Angiogenesis inhibitors for the treatment of ovarian cancer.
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ABSTRACT:
SUBMITTER: Gaitskell K
PROVIDER: S-EPMC4167846 | biostudies-literature | 2011 Sep
REPOSITORIES: biostudies-literature
Publications
Angiogenesis inhibitors for the treatment of ovarian cancer.
Gaitskell Kezia K Martinek Igor I Bryant Andrew A Kehoe Sean S Nicum Shibani S Morrison Jo J
The Cochrane database of systematic reviews 20110907 9
<h4>Background</h4>Many women with ovarian cancer eventually develop resistance to conventional chemotherapy drugs, and so novel agents are being developed to target specific molecular pathways. One such class of drugs inhibits angiogenesis (the development of new blood vessels), which is essential for tumour growth. It is important to establish whether the addition of these new drugs to conventional chemotherapy regimens improves survival, and what the side-effects may be.<h4>Objectives</h4>To ...[more]
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Project description:BACKGROUND:Angiogenesis inhibitors showed activity in ovarian cancer, but preliminary data could not accurately reflect the survival benefit. We thus did a systematic review and meta-analysis of randomized controlled trials to reassess the efficacy and safety of angiogenesis inhibitors combined with chemotherapy for ovarian cancer. METHODS:We searched PubMed, EMBASE, Cochrane, and ClinicalTrials.gov for randomized controlled trials comparing angiogenesis inhibitors containing therapy with conventional chemotherapy alone or no further treatment. Our main outcomes were the progression-free survival (PFS), overall survival (OS), and common adverse events. RESULTS:Fifteen trials were included (N = 8721 participants). For newly diagnosed ovarian cancer, combination treatment with angiogenesis inhibitors and chemotherapy yielded a lower risk of disease progression (hazard ratio [HR], 0.83; 95% confidence interval (CI), 0.71-0.97) and no improved OS (HR, 0.95; 95% CI, 0.86-1.05). In the high-risk progression subgroup, the addition of bevacizumab significantly improved PFS (HR, 0.72; 95% CI, 0.65-0.81) and OS (HR, 0.84; 95%CI, 0.74-0.96). In recurrent patients, the combined HR was 0.58 (95% CI, 0.52-0.65) for PFS, and for OS, the combined HR was 0.86 (95% CI, 0.79-0.94). We found no significant improvement for either PFS (HR, 0.80; 95% CI, 0.63-1.01) or OS (HR, 1.06; 95% CI, 0.88-1.28) in the pure maintenance therapy.In the overall population, angiogenesis inhibitors increased the incidence of gastrointestinal perforation (risk ratio [RR], 2.57; 95% CI, 1.66-3.97), hypertension (RR, 7.60; 95% CI, 2.79-20.70), arterial thromboembolism (RR, 2.27; 95% CI, 1.34-3.84), proteinuria (RR, 4.31; 95% CI, 2.15-8.64), and complication of wound healing (RR, 1.72, 95% CI, 1.12-2.63). CONCLUSIONS:Combination treatment with angiogenesis inhibitors and chemotherapy significantly improved PFS and OS in both patients with high-risk of progression and recurrent ovarian cancer, with an increased incidence of common adverse events. Conversely, we detected no statistically significant survival benefit in the pure maintenance setting. The main limitation of the review is clinical heterogeneity across the studies.
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Project description:Poly(ADP-ribose) polymerase (PARP), which was first described over 50 years ago by Mandel, are a family of protein enzymes involved in DNA damage response and works by recognizing the single-strand DNA break (ssDNA) and then effecting DNA repair. A double-strand DNA (dsDNA) break can be repaired by one of two different pathways: homologous recombination (HR) or non-homologous end joining (NHEJ). Homologous recombination occurs in the G2 or M phase of the cell cycle when a sister chromatid is available to use as a template for repair. Because a template is available, HR is a high fidelity, error-free form of DNA repair. With NHEJ there is not a template and the DNA is trimmed and ligated which is a very error-prone process of repair which can lead to genetic instability. Exploiting these mechanism led to development of PARP inhibitors with the idea of utilizing synthetic lethality, where two deficiencies each having no effect on the cellular outcome become lethal when combined, as single agent in BRCA deficient patients or as chemotherapy/radiotherapy combinations to inhibit ssDNA repair. The recent approval of olaparib in BRCA deficient ovarian cancer patients in US and Europe has opened up a whole new treatment option for ovarian cancer patients. This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future.
