Molecular targeted therapy in ovarian cancer: what is on the horizon?

Over the past two decades, empirical optimization of cytotoxic chemotherapy combinations and surgical debulking procedures have improved outcomes and survival in epithelial ovarian cancer. Yet, this disease remains the fifth leading cause of cancer-related deaths in the US, as cure rates seem to have reached a plateau at approximately 20% with conventional chemotherapy. Novel high-throughput genomic and proteomic analyses have improved the molecular understanding of ovarian carcinogenesis, thereby providing a vast array of new potential drug targets with complex signalling interactions. In order to yield the most significant impact on disease outcome, it is necessary to carefully select, and subsequently target, the driving molecular pathway(s) within a tumour or tumour subtype, which are most likely to correspond to high-frequency mutations and genomic aberrations. The identification of biomarkers predictive of response to targeted therapy is essential to avoid poor responses to potentially useful drugs in unselected trial populations. With some promising, albeit early, phase III data on the angiogenesis inhibitor bevacizumab, exciting new opportunities lie ahead with the ultimate goal of personalizing therapies to individual tumour profiles.     

Do nonsteroidal anti-inflammatory drugs affect the risk of developing ovarian cancer? A meta-analysis

AIM: The relationship between the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, and the risk of ovarian cancer has been controversial. This study examines the strength of this association by conducting a detailed meta-analysis of the studies published in peer-reviewed literature on the subject. METHODS: A comprehensive search for articles published up to April 2004 was performed, reviews of each study were conducted and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated. RESULTS: Ten reports (six case-control and four cohort studies), published between 1998 and 2004, were identified. There was no evidence of an association between aspirin use and ovarian cancer risk either assuming a random-effects model (RR = 0.92, 95% CI 0.80, 1.06), or a fixed-effects model (RR = 0.93, 95% CI 0.81, 1.06). Similarly, we did not find evidence of an association between non-aspirin NSAID use and ovarian cancer, both on the basis of a random-effects model (RR = 0.86, 95% CI 0.68, 1.08), and on the basis of a fixed-effects model (RR = 0.88, 95% CI 0.76, 1.01). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, our analysis did not show decreasing risks with increasing frequency or duration of use, features often associated with causal relationships. CONCLUSIONS: Our meta-analysis findings do not support that NSAID use plays a role in the chemoprevention of ovarian cancer. Future research should examine potential relationships between specific NSAIDs and ovarian cancer, taking into account the possible biases that may have affected this meta-analysis.     

Activity of tricyclic nucleoside 5′-phosphate in model systems of human ovarian cancer

Tricyclic nucleoside 5-phosphate (TCN-P) was evaluated in two models of human ovarian cancer. TCN-P reduced both colony number and volume in clonogenic assays employing human ovarian cancer cell lines. TCN-P cytotoxicity depended on the concentration, exposure duration and cell line studied, but not on cell line plating efficiency or growth rate in soft agarose. Comparison of experimental IC₅₀ concentrations for 1 hour or continuous TCN-P exposure with reported clinically relevant concentrations suggests that therapeutic TCN-P levels are more likely to be achieved by continuous infusions. Cell lines and sublines with resistance to several standard chemotherapeutic agents acquired both in vivo and in vitro were at most 2.6-fold cross-resistant to TCN-P with 1 hour drug exposure. Cross-resistance was not evident with continuous TCN-P exposure. Intermittent bolus TCN-P (100 mg/kg/d × 5) was ineffective in an in vivo xenograft model of human ovarian cancer. These data suggest that TCN-P is most likely to be clinically effective against ovarian cancer, and may be non-cross-resistant with several standard agents, if administered by continuous infusion. Preclinical evaluation of new agents, such as TCN-P, in these experimental models may provide information useful in subsequent clinical trials.Abbreviations CRI cross-resistance index - EGF epidermal growth factor - IC₅₀ drug concentration causing 50% inhibition of colony formation - LD₁₀ lethal dose in 10% of animals - NS normal saline - r correlation coefficient - RCV relative colony volume - RPMI Roswell Park Memorial Institute - SF surviving fraction - TCN tricyclic nucleoside - TCN-P tricyclic nucleoside 5-phosphate     

Optimal therapy for platinum-resistant recurrent ovarian cancer: doxorubicin, gemcitabine or topotecan?

