Publications
331 results found
Tan DSP, Iravani M, McCluggage WG, et al., 2011, Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 1521-1534, ISSN: 1078-0432
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- Citations: 99
Fotopoulou C, McIndoe A, Sehouli J, et al., 2011, Current clinical trials in ovarian cancer, Gynaecological Cancers: Biology and Therapeutics, Pages: 205-222, ISBN: 9781906985448
Epithelial ovarian cancer (EOC) is the most common cause of death among women who develop gynaecological cancer and the fifth most common cause of cancer-related death in females in western countries. The latest data show that one in 43 women will develop EOC during their lifetime. Women with a mutated BRCA1 or BRCA2 gene are at increased risk, ranging between 25% and 60% depending on the specific mutation.Owing to its unusual tumour biology and clinical behaviour, the disease presents late, typically with extensive locoregional dissemination throughout the peritoneal cavity with surprisingly rare incidence of truly visceral metastatic disease, although nodal involvement is not uncommon and of unclear significance.This unusual natural history has led to unique therapeutic strategies that reflect the importance of locoregional control to survival for this disease.Primary cytoreduction: quality criteria.Surgery aimed at maximal tumour reduction, ideally without any macroscopic tumour residual disease, followed by adjuvant systemic chemotherapy typically with paclitaxel and carboplatin, constitutes the current gold standard in the primary management of the disease. Nevertheless, median progression-free survival (PFS) ranges only between 16 and 22 months, and median overall survival (OS) is rather limited, at 3—5 years. There is thus a great need for future strategies to improve the OS.The rate of optimal residual disease (less than 1 cm), particularly the rate of complete macroscopic tumour resection, is broadly considered to be an appropriate evaluation tool for assessing surgical quality in advanced EOC.
Stronach EA, Cheraghchi-Bashi A, Chen M, et al., 2011, Targeting the AKT Pathway in Ovarian Cancer, EMERGING THERAPEUTIC TARGETS IN OVARIAN CANCER, Editors: Kaye, Brown, Gabra, Gore, Publisher: SPRINGER, Pages: 73-94, ISBN: 978-1-4419-7215-6
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- Citations: 2
Kaye S, Brown R, Gabra H, et al., 2010, Emerging Therapeutic Targets in Ovarian Cancer, Publisher: Springer Verlag, ISBN: 9781441972156
This book offers a progress report on efforts to meet the challenges faced by ovarian cancer patients and their doctors.
Gabra H, 2010, A new network for translational research in ovarian cancer. Interview by Helen Saul., Eur J Cancer, Vol: 46
Ledermann JA, Gabra H, Jayson GC, et al., 2010, Inhibition of Carboplatin-Induced DNA Interstrand Cross-link Repair by Gemcitabine in Patients Receiving these Drugs for Platinum-Resistant Ovarian Cancer, CLINICAL CANCER RESEARCH, Vol: 16, Pages: 4899-4905, ISSN: 1078-0432
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- Citations: 32
Burrows C, Latip NA, Lam S-J, et al., 2010, The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration, Nucleic Acids Research, Vol: 38, Pages: 5542-5553, ISSN: 0305-1048
The RNA binding protein Larp1 was originally shown to be involved in spermatogenesis, embryogenesis and cell-cycle progression in Drosophila. Our data show that mammalian Larp1 is found in a complex with poly A binding protein and eukaryote initiation factor 4E and is associated with 60S and 80S ribosomal subunits. A reduction in Larp1 expression by siRNA inhibits global protein synthesis rates and results in mitotic arrest and delayed cell migration. Consistent with these data we show that Larp1 protein is present at the leading edge of migrating cells and interacts directly with cytoskeletal components. Taken together, these data suggest a role for Larp1 in facilitating the synthesis of proteins required for cellular remodelling and migration.
