Anti-angiogenic therapy in ovarian cancer: Current understandings and prospects of precision medicine

Abstract

Ovarian cancer (OC) remains the most fatal disease of gynecologic malignant tumors. Angiogenesis refers to the development of new vessels from pre-existing ones, which is responsible for supplying nutrients and removing metabolic waste. Although not yet completely understood, tumor vascularization is orchestrated by multiple secreted factors and signaling pathways. The most central proangiogenic signal, vascular endothelial growth factor (VEGF)/VEGFR signaling, is also the primary target of initial clinical anti-angiogenic effort. However, the efficiency of therapy has so far been modest due to the low response rate and rapidly emerging acquiring resistance. This review focused on the current understanding of the in-depth mechanisms of tumor angiogenesis, together with the newest reports of clinical trial outcomes and resistance mechanism of anti-angiogenic agents in OC. We also emphatically summarized and analyzed previously reported biomarkers and predictive models to describe the prospect of precision therapy of anti-angiogenic drugs in OC.

Keywords: angiogenesis; anti-angiogenic therapy; biomarker; ovarian cancer; precision medicine.

FIGURE 1

Major mechanisms of tumor angiogenesis and therapeutic agents implicated in OC. Tumor angiogenesis is induced by a series of proangiogenic factors. This diagram exhibits the principal angiogenic signaling pathways, as well as the molecular targets and therapeutic mechanisms of anti-angiogenic agents implicated in OC. CAFs, cancer associated fibroblasts; TAMs, tumor-associated macrophages.

FIGURE 2

Clinical trials assessing biomarkers in relation to PFS of anti-angiogenic drugs in OC. BEV: Bevacizumab; CT: Chemotherapy; PC:TAXOL and CBP; DNA, Deoxyribonucleic Acid; RNA, Ribonucleic Acid; cfDNA, cell-free DNA; EGFR, Epidermal Growth Factor Receptor; HER2, Human Epidermal GrowthFactor Receptor 2; MYC, MYC Proto-Oncogene; CCNE1, Cyclin E1; ADAM17, a disintegrin and metalloprotease 17; MVD, microvessel density; SMA_MVD: Alfa-Smooth Muscle Actin + microvessel density; Ratio, α-SMA + MVD/MVD ratio; miRNA, microRNA; VEGFA, vascular endothelial growth factor A; VEGFB, vascular endothelial growth factor B; HIF-a, Hypoxia-Inducible Factor 1-alpha; OPN, osteopontin; SDF-1, stromal cell–derived factor-1; IL6R, IL6 receptor; FLT4, fms-like tyrosine kinase-4; AGP, a 1 -acid glycoprotein; BMI, body mass index; VFA, visceral fat area; SFA, subcutaneous fat area; ΔBF, change of Tumor Blood Flow; ΔBV, change of Tumor Blood Volume; ΔPS, change of Vessel Permeability Surface Product; PDS/NACT, Primary Debulking Surgery/Neoadjuvant chemotherapy; RT, Residual Tumor; PS, Performance Status; CR, Completeness of resection; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune inflammation index.

FIGURE 3

Clinical trials assessing biomarkers in relation to OS of anti-angiogenic drugs in OC. BEV: Bevacizumab; CT: Chemotherapy; PC:TAXOL and CBP; DNA, Deoxyribonucleic Acid; RNA, Ribonucleic Acid; cfDNA, cell-free DNA; ADAM17, a disintegrin and metalloprotease 17; MVD, microvessel density; SMA_MVD: Alfa-Smooth Muscle Actin + microvessel density; Ratio, α-SMA + MVD/MVD ratio; miRNA, microRNA; VEGFA, vascular endothelial growth factor A; VEGFB, vascular endothelial growth factor B; HIF-a, Hypoxia-Inducible Factor 1-alpha; OPN, osteopontin; SDF-1, stromal cell–derived factor-1; IL6R, IL6 receptor; FLT4, fms-like tyrosine kinase-4; AGP, a 1 -acid glycoprotein; BMI, body mass index; VFA, visceral fat area; SFA, subcutaneous fat area; ΔBF, change of Tumor Blood Flow; ΔBV, change of Tumor Blood Volume; ΔPS, change of Vessel Permeability Surface Product; PDS/NACT, Primary Debulking Surgery/Neoadjuvant chemotherapy; RT, Residual Tumor; PS, Performance Status; CR, Completeness of resection; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune inflammation index; SFD, subcutaneous fat density; VFD, visceral fat density.