Ovarian cancer is more fatal than all the other gynaecological malignancies combined. Although most patients respond to first-line combination chemotherapy, the vast majority (50-75%) of patients with advanced disease will relapse. The management of patients with recurrent ovarian cancer is based on their response profile to platinum: patients with platinum-sensitive disease can be rechallenged with platinum-based chemotherapy, whereas the management of patients with platinum-resistant or -refractory disease remains an area of active investigation. In this review, the data for second-line therapy in this latter group of patients will be summarised and recommendations for their optimal management will be made.     

Pro-apoptotic activity of new analog of anthracyclines – WP 631 in advanced ovarian cancer cell line

In this work we investigated the mode of cell death induced by WP 631, a novel anthracycline antibiotic, in the ovarian cancer cell line (OV-90) derived from the malignant ascites of a patient diagnosed with advanced disease. The effects were compared with those of doxorubicin (DOX), a first generation anthracycline. The ability of WP 631 to induce apoptosis and necrosis was examined by double staining with Annexin V and propidium iodide, measurements of the level of intracellular calcium ions and cytochrome c, PARP cleavage. We also investigated the possible involvement of the caspases activation, DNA degradation (comet assay) and intracellular reactive oxygen species (ROS) production in the development of the apoptotic events and their significance for drug efficiency.The results obtained clearly demonstrate that antiproliferative capacity of WP 631 in tested cell line was a few times greater than that of DOX. Furthermore, ovarian cancer cells treated with WP 631 showed a higher mean level of basal DNA damage in comparison to DOX.In conclusion, WP 631 is able to induce caspase – dependent apoptosis in human ovarian cancer cells. Obtained results suggested that WP 631 may be a candidate for further evaluation as chemotherapeutic agents for human cancers.     

Phase II study of esorubicin (4 ′ deoxydoxorubicin) in anthracycline naive patients with ovarian cancer

Summary Sixteen patients with metastatic ovarian cancer who had not previously been treated with anthracyclines were treated with 4 deoxydoxorubicin at a dose of 30 mg/m² intravenously every 3 weeks. There were no clinical responses in this group of patients. Toxicities were infrequent with neutropenia and thrombocytopenia being dose limiting. Nausea and vomiting occurred in only 4 patients. We conclude that 4 deoxydoxorubicin is an inactive drug in this patient population and does not warrant further investigation in this disease.N. Colombo is a recipient of a fellowship from the American-Italian Foundation for Cancer Research.     

Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth

Ovarian cancer is the most lethal gynecological malignancy among US women. Paclitaxel/carboplatin is the current drug therapy used to treat ovarian cancer, but most women develop drug resistance and recurrence of the disease, necessitating alternative strategies for treatment. A possible molecular target for cancer therapy is glycogen synthase kinase 3β (GSK3β), a downstream kinase in the Wnt signaling pathway that is overexpressed in serous ovarian cancer. Novel maleimide-based GSK3β inhibitors (GSK3βi) were synthesized, selected, and tested in vitro using SKOV3 and OVCA432 serous ovarian cancer cell lines. From a panel of 10 inhibitors, GSK3βi 9ING41 was found to be the most effective in vitro. 9ING41 induced apoptosis as indicated by 4',6-diamidino-2-phenylindole-positive nuclear condensation, poly (ADP-ribose) polymerase cleavage, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The mechanism for apoptosis was through caspase-3 cleavage. GSK3βi upregulated phosphorylation of the inhibitory serine residue of GSK3β in OVCA432 and SKOV3 cell lines and also inhibited phosphorylation of the downstream target glycogen synthase. An in-vivo xenograft study using SKOV3 cells demonstrated that tumor progression was hindered by 9ING41 in vivo. The maximum tolerated dose for 9ING41 was greater than 500 mg/kg in rats. Pharmacokinetic analysis showed 9ING41 to have a bioavailability of 4.5% and to be well distributed in tissues. Therefore, GSK3β inhibitors alone or in combination with existing drugs may hinder the growth of serous ovarian cancers.     

Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.     