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Project description:IntroductionThis meta-analysis was performed to evaluate the efficacy and safety of angiogenesis inhibitors (Ais) combined with poly ADP ribose polymerase inhibitors (PARPi) in the maintenance treatment of advanced ovarian cancer (OC).Materials and methodsA systematic search was conducted in four databases (Pubmed, Embase, Web of Science, and Cochrane) for articles published from the inception of the databases until January 15, 2024. The focus of the search was on articles investigating the combination of Ais with PARPi in the maintenance treatment of ovarian cancer. Meta-analyses were conducted to assess the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the risk of Grade ≥ 3 adverse events (Grade≥ 3 AEs).ResultsTotally nine studies were included for meta-analysis. The overall pooled ORR of Ais combined with PARPi was 57% (95% CI, 35% to 77%). Subgroup analyses showed that the ORR for patients with platinum-resistant recurrent ovarian cancer, platinum-sensitive recurrent ovarian cancer and newly diagnosed advanced ovarian cancer were 30% (95% CI, 12% to 52%), 70% (95% CI, 61% to 78%) and 59% (95% CI, 55% to 63%), respectively. The median PFS was 5.8 months (95% CI, 5.3 to 7.1), 12.4 months (95% CI, 10.6 to 13.2) and 22.4 months (95% CI, 21.5 to 24.2), respectively. The median OS was 15.5 months (95% CI, 12.3 to 24.8), 40.8 months (95% CI, 33.4 to 45.2) and 56.3 months (95% CI, 49.0 to 62.0), respectively. The rate Grade≥ 3 TRAEs rate was found to be 0.22 (95% CI, 0.13 to 0.33).ConclusionsOur results confirmed that PARPi plus Ais was a feasible and safe option for the maintenance treatment of advanced ovarian cancer. The combination therapy should be recommended as the first-line maintenance treatment for patients with advanced ovarian cancer. PARPi plus Ais yielded more favorable oncological prognosis for patients with platinum-sensitive recurrent ovarian cancer, compared to patients with platinum-resistant recurrent ovarian cancer.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024543590, identifier CRD42024543590.
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Project description:ObjectiveTo investigate the efficacy and safety of angiogenesis inhibitors in the treatment of recurrent ovarian cancer (OC).MethodsElectronic databases including PubMed, Web of Science, and the Cochrane Library were searched to find eligible studies until August 10, 2021. The data on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were pooled. Furthermore, grade ≥ 3 adverse events (AEs) were investigated.ResultsA total of 13 studies with 3953 patients were included. Compared with control group, angiogenesis inhibitors resulted in significant improvement in PFS (hazard ratio (HR) = 0.61, 95%CI, 0.54-0.69), OS (HR = 0.88, 95%CI, 0.81-0.95), and ORR (odds ratio (OR) = 2.15, 95% CI, 1.74-2.65). However, angiogenesis inhibitors were associated with a higher risk of grade ≥ 3 AEs (relative risk (RR), 1.20, 95% CI, 1.04-1.38).ConclusionAngiogenesis inhibitors can improve ORR, PFS, and OS in patients with recurrent OC, but they can increase the incidence of AEs ≥ 3.
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Project description:The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.
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Project description:IntroductionDue to the difficulty of early diagnosis, nearly 70% of ovarian cancer patients are first diagnosed at an advanced stage. Thus, improving current treatment strategies is of great significance for ovarian cancer patients. Fast-developing poly (ADP-ribose) polymerases inhibitors (PARPis) have been beneficial in the treatment of ovarian cancer at different stages of the disease, but PARPis have serious side effects and can result in drug resistance. Using PARPis in combination with other drug therapies could improve the efficacy of PRAPis.In this study, we identified Disulfiram as a potential therapeutic candidate through drug screening and tested its use in combination with PARPis.MethodsCytotoxicity tests and colony formation experiments showed that the combination of Disulfiram and PARPis decreased the viability of ovarian cancer cells.ResultsThe combination of PARPis with Disulfiram also significantly increased the expression of DNA damage index gH2AX and induced more PARP cleavage. In addition, Disulfiram inhibited the expression of genes associated with the DNA damage repair pathway, indicating that Disulfiram functions through the DNA repair pathway.DiscussionBased on these findings, we propose that Disulfiram reinforces PARPis activity in ovarian cancer cells by improving drug sensitivity. The combined use of Disulfiram and PARPis provides a novel treatment strategy for patients with ovarian cancer.
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