reduction in CA-125 levels noted in 47% of patients [43]. The most common toxicities were diarrhea and elevation of liver enzymes.

Ongoing Phase III trials

A randomized Phase III international study in patients with platinum-sensitive ovarian cancer (ICON6) will compare standard carboplatin and paclitaxel with and without cediranib (AZD 2171), given concurrently and as maintenance therapy. The accrual goal is 2000 patients randomized to one of three treatment arms, including the reference arm (A) which is chemotherapy alone, versus chemotherapy with concurrent cediranib (arm B), versus chemotherapy with concurrent cediranib plus maintenance cediranib (arm C).

A Gynecological Cancer Intergroup (GCIG) trial of pazopanib (AGO-OVAR 16) is a randomized, double-blind, placebo-controlled study in ovarian cancer designed to evaluate pazopanib monotherapy in patients who have not progressed following standard first-line chemotherapy. The goal duration of study-drug therapy is 12 months. This study opened in 2009 with an accrual goal of 900 subjects.

Other agents under investigation

Sunitinib malate is an oral multitargeted TKI with antitumor and antiangiogenic activity via inhibition of the VEGF and platelet-derived growth factor receptor pathways [44,45]. Sunitinib has undergone small-scale early-phase trials in EOC. Preliminary results from the National Cancer Institute of Canada Clinical Trials Group IND 185 study showed activity and tolerability in advanced ovarian cancer [46].

Combretastatin A-4 phosphate (CA4P) is a novel tubulin-binding vascular-disrupting agent that has been shown to decrease tumor blood flow in animal models and Phase I human subject trials [47,48], and may potentiate antitumor activity of cytotoxic chemotherapy [49]. CA4P has been studied in combination with carboplatin and paclitaxel in a Phase II study of patients with platinum-resistant EOC and appears to increase the RR of chemotherapy without adding significant toxicity [50]. A Phase III trial of CA4P is anticipated.

BIBF 1120 (Vargatef™) is a triple angiokinase inhibitor that targets VEGFR, PDGFR and FGF. A randomized Phase II placebo-controlled study of BIBF 1120 in relapsed EOC showed delayed disease progression with a 36-week PFS rate of 15.6% in the study arm compared with 2% in the placebo group [51]. Gastrointestinal toxicities and transaminitis occurred more frequently in the BIBF 1120 arm.

Vandetanib (ZD6474), a multitargeted TKI with activity against KDR/VEGFR-2 and EGFR [52], is currently undergoing Phase II evaluation in EOC (NCT00445549). CP 547,632 is an orally bioavailable multikinase inhibitor with activity against VEGFR-2 and basic FGFR kinase [53] and is also undergoing Phase II trials in recurrent EOC (NCT00096239).

Inhibition of Erb family pathways

The Erb family of transmembrane receptors includes EGFR or HER1/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 [54]. Increased EGFR expression has been reported in 19–98% of epithelial ovarian cancers [55 –57] and has been shown to be a predictor of poor-prognosis disease [58 –60]. However, clinical trials of EGFR inhibitors in ovarian cancer, either in the form of small molecule TKIs or monoclonal antibodies directed at cell surface receptors, have been mostly disappointing.

Erlotinib (Tarceva®), an orally available small molecule EGFR/HER1 TKI, showed minimal antitumor single-agent activity, with 6% overall response noted in a Phase I–II study in recurrent advanced ovarian cancer [61]. A total of 44% of patients on this trial had stable disease and the 1-year survival rate was 35%, suggesting that erlotinib, similar to other targeted agents, may contribute to disease stabilization rather than inducing a response. However, valid interpretation of such findings in small trials is difficult and may simply reflect patient selection and natural disease course. Patients on this study had EGFR-positive disease by immunohistochemistry, but there was no correlation between EGFR expression and response to therapy. The treatment was well tolerated, with the dose-limiting toxicity being diarrhea. Rash was a commonly encountered toxicity and, as has been noted in studies of erlotinib in other tumor types [62], increased severity of the rash was associated with improved survival.

A feasibility study of erlotinib in combination with first-line docetaxel 75 mg/m² and carboplatin area under the curve of 5 in patients with ovarian cancer, established an maximally tolerated dose (MTD) for erlotinib of 75 mg/day, with dose-limiting toxicities including persistent diarrhea and emesis [63]. The MTD of 75 mg/day was lower than that established in other combination trials, perhaps owing to the additive toxicities of carboplatin and docetaxel. The overall RR was modest at 52%.

Gefitinib (Iressa®), another TKI of EGFR, was evaluated as a single agent in Phase II trials in recurrent ovarian cancer and has shown disappointing results [64,65]. As observed in similar studies with erlotinib, a small number of patients had prolonged (>6 months) PFS [65], which on this study was correlated with EGFR expression. A Phase II trial of gefitinib and tamoxifen in platinum-resistant or refractory disease did not demonstrate any clinically significant activity [66].

Cetuximab (Erbitux®) is a monoclonal antibody that inhibits the activity of EGFR by effectively competing for cell surface receptor binding with EGF ligands. Cetuximab demonstrated only minimal activity as a single agent in epithelial ovarian cancer and failed to improve the response and the survival rates when added to chemotherapy [67 –69], despite attempts to dose cetuximab based on the skin acneiform rash, which correlated with activity in other tumor types [70].

Targeting HER2

Abnormal expression of HER2 has been observed in a number of solid tumor types, most notably in breast cancer where HER2 gene amplification occurs in approximately 30% of invasive tumors and confers a poor prognosis [71]. HER2 overexpression in ovarian cancer is also associated with decreased survival and poor prognosis; however, estimates of its frequency vary widely in the published literature, from 6.6 to over 50% [72].

