BACKGROUND: Ovarian cancer stem cells are characterized by self-renewal capacity, ability to differentiate into distinct lineages, as well as higher invasiveness and resistance to many anticancer agents. Since they may be responsible for the recurrence of ovarian cancer after initial response to chemotherapy, development of new therapies targeting this special cellular subpopulation embedded within bulk ovarian cancers is warranted.
A high-throughput screening (HTS) campaign was performed with 825 compounds from the Mechanistic Set chemical library [Developmental Therapeutics Program (DTP)/National Cancer Institute (NCI)] against ovarian cancer stem-like cells (CSC) using a resazurin-based cell cytotoxicity assay. Identified sets of active compounds were projected onto self-organizing maps to identify their putative cellular response groups.
From 793 screening compounds with evaluable data, 158 were found to have significant inhibitory effects onovarian CSC. Computational analysis indicates that the majority of these compounds are associated with mitotic cellular responses.
Our HTS has uncovered a number of candidate compounds that may, after further testing, prove effective in targeting both ovarian CSC and their more differentiated progeny.
Departments of Pharmacology; Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322; Departments of Winship Cancer Institute; Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322.
Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over-expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15-mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression.
Author Affiliations: Department of Nursing and Patient Care Services (Drs Gross and Fonteyn) and Medical Gynecologic Oncology (Dr Matulonis), Dana-Farber Cancer Institute; Harvard Medical School, Boston, Massachusetts; and College of Nursing and Health Sciences, University of Massachusetts, Boston (Drs Cromwell and Hayman).
BACKGROUND:Hopelessness negatively affects ovarian cancer patients' quality of life (QOL). Research validating the effects of complementary and alternative medicine (CAM) use on QOL and hope is scarce, even though QOL and hope are reasons that patients cite for using CAM therapy. Clinicians need effective, evidence-based interventions to improve QOL and reduce hopelessness.
OBJECTIVE:The objectives of this study were to examine factors influencing hopelessness in patients with newly diagnosed disease, long-term survivors, and patients experiencing ovarian cancer recurrence and to examine the effects of CAM on hopelessness in the same population.
METHODS: Surveys of ovarian cancer patients (N = 219) undergoing treatment at a comprehensive cancer center in the United States were analyzed. Descriptive, correlation, and multivariate analyses described variables and demonstrated the effects of sociodemographics, disease state, psychological distress, QOL, CAM use, and faith on hopelessness.
RESULTS: Patients ages 65 years or older (-0.95, P = .03), with strong faith (-0.28, P = .00), and good QOL (0.11, P = .00) directly reduced hopelessness scores (mean, 3.37). Massage therapy substantially reduced hopelessness scores (-1.07, P = .02); holding age constant, employed patients were twice as likely to use massage (odds ratio, 2.09; P = .04). Patients who had newly diagnosed and recurrent ovarian cancer were more hopeless because of greater distress from symptoms and adverse effects of treatment.
CONCLUSION: Patients who used massage therapy were significantly less hopeless, as were those with strong faith and well-controlled disease symptoms and treatment for adverse effects.
IMPLICATIONS FOR PRACTICE:Support of spiritual needs and symptom management are important interventions to prevent and/or reduce hopelessness, especially for patients with newly diagnosed and recurrent ovarian cancer. Further research testing the positive effect of massage interventions on hopelessness is needed.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba Israel, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: email@example.com.
To explore the pattern of chemotherapy (beyond the second-line) used to treat patients with recurrent epithelial ovarian cancer (including primary peritoneal carcinoma).
This retrospective study included 156 patients with recurrent epithelial ovarian cancer and primary peritoneal carcinoma who were treated in the Gynecologic Oncologic Department at Meir Medical Center between November 1995 and December 2003. Clinical characteristics and data regarding the surgery, chemotherapy, and response to treatment were abstracted from the patients' medical records to determine patient response to advanced lines of chemotherapy for recurrent epithelial ovarian cancer.
Of the 156 patients, 63 (40%) were treated beyond second-line chemotherapy. Clinical response to third-line chemotherapy was 11.9% (6.8% had complete clinical response and 5.1% partial clinical response) and 3.4% had stable disease. A total of 17% did not show immediate progression, with a median progression free-interval of 1.5 months. A drastic decline in clinical response rates was shown beyond third-line chemotherapy. Any response to treatment in more advanced lines was consistently under 5%.
These results imply that advanced lines of chemotherapy are associated with low response rates, although a small percentage of patients showed some clinical response or remained with stable disease at the end of treatment. Along with patient preferences, the advantages and disadvantages of continued therapy should be considered, for the side effects of each treatment cannot be overlooked.
Cancer Epigenetics and Biology Program; Bellvitge Biomedical Research Institute; Barcelona, Catalonia Spain.
Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancerpatients undergoing chemotherapy with cisplatin.
Department of Obstetrics and Gynecology, Miyoshi Central Hospital, 531 Higashisakeyamachi, Miyoshi, Hiroshima, 728-8502, Japan, firstname.lastname@example.org.