Gabra H, 2010, Back to the future: Targeting molecular changes for platinum resistance reversal, GYNECOLOGIC ONCOLOGY, Vol: 118, Pages: 210-211, ISSN: 0090-8258
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- Citations: 4
Agarwal R, Gourley C, Perren TJ, et al., 2010, First-line therapy for ovarian cancer with carboplatin followed by paclitaxel-gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series, EUROPEAN JOURNAL OF CANCER, Vol: 46, Pages: 2020-2026, ISSN: 0959-8049
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- Citations: 5
McKie A, Vaughan S, Okon I, et al., 2010, The OPCML tumour suppressor functions as a repressor-adaptor, negatively regulating receptor tyrosine kinases in ovarian cancer, 21st Meeting of the European-Association-for-Cancer-Research, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 108-108, ISSN: 1359-6349
Slesser AAP, Paige A, Gabra H, et al., 2010, The expression of WWOX in pancreatic adenocarcinoma, 6th International Conference on Clinical Cancer Prevention (SG-CAP 2010), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 10-10, ISSN: 1359-6349
Paige AJW, Zucknick M, Janczar S, et al., 2010, <i>WWOX</i> tumour suppressor gene polymorphisms and ovarian cancer pathology and prognosis, EUROPEAN JOURNAL OF CANCER, Vol: 46, Pages: 818-825, ISSN: 0959-8049
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- Citations: 24
Barker D, Sharma R, McIndoe A, et al., 2010, An Unusual Case of Sex Cord Tumor With Annular Tubules With Malignant Transformation in a Patient With Peutz-Jeghers Syndrome, INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, Vol: 29, Pages: 27-32, ISSN: 0277-1691
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- Citations: 17
Rustin GJ, van der Burg ME, Griffin CL, et al., 2010, Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial., Lancet, Vol: 376, Pages: 1155-1163
Ang JE, Shah RN, Everard M, et al., 2009, A feasibility study of sequential doublet chemotherapy comprising carboplatin-doxorubicin and carboplatin-paclitaxel for advanced endometrial adenocarcinoma and carcinosarcoma, ANNALS OF ONCOLOGY, Vol: 20, Pages: 1787-1793, ISSN: 0923-7534
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- Citations: 11
Gabra H, 2009, Dose density and altered scheduling of adjuvant chemotherapy in ovarian cancer: teaching old dogs new tricks?, Discov Med, Vol: 8, Pages: 140-144
A recent Japanese Gynecologic Oncology Group phase III clinical trial in patients with ovarian cancer receiving the conventional paclitaxel-carboplatin combination once every 3 weeks or "dose-dense" paclitaxel once a week with carboplatin once every 3 weeks has reported a large progression free survival advantage for the dose-dense therapy. Recent advances in the molecular understanding of ovarian cancer point to molecular differences between paclitaxel and carboplatin sensitivity which link to the status of BRCA genes--so called familial and sporadic "BRCAness." It may be that the change in the way we use paclitaxel allows us to more effectively target the heterogeneity of such intrinsic sensitivity/resistance to these agents in the adjuvant therapy of ovarian cancer, leading to significant improvement in the management of the disease.