A Phase II trial of single-agent trastuzumab in recurrent ovarian cancer showed minimal activity, with a reported overall RR of 7% [73]. Of the screened population, only 11% demonstrated HER2 overexpression. Another Phase II trial investigating the addition of trastuzumab to carboplatin and paclitaxel in patients with resistant advanced ovarian cancer demonstrated similar low rates of HER2 overexpression in only 6.4% of 320 screened patients [74]. Of the 20 with HER2-positive disease, only seven met eligibility criteria. However, three of the seven patients achieved a CR, suggesting that the addition of trastuzumab to platinum-based chemotherapy may reverse platinum resistance in HER2-positive ovarian cancer.

Pertuzumab (Omnitarg™) is a humanized monoclonal antibody that inhibits dimerization of HER2 with other ligand-activated HER receptors, independently of HER2 expression levels [75,76]. This suggests a more promising role of pertuzumab compared with trastuzumab in ovarian cancer, where HER2 expression is limited. Single-agent pertuzumab has minimal activity (RR 4%) [77], but its addition to gemcitabine chemotherapy appears to significantly improve activity. In a randomized Phase II trial of 135 patients with relapsed, platinum-resistant ovarian cancer, gemcitabine plus pertuzumab showed an improved RR and a trend toward improved PFS compared with gemcitabine plus placebo [78]. The study also suggests that low HER3 mRNA expression, a possible marker of aggressive chemoresistant disease, may predict for response to pertuzumab.

A Phase II trial of lapatinib, a TKI of EGFR and HER2 in combination with topotecan in recurrent ovarian cancer was terminated early owing to poor activity [79].

In summary, EGFR and HER2/neu inhibitors have not demonstrated significant single-agent activity in ovarian cancer and there is little to suggest that combining these agents with chemotherapy will be an effective strategy.

PARP inhibition

Poly ADP-ribose polymerase-1 (PARP1) is an enzyme that serves a key role in the repair of DNA single-strand breaks via base-excision repair [80]. Loss of PARP1 activity leads to accumulation of double-stranded DNA breaks, which, in normal cells, may be repaired via homologous recombination [81]. BRCA1 and BRCA2 are tumor-suppressor genes that code for proteins that are integral to the homologous recombination repair mechanism. Tumor cells that have lost BRCA1 or BRCA2 function may therefore become vulnerable to the accumulation of DNA damage and cell death by inhibition of PARP via a process termed synthetic lethality [82]. In the era of personalized medicine, PARP inhibitors have garnered much attention in the treatment of BRCA½-mutated cancers, including breast, prostate and ovarian cancer.

A Phase I study of the oral PARP inhibitor olaparib (AZD2281) has been reported [83]. This study was initially open to patients with advanced solid tumors, but in the expansion phase, only patients with BRCA1 or BRCA2 gene mutations were enrolled. Significant activity to olaparib was seen only in mutation carriers. A total of 12 of the 19 (63%) patients with BRCA-mutated ovarian, breast or prostate cancers had a clinical benefit from treatment with olaparib, defined as radiologic or tumor-marker response or stable disease for a period of 4 months or more. This agent has a favorable toxicity profile with most toxicities limited to grade 1 or 2 nausea, fatigue, vomiting and anorexia. A low incidence of myelosuppression was observed.

A Phase II trial of olaparib in BRCA-deficient advanced ovarian cancer has also been recently reported [84]. This study enrolled patients with chemotherapy-refractory BRCA-mutated ovarian cancer. The study design included two patient cohorts treated with olaparib, 400 mg twice daily (n = 33) and 100 mg twice daily (n = 24). Patients received continuous oral olaparib in 28-day cycles. The rationale for the treatment dose and schedule was based on the Phase I study mentioned above. At the interim analysis, the overall response rate (ORR), which represented the primary efficacy end point, was 33% at the 400-mg dose level compared with 12.5% at the 100-mg dose level. The clinical benefit rate, defined as ORR and/or more than 50% decline in CA-125 level, was 57.6% at 400 mg b.i.d. compared with 16.7% at 100 mg. Olaparib was well tolerated with primarily grade ½ toxicity observed.

In addition to olaparib, multiple PARP inhibitors including AG0146999 (Pfizer), ABT-888 (Abbott) and BSI-201 (BI Par) are undergoing evaluation in Phase I and Phase II clinical trials. These studies will explore PARP inhibitors as a monotherapy and in combination with chemotherapy. For some of these agents, the optimal treatment schedule (i.e., intermittent vs continuous administration) and the most effective doses have yet to be defined. In ovarian cancer, PARP inhibitors are being investigated both in BRCA-associated and sporadic ovarian cancer.

There has also been increasing interest in PARP inhibitors in treating platinum-resistant disease. Preclinical data suggest that inhibition of PARP can increase platinum chemosensitivity or reverse platinum resistance [85]. In a BRCA-associated mouse breast cancer model, the addition of the PARP inhibitor AZD2281 to cisplatin has been shown to significantly increase recurrence-free and OS compared with carboplatin or cisplatin alone [86]. However, early clinical trials have produced unclear or contradictory results with regard to platinum-resistant and platinum-sensitive ovarian cancer [84,85]. One reason may be the development of secondary BRCA mutations, consistent with restoration of BRCA2-mediated DNA repair function [87]. Ongoing clinical trials may help to better define the target populations of women with ovarian cancer that would benefit from PARP inhibitors.

