Adjuvant Therapy For Ovarian Cancer Research Articles

Quality of life of ovarian cancer patients treated with combined platinum taxane chemotherapy: a systematic review of the literature.

Chemotherapy is the cornerstone of adjuvant therapy in ovarian cancer. Its impact on the quality of life (QoL) has been addressed in several studies; however, several misperceptions concerning this affect patient counseling and physicians' ability to overcome patient fears. In the present systematic review, we sought to accumulate current evidence in the field in order to help establish robust information that will help physicians answer patients' questions. The present systematic review is based on the PRISMA guidelines. Studies that evaluated patient QoL pre-, during, and post-chemotherapy with the use of the QLQC-30 were selected for inclusion. Their methodological quality was assessed with the before-after studies tool that is proposed by the National Institute of Health (NIH). Ten studies that involved 5181 patients were included in the present systematic review. The risk of bias and methodological quality of included studies was of good and fair overall quality. Retrieved data suggest there is substantial evidence that points toward improved global QoL among ovarian cancer patients treated with taxanes-platinum combination therapy. Individual outcomes evaluated with the QLQ-C30 also provide positive results, although underreporting was noted. Despite the significant heterogeneity in outcome reporting, the findings of this study reveal the significant benefit of combined platinum taxane chemotherapy on the QoL of ovarian cancer patients and can be used for patients counseling in order to reduce refusals that arise from fear of adverse effects that may negatively affect QoL. Graphical abstract.

Comparative Efficacy and Safety of Adjuvant Therapies for Post-Surgery Ovarian Carcinoma: A Systematic Review and Network Meta-Analysis

Background: The efficacy and safety of different adjuvant therapies for post-surgery ovarian carcinoma remains controversial. We performed a random-effects Bayesian network meta-analysis (NMA) to provide comprehensive assessment. Methods: Full text reports of randomized clinical trials in this field were identified from Pubmed, Embase and the Cochrane Library. Randomized clinical trials comparing adjuvant treatment regiments for post-surgery ovarian cancer patients were included. A random-effets Bayesian NMA was employed. Findings: 52 randomized controlled trials (20801 patients) comparing 20 different regimens were included. Compared with the classic carboplatin plus paclitaxel (CT), intraperitoneal plus intravenous (IP/IV) regimen was associated with longer overall survival (OS) with HR 0*83, 95% CI, 0*69-0*9, while carboplatin plus paclitaxel plus bevacizumab (CTBeva) provided longer progression free survival (PFS) with HR 0*85, 95% CI, 0*71-0*99. No significant distinction was found between IP/IV and CTBeva. Triplet regimens were not superior to CT as double regimens on both OS and PFS. CTBeva showed no dramatic divergences on overall toxic effect, haematological and gastrointestinal toxicity compared with CT, while IP/IV was associated with higher risk of gastrointestinal toxicity (pooled RR, 3*76; 95% CI, 1*13-9*23). In addition, the haematological toxicity of triplet regimens was worse than CT (pooled RR, 3*00; 95% CI, 1*48-5*54). Interpretation: Adjuvant therapy for ovarian cancer with IP/IV regimen provided an OS advantage over CT, while CTBeva prolonged PFS. IP/IV and CTBeva shown similar efficacy. No additional toxic effects were validated in the present comparisons except GI toxicity brought by IP/IV regimen. Furthermore, the triplet regimens were not superior. Funding Statement: This work was supported by the National Natural Science Foundation of China [grant numbers 81302455 and 31471297] and the Natural Science Foundation of Zhejiang Province [grant number LY15H160007]. Declaration of Interest: The authors declare that they have no conflict of interests. Ethics Approval Statement: Institutional Review Board approval was not required for this study.

Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts

Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

Investigating the Potential for Na+‐H+ Exchanger Isoform 1 (NHE1) Inhibitors as Adjuvant Therapies in the Treatment of Ovarian Cancer

Each year in the United States over 200,000 women are diagnosed with ovarian cancer leading to more than 130,000 deaths. A major challenge in ovarian cancer treatment is the development of drug resistance to the therapeutic agents. Increases in the expression and activity Na+‐H+ Exchanger Isoform 1 (NHE1) was recently demonstrated to regulate cell proliferation in ovarian cancer patients. NHE1 is an 815 amino acid transmembrane transport protein that regulates intracellular pH. We hypothesize that combining common ovarian cancer therapeutic agents along with compounds that directly or indirectly inhibit NHE1 will enhance the ability of the therapeutic agents to slow ovarian cancer cell proliferation and migration. Three ovarian adenocarcinoma cell lines; CAOV‐3, SKOV‐3, and OVCAR‐3 are used in this research. Using a proliferation assay, we assessed the impact of different ovarian cancer therapeutics (Rucaparib, Olaparib, Paclitaxel and Cisplatin) in these three cell lines in the presence and absence of inhibitors that decrease NHE1 activity directly or indirectly. Our previous work demonstrated that the NHE1 inhibitor cariporide and a number of protein kinase inhibitors decreased cell proliferation rates in all three cell types. Treatment with Cisplatin reduced cell proliferation most significantly in the CAOV‐3 line. Paclitaxel and Cisplatin each had significant and comparable impacts on the SKOV‐3 and OVCAR‐3 cell lines. Cell migration was evaluated using electric cell‐substrate impedance sensing (ECIS). In the SKOV‐3 and CAOV‐3 cells, inhibition with cariporide and the Rsk inhibitor BID1870 each dramatically reduced the rate of cell migration. The research presented here supports the role of NHE1 in cell proliferation, and for the first time implicates NHE1 in the regulation of cell migration in ovarian cancer cells. Data will be presented that evaluated the potential for the inhibition of NHE1 as an adjuvant therapy in ovarian cancer.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Decreasing the ratio of matriptase/HAI‑1 by downregulation of matriptase as a potential adjuvant therapy in ovarian cancer.

