1 Introduction
2 Vascular endothelial growth factor
2.1 Identification
2.2 VEGF and its receptors
2.3 Biological effects of VEGF
2.3.1 VEGF and physiological processes
2.3.2 VEGF in nonmalignant disorders
2.3.3 Role of VEGF in malignancies
3 VEGF and pathogenesis of ovarian cancer
3.1 VEGF, carcinogenesis, and tumor growth in ovarian cancer
3.2 VEGF and ovarian cancer dissemination
3.2.1 Role of VEGF in intraperitoneal dissemination of ovarian cancer
3.2.2 Extraperitoneal metastasis of ovarian cancer
4 VEGF/VEGFR-targeted therapy in ovarian cancer
Type | Drug | Target(s) | |
---|---|---|---|
VEGF binders | Bevacizumab | VEGF (all isoforms) | |
Aflibercept | VEGF, VEGF-B, PlGF | ||
Receptor tyrosine kinase inhibitors | VEGFR inhibitors | Ramucirumab | VEGFR2 |
Cediranib | VEGFR1-3, c-Kit, PDGFR-β | ||
Semaxanib | VEGFR2 | ||
Multiple RTK inhibitors | Sunitinib | VEGFR1-3, Flt-3, PDGFR-α, PDGFR-β, c-Kit, CSF-1R, RET | |
Sorafenib | VEGFR1-3, PDGFR-β, Flt-3, c-Kit, Raf-1 | ||
Vatalanib | VEGFR1-3, PDGFR-β, c-Kit, c-Fms | ||
Intedanib | VEGFR1-3, PDGFR-α, PDGFR-β, FGFR1-3 | ||
Pazopanib | VEGFR1-2, PDGFR-β, c-Kit | ||
Motesanib | VEGFR1-3, PDGFR, c-Kit | ||
Vandetanib | VEGFR2-3, EGFR | ||
AEE788 | VEGFR, EGFR |
4.1 VEGF neutralization
Single-agent therapy | ||||||
---|---|---|---|---|---|---|
Investigators | Phase | Target | No. of patients | Outcome | ||
Burger et al. [237] | II | Persistent or recurrent EOC, PPC | 62 | CR, 3%; PR, 18%; MPFS, 4.7; MOS, 17 | ||
Cannistra et al. [238] | II | Recurrent EOC or PSC | 44 | CR, 0; PR, 15.9%; MPFS, 4.4; MOS, 10.7 | ||
Combined with chemotherapy | ||||||
Micha et al. [239] | II | Newly diagnosed stage III/IV | 20 | CR, 30%; PR, 50% | ||
Garcia et al. [240] | II | Recurrent platinum-sensitive | 70 | CR, 0; PR, 24%; MPFS, 7.2; MOS, 16.9 | ||
Richardson et al. [241] | II | Recurrent platinum-sensitive | 33 | CR, 48%; PR, 30%; MPFS, 12 | ||
Penson et al. [242] | II | Newly diagnosed stage ≥IC | 62 |
CT CR, 56%; PR, 22%; CA-125 CR, 89%; PR, 7% | ||
Rose et al. [243] | II | Newly diagnosed stage IB-IV | 132 | CR, 32.8%; PR, 29.1%; SD, 32.7% | ||
Brown et al. [244] | II | Newly diagnosed stage III/IV | 13 | CR, 30.8%; PR, 30.8%; SD, 30.7%; MPFS, 5.8 | ||
Tillmanns et al. [245] | II | Recurrent platinum-resistant EOC, PPC | 48 | MPFS, 8.3; MOS, 16.5; In 39 patients, PR, 46.1%; SD, 30.8% | ||
Burger et al. [246] | III | Newly diagnosed EOC, PPC, FTC | 1,873 | CP | CP + Bev and maintenance Bev | |
10.3 | 14.1 | |||||
McGonigle et al. [247] | II | Recurrent platinum-resistant EOC, PPC, FTC | 40 | PR, 25%; SD, 35%; MPFS, 7.8; MOS, 16.6 | ||
del Carmen et al. [248] | II | Recurrent platinum-sensitive | 54 | ORR, 72.2%; MTTP, 14.1; MPFS, 14.1 | ||
Horowitz et al. [249] | II | Recurrent platinum-sensitive | 19 | CR, 5.26%; PR, 63.15%; MPFS, 8.61; MOS, 21.1 | ||
Wenham et al. [250] | II | Recurrent platinum-resistant | 37 | CR, 3%; PR, 54%; MPFS, 5.8 | ||
Aghajanian et al. [251] | III | Recurrent platinum-resistant EOC, PPC, FTC | 484 | CG | Bev + CG | |
ORR, 57.4; MPFS, 8.4 | ORR, 78.5; MPFS, 12.4 | |||||
Kristensen et al. [252] | III | Newly diagnosed EOC, PPC, FTC | 1,528 | Maintenance CP | CP + Bev and maintenance Bev | |
MPFS, 16 | MPFS, 18.3 | |||||
Overall trend: OS improvement | ||||||
Kudoh et al. [253] | N/A | Heavily pretreated ROC | 30 | ORR, 33%; CR + PD + SD, 73%; MPFS, 6 | ||
O’Malley et al. [254] | N/A | Heavily pretreated ROC | 70 | P | P + Bev | |
MPFS, 6.2 | MPFS, 13.2 | |||||
Ojeda et al. [255] | N/A | Highly pretreated, relapsed EOC | RECIST | CA-125 | Response rate was higher for the combination group. However, a similar OS was observed. | |
66 | 76 |
Investigators | Phase | Target | Results |
---|---|---|---|
Tew et al. [256] | II | Platinum-resistant and topotecan and/or liposomal doxorubicin-resistant advanced ovarian cancer | Preliminary results showed a partial response of 11%. |
Colombo et al. [257] | II | Platinum-resistant and topotecan and/or liposomal doxorubicin-resistant advanced ovarian cancer with recurrent symptomatic malignant ascites | First results demonstrated the efficacy of two weekly intravenous aflibercept in prolonging the time to repeat paracentesis in 8 out of 10 evaluable patients. |
Coleman et al. [258] | II | Recurrent EOC, PPC, FTC | ORR, 54%; CR, 21.7; MPFS, 6.2; MOS, 24.3 |