Folate receptor-α

Folate receptor-α (FRα) is a folate-binding protein that is overexpressed in greater than 70% of ovarian cancers but is only rarely present in normal tissue [88,89]. FRα is implicated in tumor proliferation, possibly owing to growth advantages provided by upregulation of folate transporters in rapidly dividing cells [89]. MORAb-003 is a humanized monoclonal antibody with strong affinity for FRα that inhibits growth of FRα overexpressing ovarian cancer cells in vitro [88]. A Phase II trial of MORAb-003 added to a platinum–taxane doublet in first relapse for platinum-sensitive ovarian cancer showed significantly increased ORR (by CA-125 normalization) compared with historical rates with the platinum–taxane combination alone [90]. The RR following two cycles of therapy was 58%; 88% of patients completed four cycles, and 100% of patients completed six cycles. No unanticipated toxicities were reported. Further trials in platinum-sensitive and platinum-resistant disease are planned.

PI3K/AKT/mTOR cell signaling pathway

Mammalian target of rapamycin (mTOR) is a protein kinase, which, as part of the mTORC1 and mTORC2 complexes, is thought to have a key role in the proliferation and angiogenesis of human cancers via the phosphoinositide-3-kinase (PI3K)/AKT cell signaling pathway [91,92]. Dysregulation of this pathway appears to be important in the development of many tumors, including ovarian cancer, and is an attractive target for novel therapy [93,94]. The mTOR inhibitors temsirolimus (Torisel®) and everolimus (Afinitor, RAD001) have been shown to be active in the treatment of renal cell carcinoma and are approved by the FDA for that indication [95,96].

The overexpression of mTOR or activation of the PI3K/AKT/mTOR pathway is not observed in normal ovarian tissue, but is common in ovarian malignancies and may be of prognostic significance [97,98]. Preclinical studies in ovarian cancer xenograft models showed that everolimus inhibited tumor growth, angiogenesis and tumor invasiveness and enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity [99]. Other preclinical data suggest that dual targeting of VEGF-A and mTOR may produce additive antitumor effects [100,101]. The results of GOG 248, a randomized Phase II trial of temsirolimus with and without concomitant hormonal therapy, are pending. Other clinical trials involving mTOR and PI3K-targeting agents are also ongoing. A multi-institutional Phase II trial sponsored by the National Cancer Institute Clinical Trials Evaluation Program of temsirolimus and bevacizumab in combination is currently ongoing.

Hormonal therapy

Endocrine therapy is a mainstay of breast cancer treatment, owing to the sensitivity of hormone receptor-expressing tumors to hormonal manipulations. A majority of ovarian cancers are known to express estrogen receptors, and response to hormonal therapy may be predicted by the degree of estrogen receptor expression [102].

A Cochrane review updated in 2002 compiled data from 11 nonrandomized series and two randomized trials [103]. A total of 60 of 623 patients treated on these protocols (9.6%) had an objective RR and 31.9% had stable disease of 4 weeks or more. The RRs reported by the individual studies varied widely, from zero to 56%. Despite this activity, the authors concluded that there is no reliable evidence that tamoxifen either prolongs survival or leads to an improved quality of life. Another review of tamoxifen in ovarian cancer reported an ORR of 13%, but suggested that this figure may be an underestimation of the activity of antiestrogen therapy since many patients who received tamoxifen had been heavily pretreated with chemotherapy [104].

Other interest in tamoxifen has grown from preclinical evidence that hormonal blockade may be important in reversing resistance to chemotherapeutic agents, particularly to platinum compounds vital to current ovarian cancer management [105 –107]. Two studies of combination therapy with platinum chemotherapy and tamoxifen have shown conflicting results. One Phase II trial of platinum (cisplatin or carboplatin) plus tamoxifen in 50 patients with relapsed or persistent ovarian cancer following platinum-based chemotherapy reported a 50% ORR (30% CR) with a median duration of 8.5 months [108]. A similar trial of carboplatin plus tamoxifen found no activity, either by measurable disease or CA-125, among 14 patients with relapsed or persistent disease [109]. This disparity may have been due to the fact that the latter study consisted of more heavily pretreated subjects with 71% deemed to have ‘taxane-resistant’ disease.

Aromatase inhibitors have also been studied in ovarian cancer. Initial trials with letrozole (Femara™) and anastrazole (Arimidex™) demonstrated the approach to be well-tolerated but with minimal antitumor activity [110,111]. However, these studies did not prospectively select patients with hormone receptor-positive disease. A study of letrozole in preselected ER-positive relapsed ovarian cancer showed a RR of 17% by CA-125 (>50% decrease) and 9% by radiographic criteria [112]. Radiographic SD was observed in 42% of patients and 26% had PFS greater than 6 months. Response was predicted by low HER2 expression.

A Phase II trial of exemestane (Aromasin®) in refractory ovarian cancer reported stable disease of greater that 14 weeks in eight of 22 patients (36%), with a median duration of 23 weeks [113]. One patient had prolonged disease stabilization exceeding 95 weeks. All patients on this trial received prior chemotherapy with platinum/taxane combinations; 68% had received two prior lines of chemotherapy.

A small Phase II study of fulvestrant (Faslodex®), an estrogen receptor antagonist without agonist effect, in multiply recurrent ER-positive ovarian cancer has been reported [114]. In this heavily pretreated cohort (median number of previous chemotherapeutic regimens: 5; range: 2–13), activity was low, with an overall RR of 8%; however, stable disease was observed in 50% of patients (by Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and the median time to progression was 62 days.