Tumor invasion and metastasis are complex biological processes. Matriptase and its endogenous inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1) are involved in invasion and metastasis. To evaluate the ratio of matriptase/HAI-1 and their potential therapeutic value in ovarian cancer, HO-8910 human ovarian cancer cells and the homologous high-metastatic HO-8910PM cells were used as in vitro cellular models ovarian cancer. The invasive and metastatic abilities, and the expression of matriptase and HAI-1 in these cells were detected using scratch assays, Transwell chamber assays, reverse transcription-quantitative polymerase chain reaction, western blotting and fluorescent immunocytochemistry. Following infection with lentivirus-mediated matriptase-targeting small interfering RNA (siRNA), cell cycle progression and apoptosis were also analyzed. The migration distance and number of invading HO-8910PM cells were significantly increased compared with HO-8910 cells. HO-8910PM cells exhibited a significantly higher ratio of matriptase/HAI-1 mRNA levels compared with HO-8910 cells (0.51 vs. 0.24, ~2.2 fold increase). Compared with HO-8910 cells, the matriptase mRNA level was increased by ~3.6 fold in HO-8910PM cells, whereas the HAI-1 mRNA level was increased by ~1.7 fold. Similar increases in protein expression levels were also observed in HO-8910PM cells compared with HO-8910 cells. Migration and invasiveness were positively correlated with matriptase expression level (r=0.994, P<0.01) and the ratio of matriptase/HAI-1 (r=0.929, P<0.01). Downregulation of matriptase using siRNA resulted in inhibition of the invasive and metastatic abilities of HO-8910PM cells, cell cycle arrest in the G0/G1 phase and increased apoptosis. The present study demonstrated that ovarian cancer cell metastasis and invasion were more dependent on upregulation of matriptase levels than downregulation of HAI-1. Matriptase may be a potential adjuvant therapeutic target for inhibiting ovarian cancer invasion and metastasis.

Comparative effectiveness research in gynecologic oncology.

The field of gynecologic oncology is faced with a number of challenges including how to incorporate new drugs and procedures into practice, how to balance therapeutic efficacy and toxicity of treatment, how to individualize therapy to particular patients or groups of patients, and how to contain the rapidly rising costs associated with oncologic care. In this chapter we examine three common and highly debated clinical scenarios in gynecologic oncology: the initial management of ovarian cancer, the role of lymphadenectomy in the treatment of endometrial cancer, and the choice of adjuvant therapy for ovarian cancer.

Abstract 2268: Suicidal tendencies: The promotion of cell death by a prolactin antagonist through autophagy in ovarian cancer

Abstract As a multifunctional pituitary hormone and cytokine, prolactin (PRL) is not only essential for normal reproduction and maintenance of pregnancy, but is involved in over 300 biological activities. There is increasing evidence that PRL plays a role in a variety of cancers including ovarian cancer. Elevated levels of PRL have been reported in patients with ovarian cancer. Furthermore, increased expression of PRL receptors (PRLr) have been shown in ovarian cancers, signifying the importance of PRL-mediated signaling in ovarian carcinogenesis. Abnormal activities of PRLr-mediated signaling pathways such as MAPK and JAK2/STAT5 lead to tumorigenicity and recurrence. Therefore, inhibition of PRL signaling is implicated as a target in cancer therapy; however, no viable strategies have been identified for blocking PRL during tumor progression. Herein, we report a novel strategy to counteract the activity of PRLr-mediated cellular survival in malignant ovarian cancer cells with autophagic cell death. Prolanta (G129R), an analog of human PRL with a single amino-acid substitution at position 129 Glycine with bulky Arginine, induces adaptive autophagy through antagonism of the PRLr expressed on human ovarian cancer cells (HeyA8 and SKOV3). The mouse ovarian cancer cell IG10, which does not express PRLr, had no induction of autophagy upon Prolanta treatment. We also identified that Prolanta competitively binds to PRLr and partially inhibits the oncogenic signaling pathways mediated by PRLr, including JNK/STAT3, PI-3K/Rac/PAK pathways that can lead to cell proliferation, differentiation and survival. In addition, we observed cell death after Prolanta treatment in 3-D-spheroid models. We explored molecular mechanisms behind this autophagic cell death induced by Prolanta. Through biomarker identification using the reverse phase protein array (RPPA), we revealed a signaling complex regulated by Pea-15, an autophagy activator through JNK-pathway, which was activated by Prolanta. Microarray analysis reported an array of autophagic genes activated by Prolanta. Furthermore, in an orthotopic mouse model, Prolanta treatment with or without a taxane caused significant inhibition of SKOV3 and HeyA8 growth. In summary, Prolanta functions as a molecular antagonist to tumor-associated PRL by inducing adaptive autophagic cell death in human ovarian cancer. These preclinical findings reveal the novelty of Prolanta as an adjuvant therapy for ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2268. doi:1538-7445.AM2012-2268