Expression and clinical significance of HER-2,TOPO-Ⅱα and PI3K in ovarian epithelial cancer

目的 探讨原癌基因人类表皮生长因子受体2(HER-2)、拓扑异构酶Ⅱ(Topo-Ⅱα)和磷脂酰肌醇3激酶(PI3K)在卵巢上皮癌组织中的表达、相互关系及临床意义.方法 采用免疫组化SP方法检测58例卵巢上皮癌(卵巢癌组)、20例卵巢良性上皮性肿瘤(良性组)及10例卵巢正常组织标本(对照组)中HER-2、TOPO-Ⅱα及PI3K的表达情况.结果 HER-2在对照组、良性组中的阳性表达率分别为10.0%、15.0%,显著低于卵巢癌组的46.6%;卵巢癌组中TOPO-Ⅱα的阳性表达率(53.4%)显著高于对照组(10.0%)和良性组(15.0%)(P<0.05);PI3K在卵巢癌组的阳性表达率(69.0%)明显高于对照组(0.0%)和良性组(20.0%) (P<0.05);而良性组和对照组间比较差异无统计学意义(P＞0.05).HER-2、TOPO-Ⅱα及PI3K的表达与卵巢上皮癌临床分期、细胞组织学分化有显著相关性(P＜0.05),而与年龄、组织学类型无显著相关性(P＞0.05);卵巢上皮癌中HER-2分别与TOPO-Ⅱα、PI3K 的表达之间均呈正相关(P＜0.05),TOPO-Ⅱα与PI3K的表达呈正相关(P＜0.05).结论 HER-2、TOPO-Ⅱα和PI3K的表达均与卵巢上皮癌的发生、发展及侵袭、转移有关,并对卵巢上皮癌的发展起协同作用,对临床治疗及预后判断具有重要的指导意义.     

Follicle-stimulating hormone peptide-conjugated nanoparticles for targeted shRNA delivery lead to effective gro-α silencing and antitumor activity against ovarian cancer

The distinct hormone molecules and receptors, such as follicle-stimulating hormone receptor (FSHR) in ovarian cancer, provide opportunities for more precisely targeted therapy. We previously developed FSHR-mediated nanoparticles and found that FSH peptides on the surface of nanoparticles improved the delivery of short interfering RNA (siRNA) into ovarian cancer cells. However, the high toxicity of the nanoparticles and the transient silencing of the siRNA in vivo limited further study. Here, we developed FSH peptide-conjugated nanoparticles with an increased amount of polyethylene glycol (PEG) grafting and encapsulated short hairpin RNA (shRNA) to silence the target gene, growth-regulated oncogene α (gro-α). The nanoparticle complexes exhibited good stability over three weeks. Expression of the target gene, gro-α, was significantly down-regulated by gro-α shRNA-loaded nanoparticles conjugated with FSH peptides (FSH33-G-NP) in FSHR-positive HEY cells. Cell proliferation, migration, and invasion were also inhibited by FSH33-G-NP. Tumor growth was delayed significantly in the mice treated with FSH33-G-NP. No significant loss of body weight or severe toxic effects were observed in any groups. In conclusion, gro-α shRNA-loaded nanoparticles conjugated with FSH peptides overcame the drawbacks of the in vivo application of RNAi therapeutics and polymer-based nanocarriers and showed safe antitumor efficacy. Our study might contribute to the application of FSHR-based targeted therapy and imaging in cancer.     

Ginsenoside 20(S)-Rg3 upregulates HIF-1α-targeting miR-519a-5p to inhibit the Warburg effect in ovarian cancer cells

The Warburg effect, one of the metabolic hallmarks of cancer, is responsible for rapid energy production through a high rate of aerobic glycolysis. Ginsenoside 20(S)-Rg3 antagonizes the Warburg effect in ovarian cancer cells by upregulating some microRNAs, including miR-519a-5p, that target key enzymes involved in aerobic glycolysis. How 20(S)-Rg3-upregulated miR-519a-5p influences the Warburg effect in ovarian cancer cells remains poorly defined, however. Here we report that while overexpression of miR-519a-5p in ovarian cancer cells inhibited the Warburg effect, inhibition of miR-519a-5p negated the suppressive action of 20(S)-Rg3 against the Warburg effect as evidenced by a decrease in glucose consumption, lactate production and HK2 expression. We identified HIF-1α as a direct target of miR-519a-5p via luciferase reporter assays and demonstrated the counteraction by overexpressed HIF-1α of 20(S)-Rg3-suppressed Warburg effect. Further, 20(S)-Rg3 decreased DNMT3A-mediated DNA methylation in the promoter region of its precursor gene, leading to an increase in the level of miR-519a-5p. In conclusion, 20(S)-Rg3 upregulates miR-519a-5p via reducing DNMT3A-mediated DNA methylation to inhibit HIF-1α-stimulated Warburg effect in ovarian cancer.     