Future perspective

With the pace of development of novel targeted therapeutics for all cancer types increasing, the need to identify new strategies for their application becomes ever more important. The term ‘targeted therapy’ implicitly suggests that molecular biomarkers may be used, at least theoretically, to predict for clinical response to agents targeting those molecules. In breast cancer, ER, PR and HER2 have been prospectively validated as predictive biomarkers for both response and survival and are used routinely in clinical settings as a means of determining appropriate therapy [115 –117]. Retrospective studies in non-small-cell lung cancer have shown mutations in the EGFR gene to be an independent predictor for response in patients receiving treatment with an EGFR TKI (gefitinib) [118 –120].

Such clinically validated predictive biomarkers for ovarian cancer have yet to be incorporated into clinical practice. Although VEGF expression has been shown to have prognostic value in preclinical and retrospective studies in ovarian cancer, it has not been correlated prospectively to clinical benefit from VEGF inhibitors such as bevacizumab. Similarly, germline mutations in BRCA promise to predict for response to PARP inhibitors; however, these data have yet to be substantiated.

The results of pivotal trials of bevacizumab, both in front-line treatment (GOG 218, 252 and ICON7) and recurrent platinum-sensitive disease (GOG 213) will help to determine the role of this agent in ovarian cancer management. Based on results from Phase II studies of single-agent bevacizumab, this drug is perhaps the most promising of the investigational agents discussed in this review to win approval from the FDA in the near future. However, its role either as an additive to first-line chemotherapy or as maintenance therapy has yet to be substantiated; in addition, the identification of factors that may predict for serious adverse toxicities, such as gastrointestinal perforation, is pending.

PARP inhibitors have also demonstrated clear promise, particularly with respect to BRCA½-mutated ovarian cancers. However, as a class their path to final approval is, at present, in its early grades, since optimal doses and treatment schedules still have to be determined.

Another matter that merits discussion is that of determining how targeted therapies will be evaluated in the future. In addition to measures of survival, the RR, based on the RECIST, has traditionally been used to assess the efficacy of cytotoxic agents. However, clinical trials evaluating targeted therapies in solid tumors have demonstrated that some agents may produce high rates of prolonged disease stabilization in the absence of significant RRs [121 –123]. Such findings suggest that tumor RRs may be less important in assessing the efficacy of targeted agents and highlight the need for establishing more appropriate statistical end points. Other data, such as pharmacological effects and disease stabilization may be more relevant in determining the utility of targeted therapies.

Executive summary

Angiogenesis-targeting agents

Increased VEGF expression is associated with poor prognosis and decreased survival in ovarian cancer.

VEGF-A, or simply VEGF, is the most important of a family of growth factors including VEGF-B, VEGF-C, VEGF-D, VEGF-E and PlGF.

Bevacizumab in ovarian cancer

Phase II trials of single-agent bevacizumab demonstrated response rates of 15.9 and 21%.

Early trials of bevacizumab in combination with chemotherapy have shown tolerability and encouraging activity in both front-line and recurrent disease settings.

Higher than expected incidences of life-threatening gastrointestinal perforation with bevacizumab suggest that this agent should be avoided in heavily pretreated, platinum-resistant disease.

Other angiogenesis targets

VEGF-trap (aflibercept) has shown significant activity (overall response rate: 11%) in a Phase II trial.

Cediranib has shown activity as a single-agent (overall response rate: 17%).

Sunitinib malate, combretastatin A-4 phosphate (CA4P), BIBF 1120 and vandetanib (ZD6474) are other promising novel agents currently under investigation.

Inhibition of ErbB-associated pathways

Erlotinib has limited activity as a single agent but acceptable toxicity profile when added to chemotherapy.

Gefitinib, an oral EGFR TKI, has not shown significant activity as a single agent therapy.

Cetuximab, either alone or in combination with chemotherapy, has also shown disappointing activity.

Targeting HER2

HER2 overexpression in ovarian cancer is associated with poor prognosis and decreased survival but occurs with variably reported frequency.

Trastuzumab has minimal activity as a single agent but may reverse platinum resistance.

Pertuzumab has shown poor activity as a single agent but may improve response in platinum-resistant relapse.

A trial of lapatinib was terminated early owing to poor activity.

Trials of EGFR- and HER2-targeted agents have been disappointing.

PARP inhibitors

Loss of PARP1 activity leads to accumulation of dsDNA breaks normally repaired by homologous recombination – a function that is lost in BRCA½-related cancers.

Tumor cells with loss of BRCA½ function, as in BRCA½-mutated cancers, are sensitive to inhibition of PARP1 via synthetic lethality.

A Phase II trial of the PARP inhibitor, olaparib, demonstrated a 57% clinical benefit rate.

Folate receptor-α

Folate receptor-α is a folate-binding protein overexpressed in more than 70% of ovarian cancers but rarely presents in normal tissue and is implicated in tumor proliferation.

A Phase II trial of MORAb-003 plus platinum/taxane chemotherapy showed increased overall response rate compared with historical rates.

mTOR inhibitors

mTOR overexpression and/or activation of the PI3K/AKT/mTOR pathway is common in ovarian malignancies and may be of prognostic significance.

Preclinical studies of the mTOR inhibitor RAD001 showed inhibition of tumor growth, angiogenesis and tumor invasiveness, with enhanced chemotherapy-induced apoptosis in cells with high AKT/mTOR activity.

Hormonal targets

The activity of tamoxifen in ovarian cancer has been reported with meta-analyses showing response rates from 9.6 to 13%.

Tamoxifen and the aromatase inhibitors (e.g., letrozole and exemestane) show minimal rates of tumor shrinkage but may produce prolonged disease stabilization in a subset of patients.

Future perspective

The findings of the large Phase III trials of bevacizumab (GOG 213, 218, 252; ICON7), which have now completed or nearly completed accrual, will help to determine the role of this agent in ovarian cancer management.