The therapeutic value of systematic lymphadenectomy for early-stage epithelial ovarian cancer (EOC) is controversial. This study evaluates the survival impact and adverse events of systematic pelvic and para-aortic lymphadenectomy in patients with pT1 and pT2 EOC.
A retrospective investigation was performed using data from patients with pT1 and pT2 EOC at multi-institutions belonging to the Sankai Gynecologic Study Group (SGSG). We selected patients who had undergone systematic pelvic and para-aortic lymphadenectomy (Group LA) (n = 284) and patients who had not undergone lymph node resection (Group no-LA) (n = 138). Outcomes for patients and peri-operative adverse events were compared between the two groups.
The median operation time was significantly longer in Group LA (288 min) than in Group no-LA (128 min) (P < 0.0001). Total blood loss was significantly higher in Group LA, 43.7 % of patients receiving blood transfusions. There were no significant differences between the treatment groups for progression-free survival (PFS) or overall survival (OS). However, for patients with pT2, PFS was significantly longer in Group LA than in Group no-LA (P = 0.0150). Lymph node metastases were detected in 23 cases (8.1 %) and these patients had significantly shorter PFS than those without metastasis (P = 0.0409). The outcome for patients who underwent chemotherapy after surgery was significantly improved in the Group no-LA, but no improvement was observed in Group LA.
Systematic lymphadenectomy may improve outcomes only in pT2 EOC patients with acceptable peri-operative events. Furthermore, accurate surgical staging may avoid unnecessary adjuvant chemotherapy in selected early-stage cases.
1Pathology, University of Colorado Anschutz Medical Campus.
A therapeutic intervention that could decrease tumor burden and increase sensitivity to chemotherapy would have a significant impact on the high morbidity rate associated with ovarian cancer. MicroRNAs (miRNAs) have emerged as potential therapeutic candidates due to their ability to down regulate multiple targets involved in tumor progression and chemoresistance. MiR-200c is down regulated in ovarian cancer cell lines and stage III ovarian tumors, and low miR-200c correlates with poor prognosis. MiR-200c increases sensitivity to taxanes in vitro, by targeting TUBB3, a tubulin known to mediate chemoresistance. Indeed, we find that patients with tumors with low TUBB3 had significantly prolonged survival (average survival 52.73 ± 4.08 months) compared to those with high TUBB3 (average survival 42.56 ±3.19 months). MiR-200c also targets TrkB, a mediator of resistance to anoikis. We demonstrate that restoration of miR-200c to ovarian cancer cells results in increased anoikis sensitivity and reduced adherence to biological substrates in vitro. Since both chemo- and anoikis-resistance are critical steps in the progression of ovarian cancer, we sought to determine how restoration of miR-200c affects tumor burden and chemosensitivity in an in vivo preclinical model of ovarian cancer. Restoration of miR-200c in an intraperitoneal xenograft model of human ovarian cancer, results in decreased tumor formation and tumor burden. Furthermore, even in established tumors, restoration of miR-200c, alone or in combination with paclitaxel, results in significantly decreased tumor burden. Our study suggests that restoration of miR-200c immediately prior to cytotoxic chemotherapy may allow for a better response or lower effective dose.
Ovarian cancer risk decreases with frequent aspirin use
Decreasing a woman’s risk for ovarian cancer may be as simple as taking common pain relievers such as aspirin, suggests a new study from Denmark. Women taking aspirin at least twice a week for one month decreased their risk for ovarian cancer by 40 percent when compared to women not taking the medication as frequently.
While aspirin was indicated as a major factor for ovarian cancer risk, researchers also found other pain relievers evaluated in the study decreased the risk for serious cancers at a lesser rate. Drugs such as acetaminophen, ibuprofen and naproxen decrease serious cancer risk in women by approximately 28 percent.
The use of painkillers, however, must be taken with caution, as other studies indicate they generate addiction and lead to other serious health concerns.
Ovarian cancer and aspirin research
For the research, the Demark researchers evaluated 750 women with ovarian cancer as well as a control group of 1500 healthy women. The study participants were asked questions pertaining to overall health and what medications were taken regularly.
Contraceptives, which have also been noted to reduce the risk of ovarian cancer, were taken into consideration. At the end of the research period, experts surmised chronic inflammation may play a role in the development of ovarian cancer, and therefore the use of anti-inflammatories decreased a woman’s risk.
Dr. Noah Kauff, told My Health News Daily, director of ovarian cancer screening and prevention at Memorial Sloan-Kettering Cancer Center in New York City, told My Health News Daily, chronic inflammation from normal ovulation can result when the surface of the ovary sustains damage from releasing an egg. As the ovary attempts to repair its damaged surface, there is an increase in cell production and cell division—actions which raise the risk of abnormal cell growth known as cancer.
“We desperately need prevention strategies [for ovarian cancer],” he said, adding there are no good methods of detecting ovarian cancer, and therefore the disease often goes undiagnosed until it is in advanced stages.
Though considered uncommon, new cases of ovarian cancer affect approximately 20,000 women annually, with 90 percent of those women over the age of 40, according to the Centers for Disease Control (CDC).
Ovarian cancer is the fifth leading cause of cancer-related deaths, and it is the most deadly of all cancers in the female reproductive tract.