Blagden S, Gabra H, 2009, Promising molecular targets in ovarian cancer, CURRENT OPINION IN ONCOLOGY, Vol: 21, Pages: 412-419, ISSN: 1040-8746
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- Citations: 19
Zhang J-Q, Li L, Song H-L, et al., 2009, [Effect of WWOX gene on the attachment and adhesion of ovarian cancer cells]., Zhonghua Fu Chan Ke Za Zhi, Vol: 44, Pages: 529-532, ISSN: 0529-567X
OBJECTIVE: To explore the relationship between WWOX gene and attachment and adhesion of ovarian cancer. METHODS: The expression of WWOX mRNA was detected by RT-PCR, the expression of the WWOX protein was evaluated by western blot in WWOX-transfected PEO1 cells (H6, H7, H8 cell) and vector-transfected control cells (vec-1, vec-2 cell). Attachment assay was used to assess the adhesion of the transfection in PEO1 cells via culturing the cells on the pre-coated fibronectin wells. RNA interference (RNAi) was used to knockdown the endogenous expression of WWOX in the A2780 ovarian cancer cell line by liposome. Attachment assay was detected the adhesion to fibronectin after gene silencing. RESULTS: RT-PCR showed that expression of mRNA WWOX in exon9 was in all transfection cells (H6, H7, H8, vec-1, vec-2 cell). Western blot showed that expression of WWOX protein was in the WWOX-transfected cells (H6, H7, H8 cell), but not in the vector-transfected cells (vec-1, vec-2 cell). Attachment assay showed that H6, H7, H8 cell (0.098 +/-0. 003, 0.091 +/- 0.004, 0.099 +/- 0.003) adhered more slowly to fibronectin than vec-1, vec-2 cell (0.185 +/- 0.003, 0.175 +/- 0.006) and non-transfected PEO1 cell (0.211 +/- 0.007), and demonstrated significantly reduced adhesion after 2 hours (P < 0.01). A2780 adhesive cells that WWOX gene be knockdown was 0.059 +/- 0.005, adhered more significantly rapid than those untreated cells that was 0.029 +/- 0.003 after treated 30 minutes (P < 0.05). CONCLUSIONS: WWOX gene can suppress adhesion to fibronectin in ovarian cancer cells. This suggests an important role for loss of WWOX gene in promoting attachment and adhesion of ovarian cancer cells on loco-regional peritoneum, and further resulting in enhancing loco-regional peritoneal tumor invasiveness and spread.
Gourley C, Paige AJW, Taylor KJ, et al., 2009, <i>WWOX</i> Gene Expression Abolishes Ovarian Cancer Tumorigenicity <i>In</i> <i>vivo</i> and Decreases Attachment to Fibronectin via Integrin α<sub>3</sub>, CANCER RESEARCH, Vol: 69, Pages: 4835-4842, ISSN: 0008-5472
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- Citations: 84
Zhang J-Q, Li L, Song H-L, et al., 2009, [Effects of WWOX on ovarian cancer cell attachment in vitro]., Zhonghua Zhong Liu Za Zhi, Vol: 31, Pages: 414-417, ISSN: 0253-3766
OBJECTIVE: To observe the effects of WWOX on cell attachment in ovarian cancer, and to explore its mechanisms of action. METHODS: Attachment assay was used to assess the adhesion of wwox-transfected PEO1 cells and vector-transfected PEO1 cells that were constructed, as well as PEO1 parent cells. Alpha/beta integrin-mediated cell adhesion assays were designed to identify cells surface integrins in PEO1 clone cells. Integrin function blocking experiments were designed to further determine integrins in PEO1 clone cells according to the integrin that was selected in integrin expression profiling. FACS analysis was used to further detect the level of integrin alpha3 on the cell membrane. RESULTS: Attachment assay showed that adhesion of WWOX-transfected PEO1 cells to fibronectin was significantly slower than that in vector-transfected controls or PEO1 parent cells, cultured on the pre-coated fibronectin for 2 hours (P<0.01). The level of membranous integrins alpha2 and alpha3 in the WWOX-transfected PEO1 cells was significantly decreased, as compared with that in vector-transfected controls (P<0.05), but there was no association with the level of functioning integrins betal or beta2 in clone cells (P>0.05). The attachment assays were repeated after pre-incubating the cells with integrin alpha2 or alpha3 function-blocking antibodies. These results showed that blocking integrin alpha3 significantly reduced the binding to fibronectin of all the PEO1 clonal lines, as compared with cells pre-incubated with a non-specific IgG antibody (P<0.05). In contrast, preincubation with alpha2 blocking antibody had very little effect on fibronectin binding in these cells (P>0.05). FACS analysis showed that membranous integrin alpha3 expression revealed a marked reduction in WWOX-transfected cells than that in vector-transfected cells. CONCLUSION: WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix, decreas