PARP inhibitors are promising agents in BRCA-mutated ovarian cancers. Improved patient selection and individualized assessment of tumor biology will aid in identifying the appropriate targets for these novel therapies.

Further evolution of the concept of targeted therapy in ovarian cancer, both in the development of active targeted agents as well as the incorporation of robust and clinically validated predictive biomarkers, is required to fulfill the promise of truly personalized cancer care.

In the future, improved patient selection and individualized assessment of tumor biology will serve to aid in identifying the appropriate targets for these current novel therapies and others that are sure to come. Further development of the concept of targeted cancer therapy promises to usher in an era of truly personalized cancer care.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:.

of interest

of considerable interest.

Jemal

Siegel

Ward

Hao

Thun

: Cancer statistics, 2009. CA Cancer J. Clin. 59(4), 225–249 (2009).

American Cancer Society: Cancer Facts & Figures 2009. American Cancer Society, Atlanta (2009).

Young

Walton

Ellenberg

: Adjuvant therapy in grade I and grade II epithelial ovarian cancer. Results of two prospective randomized trials. N. Engl. J. Med. 322(15), 1021–1027 (1990).

McGuire

Hoskins

Brady

: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with grade III and grade IV ovarian cancer. N. Engl. J. Med. 334(1), 1–6 (1996).

Introduces paclitaxel as a new standard chemotherapy.

Ozols

Bundy

Greer

: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected grade III ovarian cancer: a Gynecologic Oncology Group study. J. Clin. Oncol. 21(17), 3194–3200 (2003).

10.

Establishes carboplatin and paclitaxel as a standard of care.

11.

Vasey

Jayson

Gordon

: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J. Natl Cancer Inst. 96(22), 1682–1691 (2004).

12.

Demonstrates noninferiority of docetaxel compared with paclitaxel.

13.

Bookman

Brady

McGuire

: Evaluation of new platinum-based treatment regimens in advanced-grade ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J. Clin. Oncol. 27(9), 1419–1425 (2009).

14.

Alberts

Liu

Hannigan

: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for grade III ovarian cancer. N. Engl. J. Med. 335(26), 1950–1955 (1996).

15.

Establishes intraperitoneal chemotherapy as a standard of care.

16.

Armstrong

Bundy

Wenzel

: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 354(1), 34–43 (2006).

17.

Establishes intraperitoneal chemotherapy as a standard of care.

18.

Markman

Bundy

Alberts

: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume grade III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J. Clin. Oncol. 19(4), 1001–1007 (2001).

19.

Establishes intraperitoneal chemotherapy as a standard of care.

20.

Rao

Crispens

Rothenberg

: Intraperitoneal chemotherapy for ovarian cancer: overview and perspective. J. Clin. Oncol. 25(20), 2867–2872 (2007).

21.

Armstrong

: Relapsed ovarian cancer: challenges and management strategies for a chronic disease. Oncologist 7(Suppl. 5), 20–28 (2002).

22.

Ferrara

: Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 9(Suppl. 1), 2–10 (2004).

23.

Folkman

: Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285(21), 1182–1186 (1971).

24.

Cooper

Ritchie

Broghammer

: Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin. Cancer Res. 8(10), 3193–3197 (2002).

25.

Frumovitz

Sood

: Vascular endothelial growth factor (VEGF) pathway as a therapeutic target in gynecologic malignancies. Gynecol. Oncol. 104(3), 768–778 (2007).

26.

Hefler

Zeillinger

Grimm

: Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer. Gynecol. Oncol. 103(2), 512–517 (2006).

27.

Paley

Staskus

Gebhard

: Vascular endothelial growth factor expression in early grade ovarian carcinoma. Cancer 80(1), 98–106 (1997).

28.

Shen

Ghazizadeh

Kawanami

: Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma. Br. J. Cancer 83(2), 196–203 (2000).

29.

Cannistra

Matulonis

Penson

: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J. Clin. Oncol. 25(33), 5180–5186 (2007).

30.

Demonstrates the single-agent activity of bevacizumab.

31.

Hurwitz

Fehrenbacher

Novotny

: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350(23), 2335–2342 (2004).

32.

Burger

Sill

Monk

Greer

Sorosky

: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J. Clin. Oncol. 25(33), 5165–5171 (2007).

33.

Demonstrates the single-agent activity of bevacizumab.

34.

Hapani

Chu

: Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol. 10(6), 559–568 (2009).

35.

Burger

: Experience with bevacizumab in the management of epithelial ovarian cancer. J. Clin. Oncol. 25(20), 2902–2908 (2007).

36.

Friberg

Oza

Morgan

Vokes

Gandara

Fleming

: Bevacizumab plus erlotinib for patients with recurrent ovarian and fallopian tube cancer: preliminary results of a multi-center Phase II trial. J. Clin. Oncol. 24(Suppl. 18S), (2006).

37.

Sandler

Gray

Perry

: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355(24), 2542–2550 (2006).

38.

Garcia

Hirte

Fleming

: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II consortia. J. Clin. Oncol. 26(1), 76–82 (2008).

39.

Provides a rationale for the use of bevacizumab in combination with chemotherapy.

40.

McGonigle

Muntz

Vuky

: Phase II prospective study of weekly topotecan and bevacizumab in platinum refractory ovarian cancer or peritoneal cancer. J. Clin. Oncol. 26(Suppl. 15), 5551 (2008).

41.

Provides a rationale for the use of bevacizumab in combination with chemotherapy.

42.

Kikuchi

Kouta

Kikuchi

: Effects of weekly bevacizumab and pegylated liposomal doxorubicin in heavily pretreated patients with recurrent or progressed ovarian cancer. J. Clin. Oncol. 27(Suppl. 15), 5547 (2009).

