Antiangiogenic Therapies in Epithelial Ovarian Cancer

Deanna G. K. Teoh, MD; Angeles Alvarez Secord, MD

Cancer Control. 2011;18(1):31-43.

The Role of Vascular Endothelial Growth Factors in Ovarian Cancer

Ovarian tumors, like many malignancies, overexpress proangiogenic factors including vascular endothelial growth factors (VEGFs), fibroblast growth factors, angiopoietin, platelet-derived growth factors (PDGFs), and pro-angiogenic cytokines such as tumor necrosis factor alpha and interleukins 6 and 8.^[27] Of these, members of the VEGF family are the most potent pro-angiogenic factors. VEGF activation promotes endothelial cell proliferation and migration for the formation of new blood vessels and increases permeability of existing blood vessels to allow for the leakage of multiple plasma proteins, including those playing a role in angiogenesis.^[28] Also, VEGF inhibits apoptosis of the newly formed hyperpermeable blood vessels.^[29] By this mechanism, VEGF also plays a key role in the formation of ascites and pleural effusions.

Additionally, VEGF plays a significant part in the normal function of the ovary, with serum VEGF levels rising and falling in a predictable pattern during the ovulatory cycle.^[30] Therefore, it is not surprising that VEGF plays a role in the biology of ovarian cancer. Preclinical studies have demonstrated that animals inoculated with VEGF/green fluorescent protein (GFP)-positive ID8 in vitro transformed C57BL6 murine ovarian epithelial cells developed diffuse peritoneal carcinomatosis and ascites in a pattern similar to metastatic ovarian cancer.^[31]

VEGF expression is higher in ovarian cancers than in normal ovarian tissue or benign ovarian neoplasms, and increasing VEGF expression in either cytosolic fractions derived from ovarian cancers or serum VEGF levels in preoperative serum was associated with advanced stage and worse survival.^[32–34] Even for patients with early-stage disease, cancers with elevated VEGF expression and preoperative serum VEGF levels were associated with a higher risk of disease recurrence and worse overall and diseasefree survival.^[35,36] In a study by Paley et al,^[35] multivariate analysis showed that increased VEGF transcript expression was the strongest prognostic factor for a worse prognosis compared with other high-risk features such as stage IC-IIC disease, tumor rupture, poorly differentiated histology, malignant peritoneal cytology, and postoperative adjuvant therapy. For women with advanced-stage cancer, high serum VEGF levels have been associated with a more aggressive disease phenotype and were an independent risk factor for ascites, increased metastases, suboptimal tumor debulking, and decreased survival.^[34,36] The strong association between tumor angiogenesis, VEGF expression and serum levels, and clinical outcome in ovarian cancer makes the VEGF pathway an attractive therapeutic target.

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Abstract and Introduction
Angiogenesis in Ovarian Cancer
The Role of Vascular Endothelial Growth Factors in Ovarian Cancer
VEGF Targeting Therapies in Ovarian Cancer
TKIs of VEGF Receptors
Alternative Antiangiogenesis Therapies
Vascular Disrupting Agents
Conclusions
References

Table 1. Summary of Completed Ovarian Cancer Trials With Bevacizumab as a Single Agent or in Combination With Cytotoxic Agents
Trial	Recurrent/Primary	Regimen	Outcomes	Toxicity
GOG 170D³⁷	Recurrent	Bevacizumab 15 mg/kg	RR 21% (CR 3%, PR 18%) SD 21% OS 16.9 mos PFS 4.7 mos	Grade 3/4 GI events 6.5% (no GIP) Grade 3 hypertension 9.7% Grade 4 proteinuria (1)
AVF 2949g³⁸	Recurrent	Bevacizumab 15 mg/kg	PR 15.9% SD 61.4% OS 10.7 mos PFS 4.4 mos	GIP 11% ATE 6.8% Grade 3 hypertension 9.1%
NCI 5789⁴⁴	Recurrent	Bevacizumab 10 mg/kg + cyclophosphamide po 50 mg	PR 24% SD 63% OS 16.9 mos PFS 7.2 mos	Grade 3 heme toxicities 23% Grade 3 hypertension 16% GIP 4%
TEACO⁴⁵	Primary	Bevacizumab 15 mg/kg + docetaxel 75 mg/m² + oxaliplatin 85 mg/m²	RR 75% (CR 34.6%, PR 40%) SD 14% PFS 69.1 wks	Grade 3/4 neutropenia 39% Grade 3/4 hypertension 8.2% Grade 3/4 fatigue 7.3% GIP 1.1%
Micha et al⁴⁶	Primary	Bevacizumab 15 mg/kg + paclitaxel 175 mg/m² + carboplatin AUC 5	RR 80% (CR 30%, PR 50%)	Grade 3/4 neutropenia 48.3% Grade 3 hypertension 11% DVT 11% No GIP

RR = response rate, CR = complete response, PR = partial response, SD = stable disease, OS = median overall survival, PFS = median progression-free survival, GIP = gastrointestinal perforation, ATE = arterial thrombotic event, DVT = deep vein thrombosis

