Resistance to chemotherapy and anti-angiogenic therapy in ovarian cancer

Abstract

Ovarian cancer (OC) is the foremost lethal gynaecologic malignancy and among the top five deadliest cancers in women. Current treatment comprises a combination therapy of surgery, platinumbased chemotherapy and anti-vascular endothelial growth factor (VEGF) antibodies. However, patients typically experience a disease relapse within two years. Recurrent OC is incurable and resistance to platins and anti-VEGF treatment is a major determinant of prognosis. Understanding the molecular mechanisms that contribute to tumour metastasis and chemoresistance are essential to improve patient outcome and especially survival. In a current OC model, tumour metastasis and chemoresistance critically depend on the biology of cancer stem cells (CSCs). Recent studies also suggest that intratumour heterogeneity is the main cause of treatment failure due to chemoresistance. Furthermore, the proinflammatory tumour microenvironment seems to contribute to metastasis and chemoresistance. Despite an improved understanding of the complex interplay between classical mechanisms of drug inactivation or efflux, clonal selection and the tumour microenvironment, mechanisms of resistance in human OC are poorly understood. This review summarises current concepts in the treatment of OC, mechanisms of resistance to chemotherapy and angiogenic inhibitors and approaches to overcome drug resistance.

Opposite Macrophage Polarization in Different Subsets of Ovarian Cancer: Observation from a Pilot Study

“…It inhibits angiogenesis but can also promote the recruitment of TAM, immature monocytes, and other vascular modulators to the tumor site [39]. Furthermore, M2 TAMs are known to produce a wide variety of proangiogenic factors such as VEGF to further enhance tumor vascularization, eventually resulting in therapy resistance [40,41]. Moreover, MMP-9 (matrix metalloproteinase 9) secreted by macrophages can increase the bioavailability of VEGF to its receptor [42,43].…”

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…Similar results have been obtained through the combination of bevacizumab with PEGylated liposomal doxorubicin, weekly paclitaxel, or topotecan for the therapy of platinum-resistant ovarian cancer. Specifically, the median progression-free survival was 6.7 months for bevacizumab-containing therapy, as opposed to 3.4 months for chemotherapy alone [132,134]. Furthermore, the efficacy of gemcitabine and cisplatin chemotherapy combined with the anti-angiogenic drug endostar was tested in advanced thymoma and thymic carcinoma, showing improved overall response rates, i.e., 75% vs. 42.9%, but not prolonged progression-free survival and overall survival when compared to chemotherapy alone [135].…”

“…Clinical studies have proved that the combination of bevacizumab and conventional chemotherapy leads to an increase in the survival and response rates in patients with gastrointestinal cancer, non-small cell lung cancer, breast cancer [129][130][131], and ovarian cancer [128]. Specifically, by implementing bevacizumab in the first-line treatment with gemcitabine and carboplatin for the treatment of recurrent ovarian cancer (OCEANS trial), the progression-free survival was improved, the maximum duration of follow-up being almost double [132,133]. Similar results have been obtained through the combination of bevacizumab with PEGylated liposomal doxorubicin, weekly paclitaxel, or topotecan for the therapy of platinum-resistant ovarian cancer.…”

Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review

“…Finally, the mechanisms of inherent and adaptive resistance to antiangiogenic treatments and PARP inhibitors should also be considered [61,62], as should potential new patient profiles that may emerge following relapse after first-line PARP inhibitor treatment. As PARP inhibitors and antiangiogenics move into earlier lines of therapy, it remains unknown whether combined antiangiogenic and PARP inhibitor therapy will remain active in patients who have demonstrated resistance to or have previously received one or the other agent.…”