43.

Provides a rationale for the use of bevacizumab in combination with chemotherapy.

44.

Muggia

Boyd

Liebes

: Pegylated liposomal doxorubicin with bevacizumab in second-line treatment of ovarian cancer: pharmacokinetics, safety, and preliminary outcome results. J. Clin. Oncol. 27(Suppl. 15), 5548 (2009).

45.

Provides a rationale for the use of bevacizumab in combination with chemotherapy.

46.

Micha

Goldstein

Rettenmaier

: A Phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-grade epithelial ovarian, peritoneal, and fallopian tube cancer. Int. J. Gynecol. Cancer 17(4), 771–776 (2007).

47.

Provides a rationale for Phase III trials of bevacizumab.

48.

Rose

Drake

Braly

: Preliminary results of a Phase II study of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube. J. Clin. Oncol. 27(Suppl. 15), 5546 (2009).

49.

Konner

Grabon

Pezzulli

: A Phase II study of intravenous (IV) and intraperitoneal (ip) paclitaxel, ip cisplatin, and iv bevacizumab as first-line chemotherapy for optimal grade II or III ovarian, primary peritoneal, and fallopian tube cancer. J. Clin. Oncol. 27(Suppl. 15), 5539 (2009).

50.

Provides a rationale for Phase III trials of bevacizumab.

51.

McMeekin

Lanneau

Curiel

Moore

Walker

Mannel

: Phase II study of intravenous bevacizumab and paclitaxel, and intraperitoneal cisplatin, followed by bevacizumab consolidation for advanced ovarian or peritoneal cancers. J. Clin. Oncol. 27(Suppl. 15), (2009).

52.

Provides a rationale for Phase III trials of bevacizumab.

53.

Byrne

Ross

Holash

: Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin. Cancer Res. 9(15), 5721–5728 (2003).

54.

Tew

Colombo

Ray-Coquard

: VEGF-Trap for patients with recurrent platinum-resistant epithelial ovarian cancer: Preliminary results of a randomized, multicenter Phase II study. J. Clin. Oncol. 25(Suppl. 18), 5508 (2007).

55.

Wedge

Kendrew

Hennequin

: AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 65(10), 4389–4400 (2005).

56.

Drevs

Siegert

Medinger

: Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 25(21), 3045–3054 (2007).

57.

Laurie

Gauthier

Arnold

: Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. J. Clin. Oncol. 26(11), 1871–1878 (2008).

58.

Ryan

Stadler

Roth

: Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). Invest. New Drugs 25(5), 445–451 (2007).

59.

Matulonis

Berlin

Ivy

: Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J. Clin. Oncol. 27(33), 5601–5606 (2009).

60.

Hirte

Vidal

Fleming

: A Phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial. J. Clin. Oncol. 26(Suppl.), 5521 (2008).

61.

Demonstrates the single-agent activity of cediranib (AZD2171).

62.

Friedlander

Hancock

Benigno

: Pazopanib (GW786034) is active in women with advanced epithelial ovarian, fallopian tube and peritoneal cancers: initial results of a Phase II study. J. Clin. Oncol. 25(Suppl.18), 5561 (2007).

63.

Mendel

Laird

Xin

: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9(1), 327–337 (2003).

64.

O'Farrell

Abrams

Yuen

: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101(9), 3597–3605 (2003).

65.

Biagi

Oza

Grimshaw

: A Phase II study of sunitinib (SU11248) in patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma – NCIC CTG IND 185. J. Clin. Oncol. 26(Suppl. 15), 5522 (2008).

66.

Rustin

Galbraith

Anderson

: Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J. Clin. Oncol. 21(15), 2815–2822 (2003).

67.

West

Price

. Combretastatin A4 phosphate. Anticancer Drugs 15(3), 179–187 (2004).

68.

Shnyder

Cooper

Pettit

Lippert

3rd Bibby

: Combretastatin A-1 phosphate potentiates the antitumour activity of cisplatin in a murine adenocarcinoma model. Anticancer Res. 23(2B), 1619–1623 (2003).

69.

Zweifel

Jayson

Reed

: Combretastatin A-4 phosphate (CA4P) carboplatin and paclitaxel in patients with platinum-resistant ovarian cancer: final Phase II trial results. J. Clin. Oncol. 27(Suppl. 15), (2009).

70.

Ledermann

Rustin

Hackshaw

: A randomized Phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer. J. Clin. Oncol. 27(Suppl. 15), 5501 (2009).

71.

Ciardiello

Caputo

Damiano

: Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin. Cancer Res. 9(4), 1546–1556 (2003).

72.

Beebe

Jani

Knauth

: Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res. 63(21), 7301–7309 (2003).

73.

Burgess

Cho

Eigenbrot

: An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12(3), 541–552 (2003).

74.

Alper

Bergmann-Leitner

Bennett

Hacker

Stromberg

Stetler-Stevenson

: Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. J. Natl Cancer Inst. 93(18), 1375–1384 (2001).

75.

Goff

Shy

Greer

Muntz

Skelly

Gown

: Overexpression and relationships of HER-2/neu, epidermal growth factor receptor, p53, Ki-67, and tumor necrosis factor α in epithelial ovarian cancer. Eur. J. Gynaecol. Oncol. 17(6), 487–492 (1996).

76.

Kohler

Bauknecht

Grimm

Birmelin

Kommoss

Wagner

: Epidermal growth factor receptor and transforming growth factor α expression in human ovarian carcinomas. Eur. J. Cancer 28A(8–9), 1432–1437 (1992).

77.