Abstract 78: Role of 12-lipoxygenase in regulation of ovarian cancer cell proliferation and survival

Abstract Enzymes involved in eicosanoid synthesis have previously been implicated in the progression of various types of cancer, including ovarian carcinomas. Most of the current data in ovarian cancer have focused on cyclooxygenase-2 (COX-2). It is not known whether the main human 12-hydroxyeicosatetrenoate (12-HETE) generating enzyme, 12-lipoxygenase (12-LOX), contributes to the regulation of growth of ovarian cancer cells. In the present study, we examined the function of the 12-lipoxygenase pathway in the regulation of proliferation and survival of three epithelial ovarian cancer (EOC) cell lines. We found that all three EOC cells express high level of the mRNA encoding for 12-LOX, using RT-PCR. These cells also contain significant amount of immuno-reactive 12-LOX protein as revealed by western blot. Liquid chromatography/Mass Spectrometry (LC/MS) analysis confirmed that all three EOC produce 12-HETE when challenged with arachidonic acid (AA). N-benzyl-n-hydroxy-5-phenyl-pentanamide (BMD-122) is a specific 12-LOX inhibitor. Exposure of the three EOC cell lines to an increasing dose of the 12-LOX inhibitor, BMD-122 (1 μM, 10 μM and 50 μM), resulted in a dose-dependent inhibition in cell proliferation (75±9%, 51±6% and 26±4% of untreated control, respectively), measured by MTT assay in vitro. Furthermore, treatment with 10 μM BMD-122 was associated with up to ∼30% increases in the apoptosis of these EOC cells within 24 hr, measured by Annexin-V flow cytometry. This apoptosis seems to be mediated through a mechanism independent of PI-3 kinase since the expression of phosphorylated Akt was not affected by BMD-122 treatment. Furthermore, we found that BMD-122 treatment had no effect on the three EOC cell lines ability to invasion using Matrigel assay. Taken together, these data suggest that 12-LOX is involved in regulation of ovarian cancer progression and survival, an important and novel finding. Inhibition of 12-LOX may have potential as an adjuvant therapy in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 78.

Intraperitoneal photodynamic therapy for an ovarian cancer ascite model in Fischer 344 rat using hematoporphyrin monomethyl ether

With limited treatment options, intraperitoneal spread of ovarian cancer is a common problem leading to high morbidity. Intraperitoneal photodynamic therapy combined with debulking surgery to treat residual disease is an alternative choice for clinicians. Hematoporphyrin monomethyl ether (HMME) is a promising second-generation photosensitizer developed in China. Our study was designed to investigate the phototoxicity of HMME on ovarian cancer. NuTu-19, a cell line derived from adenocarcinoma of Fischer 344 rat, and its allogeneic graft ascites tumor model was used in this study. HMME was confirmed to be localized in cytolysosome, and HMME-based photosensitization induced direct necrosis as well as mitochondria damage. The photocytotoxicity of HMME was both light- and drug dose-dependent and no significant dark cytotoxicity was observed in NuTu-19 cells. With the ascite tumor-bearing Fischer 344 rat model, HMME-based intraperitoneal photodynamic therapy was proved to be useful in improving the prognosis of ovarian cancer. Thus, this study provides evidence that HMME-based photodynamic therapy is an effective adjuvant therapy for ovarian cancer.

LONG-TERM FOLLOW-UP RESULTS OF PATIENTS WITH STAGE IC-IV OVARIAN-CANCER TREATED WITH CISPLATIN, EPIRUBICIN AND IFOSFAMIDE CHEMOTHERAPY

Sixty-three patients with stage Ic-IV ovarian cancer received cisplatin, epirubicin and ifosfamide chemotherapy following a staging surgery between 1985 and 1992. The optimal surgery (without macroscopic residual was completed in 44 patients including 12 stage III cases. A 5-year survival of 97.5% was obtained for the optimal cases; whereas that for suboptimal cases was only 24.0%. From the results, the regimen proved to be a promising adjuvant therapy for ovarian cancer after optimal surgery; moreover a need for a drastic amelioration of strategy is emphasized in the treatment of advanced ovarian cancer with extensive metastases.