Table 2. Summary of Tyrosine Kinase Inhibitors Under Investigation in Solid Tumors, Including Ovarian Cancers
Compound	Inhibits	Development Phase	Outcomes	Toxicity
Cediranib (AZD2171)	VEGFR-1, -2, -3 c-kit	II - Monotherapy, recurrent ovarian cancer	PR 17% SD 13% PFS 5.2 mos OS not yet reached	Grade 3: hypertension 46%, fatigue 24%, diarrhea 13% Grade 4: CNS hemorrhage (1), dehydration (1), percholesterolemia (1)
Cediranib (AZD2171)	VEGFR-1, -2, -3 c-kit	III - Carboplatin + paclitaxel ± cediranib, recurrent ovarian cancer	Pending	Pending
Sorafenib (Nexavar)	VEGFR-2, -3 Ras/Raf/Mek/ERK pathways PDGFR-β	I - Monotherapy, advanced solid tumors	SD 22%, median duration 7.2 mos	Dermatologic changes, fatigue, GI effects (diarrhea, nausea, anorexia)
		I - Gemcitabine + sorafenib, advanced solid tumors	PR 5% SD 63.2% Dose 400 mg bid with gemcitabine 1,000 mg/m² weekly	Grade 3/4: thrombocytopenia (29%), lymphopenia (21%), lipase elevation (19%), neutropenia (17%), fatigue (14%)
		I - Oxaliplatin + paclitaxel + sorafenib, advanced carcinomatosis	Pending	Pending
		II - Bevacizumab + sorafenib, recurrent ovarian cancer	Pending	Pending
		II - Sorafenib ± paclitaxel and carboplatin, recurrent ovarian cancer	Pending	Pending
Sunitinib (SU11248)	VEGFR-1, -2, -3 PDGFR-α, -β	II - Monotherapy, advanced ovarian cancer	Pending	Pending
Pazopanib (Votrient)	VEGFR-1, -2, -3 PDGFR-α, -β c-kit	II - Monotherapy; recurrent ovarian cancer	CA-125 response 47% SD 27%	Grade 3/4: diarrhea, ALT elevation
Vatalanib (PTK 787)	VEGFR-1, -2, -3 PDGFR-β c-kit	Ib - Carboplatin + paclitaxel + vatalanib, first-line ovarian cancer	CR + PR 9% SD 9% Dose 1,250 mg/day with paclitaxel	Grade 3/4: neutropenia (31%), leukopenia (18%), hypertension (10%)
Vatalanib (PTK 787)	VEGFR-1, -2, -3 PDGFR-β c-kit	I - Carboplatin + paclitaxel + vatalanib	PR 29% SD 21% MTD pending	Hyperglycemia (29%), hypertension (7%), diarrhea (7%), transaminitis (7%)

SD = stable disease, CR = complete response, PR = partial response, MTD = maximum tolerated dose, OS = overall survival, PFS = progression-free survival.

Table 3. Vascular Disrupting Agents (VDAs): Primarily Tubulin Depolymerising Agents Designed to Disrupt Existing Vasculature
Compound	Mechanism	Development Phase	Outcomes	Toxicity
Combretastatin (CA4P)	Tubulin depolymerising agent	I - Monotherapy, advanced solid tumors	CR (1/25) SD (3/25) Dose ≤60 mg/m² every 3 wks	Tumor pain Grade 3 myelosuppression (3/107 courses) Grade 1 QTc prolongation (7 episodes)
Oxi4503	Tubulin depolymerising agent	Preclinical: Colorectal, renal cell, breast and sarcoma xenografts	Reduction of tumor blood vessels and tumor necrosis	N/A
ZD6126	Tubulin depolymerising agent	I - Monotherapy, advanced solid tumors	SD 22% DCE-MRI evidence of decreased tumor blood flow Dose 80 mg/m² every 2–3 wks	Common: Abdominal pain, nausea, constipation, dyspnea DLTs (11%): hypotension, abnormal LVEF, myocardial ischemia
		Preclinical: Monotherapy and docetaxel combination in ovarian cancer xenograft	65% tumor reduction 86% tumor reduction and improved survival in combination group	N/A
		I - Monotherapy, advanced malignancies	DCE-MRI evidence of decreased vascular flow Dose 30 mg/m² weekly × 3 wks every 28 days	Asymptomatic systolic hypotension without cardiac compromise
AVE8062	Tubulin depolymerising agent	III - In development	N/A	N/A
ABT751	Sulfonamide colchicine-binding antimitotic agent	I - Monotherapy, refractory solid tumors	SD (4/39) Dose 250 mg po daily × 7 days, then 150 mg bid × 7 days every 21 days	Common: fatigue, asthenia, anorexia, constipation/ileus, peripheral neuropathy, myalgias Grade 3/4: neuropathy, nausea, constipation/ileus, abdominal pain, arthalgia/myalgia

DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging, CR = complete response, SD = stable disease, DLT = dose-limiting toxicity, LVEF = left ventricular ejection fraction.

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