Skirnisdottir

Sorbe

Seidal

: The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early grade (FIGO I-II) epithelial ovarian carcinoma. Int. J. Gynecol. Cancer 11(2), 119–129 (2001).

78.

Fischer-Colbrie

Witt

Heinzl

: EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients. Anticancer Res. 17(1B), 613–619 (1997).

79.

Nicholson

Gee

Harper

: EGFR and cancer prognosis. Eur. J. Cancer 37(Suppl. 4), 9–15 (2001).

80.

Gordon

Finkler

Edwards

: Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a Phase II multicenter study. Int. J. Gynecol. Cancer 15(5), 785–792 (2005).

81.

Perez-Soler

Chachoua

Hammond

: Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J. Clin. Oncol. 22(16), 3238–3247 (2004).

82.

Vasey

Gore

Wilson

: A Phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers. Br. J. Cancer 98(11), 1774–1780 (2008).

83.

Posadas

Liel

Kwitkowski

: A Phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer. Cancer 109(7), 1323–1330 (2007).

84.

Schilder

Sill

Chen

: Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin. Cancer Res. 11(15), 5539–5548 (2005).

85.

Wagner

du Bois

Pfisterer

: Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum-taxane based therapy–α Phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6). Gynecol. Oncol. 105(1), 132–137 (2007).

86.

Konner

Schilder

DeRosa

: A Phase II study of cetuximab/paclitaxel/carboplatin for the initial treatment of advanced-grade ovarian, primary peritoneal, or fallopian tube cancer. Gynecol. Oncol. 110(2), 140–145 (2008).

87.

Schilder

Pathak

Lokshin

: Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash. Gynecol. Oncol. 113(1), 21–27 (2009).

88.

Secord

Blessing

Armstrong

: Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: a Gynecologic Oncology Group study. Gynecol. Oncol. 108(3), 493–499 (2008).

89.

Susman

: Rash correlates with tumour response after cetuximab. Lancet Oncol. 5(11), 647 (2004).

90.

Slamon

Clark

Wong

Levin

Ullrich

McGuire

: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785), 177–182 (1987).

91.

Tuefferd

Couturier

Penault-Llorca

: HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients. PLoS one 2(11), e1138 (2007).

92.

Bookman

Darcy

Clarke-Pearson

Boothby

Horowitz

: Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a Phase II trial of the Gynecologic Oncology Group. J. Clin. Oncol. 21(2), 283–290 (2003).

93.

Ray-Coquard

Guastalla

Djelila

: HER2 overexpression/amplification and trastuzumab treatment in advanced ovarian cancer: A GINECO Phase II study. Clin. Ovarian Cancer Special Issue 17–22 (2009).

94.

Agus

Akita

Fox

: Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer cell 2(2), 127–137 (2002).

95.

Franklin

Carey

Vajdos

Leahy

de Vos

Sliwkowski

: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer cell 5(4), 317–328 (2004).

96.

Gordon

Matei

Aghajanian

: Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J. Clin. Oncol. 24(26), 4324–4332 (2006).

97.

Makhija

Amler

Glenn

: Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer. J. Clin. Oncol. 28(7), 1215–1223 (2009).

98.

Joly

Weber

Pautier

: Combined topotecan and lapatinib in patients with early recurrent ovarian or peritoneal cancer after first line of platinum-based chemotherapy: a French FEDEGYN-FNCLCC Phase II trial. J. Clin. Oncol. 27(Suppl. 15S), 5555 (2009).

99.

Schreiber

Dantzer

Ame

de Murcia

: Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 7(7), 517–528 (2006).

100.

Schultz

Lopez

Saleh-Gohari

Helleday

: Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 31(17), 4959–4964 (2003).

101.

Iglehart

Silver

: Synthetic lethality – a new direction in cancer-drug development. N. Engl. J. Med. 361(2), 189–191 (2009).

102.

Fong

Boss

Yap

: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361(2), 123–134 (2009).

103.

Audeh

Penson

Friedlander

: Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J. Clin. Oncol. 25(Suppl. 15S) (2009).

104.

Demonstrates the single-agent activity of olaparib (AZD2281) in BRCA-mutated ovarian cancer.

105.

Nguewa

Fuertes

Cepeda

: Poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells. Med. Chem. (Shariqah (United Arab Emirates)), 2(1), 47–53 (2006).

106.

Rottenberg

Jaspers

Kersbergen

: High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105(44), 17079–17084 (2008).

107.

Sakai

Swisher

Karlan

: Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451(7182), 1116–1120 (2008).

108.

Ebel

Routhier

Foley

: Preclinical evaluation of MORAb-003, a humanized monoclonal antibody antagonizing folate receptor-α. Cancer Immun. 7, 6 (2007).

109.

Kalli

Oberg

Keeney

: Folate receptor α as a tumor target in epithelial ovarian cancer. Gynecol. Oncol. 108(3), 619–626 (2008).

110.

Armstrong

Bicher

Coleman

: Exploratory Phase II efficacy study of MORAb-003, a monoclonal antibody against folate receptorα, in platinum-sensitive ovarian cancer in first relapse. J. Clin. Oncol. 26(Suppl. 15), 5500 (2008).

111.

Del Bufalo

Ciuffreda

Trisciuoglio

: Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 66(11), 5549–5554 (2006).

112.

Sabatini

: mTOR and cancer: insights into a complex relationship. Nat. Rev. Cancer 6(9), 729–734 (2006).

113.

Faivre

Kroemer

Raymond

: Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov. 5(8), 671–688 (2006).

114.

Steelman

Stadelman

Chappell

: Akt as a therapeutic target in cancer. Expert Opin. Ther. Targets 12(9), 1139–1165 (2008).

115.