TGF-β: friend or foe? The role of TGF-β/SMAD signaling in epigenetic silencing of ovarian cancer and its implication in epigenetic therapy

Importance of the field: The TGF-β signaling pathway plays an important role in regulating numerous cellular processes including growth inhibition of ovarian surface epithelial (OSE) cells. However, epithelial ovarian cancer is refractory to the inhibitory functions of TGF-β, and yet TGF-β induces metastasis or epithelial–mesenchymal transition (EMT) in advanced ovarian cancer. How TGF-β plays a certain role in one cell but a different role in its malignant counterpart is not fully understood.

Areas covered in this review: The role of TGF-β/SMAD signaling both in normal OSE cells and ovarian cancer as well as how dysregulation of this signaling pathway leads to epigenetic silencing of its downstream targets in ovarian neoplasias are reviewed. The therapeutic implication of this signaling pathway in epigenetic therapy of ovarian cancer are also discussed.

What the reader will gain: The reader will gain insight on how dysregulation of TGF-β signaling alters promoter methylation and histone modifications of TGF-β downstream targets in ovarian cancer.

Take home message: Disruption of TGF-β/SMAD signaling leads to epigenetic silencing of its target genes transiently through histone modifications but permanently by promoter hypermethylation. Targeting the TGF-β signaling pathway may be a novel therapeutic strategy in ovarian cancer.     

Can cancer centres in New Zealand help the cancer registry generate survival data? A pilot study in prostate cancer

AIMS: One of the current limitations of reports issued by the New Zealand Cancer Registry (NZCR) is that the only measure of the success of treatment is provided by the mortality ratio. A pilot study was therefore carried out to see if collaboration between cancer centres and the NZCR might allow the generation of more meaningful survival data that could be used for the audit of treatment outcome. METHODS: Clinical details of patients seen at the Wellington Cancer Centre (WCC), in whom a diagnosis of prostate cancer was made in 1997, were provided to the NZCR. These details were matched with registration and mortality data held by the NZCR. RESULTS: WCC records identified 82 patients who were diagnosed with prostate cancer in 1997. Of these, the NZCR registered 60 (73%) in 1997, 3 (4%) prior to 1997, and 14 (17%) after 1997. Five patients (6%) were not registered at all. In the cohort of 82 patients, 17 (21%) had subsequently died. Of these, 11 (65%) had been treated with palliative intent, and six (35%) with radical intent. Of those patients treated radically, three had died of prostate cancer and three of other causes. CONCLUSIONS: Cooperation between Cancer Centres and the NZCR would allow the NZCR to generate useful survival data. This could help evaluate the impact on survival of specific treatments and interventions, such as screening programs. Regional variations in outcome could be detected. The exercise is feasible, without compromising patient confidentiality.     

Chemokines and breast cancer: a gateway to revolutionary targeted cancer treatments?

Breast cancer is an example of a solid tumour which is well treated in the early stages of disease by surgical excision, but once metastatic spread has occurred, medical therapies (chemotherapy and radiotherapy) are highly toxic, expensive and palliative. It is known that certain tumours exhibit specific patterns of metastasis, chemokines may provide a molecular answer to this mystery. Chemokines and their receptors play important roles in the various stages of tumour development and metastasis. Chemokines interact with their specific receptors as well as interacting with the glycosaminoglycan (GAG) component of proteoglycan. We discuss the basic metastatic process and the involvement of chemokines in breast cancer biology. Finally, we summarize potential therapeutic applications of chemokines and chemokine/glycosaminoglycan interactions including chemokine agonists, antagonists, anti-sense therapy, immunotherapy and soluble GAGs, as well as future perspectives in this field.