Hudes

Carducci

Tomczak

: Temsirolimus, interferon α, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356(22), 2271–2281 (2007).

116.

Motzer

Bukowski

: Targeted therapy for metastatic renal cell carcinoma. J. Clin. Oncol. 24(35), 5601–5608 (2006).

117.

Noske

Lindenberg

Darb-Esfahani

: Activation of mTOR in a subgroup of ovarian carcinomas: correlation with p-eIF-4E and prognosis. Oncol. Rep. 20(6), 1409–1417 (2008).

118.

Zhang

Sun

: Aberration of the PI3K/AKT/mTOR signaling in epithelial ovarian cancer and its implication in cisplatin-based chemotherapy. Eur. J. Obstet. Gynecol. Reprod. Biol. 146(1), 81–86 (2009).

119.

Mabuchi

Altomare

Cheung

: RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin. Cancer Res. 13(14), 4261–4270 (2007).

120.

Huynh

Teo

Soo

: Bevacizumab and rapamycin inhibit tumor growth in peritoneal model of human ovarian cancer. Mol. Cancer Ther. 6(11), 2959–2966 (2007).

121.

Trinh

Tjalma

Vermeulen

: The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer. Br. J. Cancer, 100(6), 971–978 (2009).

122.

Hatch

Beecham

Blessing

Creasman

: Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients. Cancer 68(2), 269–271 (1991).

123.

Williams

: Tamoxifen for relapse of ovarian cancer. Cochrane Database Syst. Rev. (2), CD001034 (2000).

124.

Perez-Gracia

Carrasco

: Tamoxifen therapy for ovarian cancer in the adjuvant and advanced settings: systematic review of the literature and implications for future research. Gynecol. Oncol. 84(2), 201–209 (2002).

125.

Geisinger

Berens

Duckett

Morgan

Kute

Welander

: The effects of estrogen, progesterone, and tamoxifen alone and in combination with cytotoxic agents against human ovarian carcinoma in vitro. Cancer 65(5), 1055–1061 (1990).

126.

McClay

Albright

Jones

Christen

Howell

: Tamoxifen modulation of cisplatin cytotoxicity in human malignancies. Int. J. Cancer 55(6), 1018–1022 (1993).

127.

Panasci

Jean-Claude

Vasilescu

: Sensitization to doxorubicin resistance in breast cancer cell lines by tamoxifen and megestrol acetate. Biochem. Pharmacol. 52(7), 1097–1102 (1996).

128.

Panici

Benedetti P

Greggi

Amoroso

: A combination of platinum and tamoxifen in advanced ovarian cancer failing platinum-based chemotherapy: results of a Phase II study. Int. J. Gynecol. Cancer 11(6), 438–444 (2001).

129.

Markman

Webster

Zanotti

Peterson

Kulp

Belinson

: Phase II trial of carboplatin plus tamoxifen in platinum-resistant ovarian cancer and primary carcinoma of the peritoneum. Gynecol. Oncol. 94(2), 404–408 (2004).

130.

del Carmen

Fuller

Matulonis

: Phase II trial of anastrozole in women with asymptomatic mullerian cancer. Gynecol. Oncol. 91(3), 596–602 (2003).

131.

Papadimitriou

Markaki

Siapkaras

: Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a Phase II study. Oncology 66(2), 112–117 (2004).

132.

Smyth

Gourley

Walker

: Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. Clin. Cancer Res. 13(12), 3617–3622 (2007).

133.

Verma

Alhayki

: Phase II study of exemestane in refractory ovarian cancer. J. Clin. Oncol. 24 (Suppl. 18), (2006).

134.

Argenta

Thomas

Judson

: A Phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer. Gynecol. Oncol. 113(2), 205–209 (2009).

135.

Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352(9132), 930–942 (1998).

136.

Fisher

Costantino

Redmond

: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N. Engl. J. Med. 320(8), 479–484 (1989).

137.

Romond

Perez

Bryant

: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353(16), 1673–1684 (2005).

138.

Cortes-Funes

Gomez

Rosell

: Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann. Oncol. 16(7), 1081–1086 (2005).

139.

Han

Kim

Hwang

: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J. Clin. Oncol. 23(11), 2493–2501 (2005).

140.

Mitsudomi

Kosaka

Endoh

: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J. Clin. Oncol. 23(11), 2513–2520 (2005).

141.

Gore

Escudier

: Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma. Oncology (Williston Park) 20(6 Suppl 5), 19–24 (2006).

142.

Kummar

Gutierrez

Doroshow

Murgo

: Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br. J. Clin. Pharmacol. 62(1), 15–26 (2006).

143.

Llovet

Ricci

Mazzaferro

: Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359(4), 378–390 (2008).

144.

Genentech, Inc: Genentech Announces Positive Results of Avastin Phase III Study in Women with Advanced Ovarian Cancer (February 24, 2010) [Press release]. www.gene.com/gene/news/pressreleases/display.do?method=detail&id=12647.

Targeted Agents in Ovarian Cancer

Abstract

Keywords

Targeting angiogenesis

Anti-VEGF therapy

Clinical experience with single-agent bevacizumab

Bevacizumab in combination with chemotherapy

Bevacizumab in combination with first-line chemotherapy

Ongoing Phase III trials of bevacizumab in ovarian cancer

Other targets in the VEGF pathway: VEGF trap

Inhibition of angiogenesis by small molecule kinase inhibitors

Ongoing Phase III trials

Other agents under investigation

Inhibition of Erb family pathways

Targeting HER2

PARP inhibition

Folate receptor-α

PI3K/AKT/mTOR cell signaling pathway

Hormonal therapy

Future perspective

Footnotes

References