Kaye SB, Vasey P, Rustin G, et al., 2009, Randomized trial of intrapatient dose escalation of single agent carboplatin as first-line treatment for advanced ovarian cancer: An SGCTG study (SCOTROC 4), 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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- Citations: 1
Kaye SB, Vasey P, Rustin G, et al., 2009, Randomized trial of intrapatient dose escalation of single agent carboplatin as first-line treatment for advanced ovarian cancer: An SGCTG study (SCOTROC 4)., J Clin Oncol, Vol: 27
5537 Background: In the absence of toxicity, carboplatin (the most widely used drug in ovarian cancer) is generally given at the same (flat) dose with each treatment cycle. However, retrospective data suggest a correlation between extent of myelosuppression and outcome, as has been observed in other diseases. Our hypothesis was therefore that intrapatient dose escalation, according to nadir blood counts, could lead to an improved outcome compared to conventional flat dosing. METHODS: Patients with previously untreated stage IC to IV ovarian cancer were randomized to receive 6 cycles of carboplatin AUC 6 q3 w either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir FBC (Arm B). The primary outcome measure was progression-free survival (PFS), and a target accrual of 1300 pts was envisaged, aimed at detecting a 20% increase in PFS with 80% power (5% 2-sided level of statistical significance). RESULTS: From March 2004 to November 2008, 937 pts were recruited from 70 centres. Dose escalation occurred in 82% pts on Arm B. The median AUCs actually received were 6.0 (Arm A) and 6.84 (Arm B). As expected, more myelosuppression was seen in Arm B (p < 0.001 for all parameters). More grade 3/4 non-haematological toxicity was also seen in Arm B (31%, vs 22% in Arm A, p < 0.001) but there was no significant difference in global quality of life. To date, 477 PFS events have been observed out of a planned total of 950. The median PFS was 13.9m in Arm A, and 13.5m in Arm B, and the observed hazard ratio (Arm B/Arm A) is 1.04, with 95% C.I. of 0.87 to 1.24. This excludes the clinically relevant benefit of 0.83 used to design the study. A futility analysis also indicated that the probability of a statistically significant result in favour of Arm B at the planned study end was 0.12 at best. CONCLUSIONS: Following the Data Monitoring Committee recommendation, the trial has therefore been closed to recruitment, with no evide
Ledermann JA, Rustin GJ, Hackshaw A, et al., 2009, A randomized phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)., J Clin Oncol, Vol: 27
5501 Background: BIBF 1120 is a new targeted therapeutic agent for maintenance therapy in OC. It is a unique triple angiokinase inhibitor, targeting 3 receptor classes involved in the formation of blood vessels (VEGFR, PDGFR, and FGFR). METHODS: Continuous BIBF 1120 (250 mg, oral, twice daily) for up to 9 months (mo) was compared with placebo in a novel application of a randomized double-blind trial in pts who responded to their last (at least second line) chemotherapy. The primary endpoint, progression-free survival at 36 weeks, was confirmed by CT assessment, performed at 12-week intervals. RESULTS: 84 pts were randomized (44 BIBF 1120; 40 placebo), mean age 60y (range 27-76). All had responded according to GCIG criteria. Treatment-free interval before prior chemotherapy was <6 mo for 41% and 6-12 mo for 59% of pts. Median treatment duration was 116 days (d), range, 2-281d (BIBF 1120) and 101 d, 2-239d (placebo). Five BIBF 1120 pts completed 9 mo of treatment vs 0 placebo pts. The 36-wk PFS rates (95% confidence interval [CI]) were 15.6% (3.8, 27.3) for BIBF 1120 and 2.9% (0.0, 8.4) for placebo. Although the trial was not powered for a direct comparison, the PFS hazard ratio was 0.68 (95% CI: 0.42, 1.09). Median time to RECIST progression (mo) was 4.8 for BIBF 1120, and 2.8 for placebo. There were no deaths during treatment. Grade 3 and 4 adverse events (AE) were seen in 54 and 7% (BIBF 1120) and 25 and 3% (placebo) of pts. Expected gastrointestinal toxicities occurred slightly more frequently in the BIBF 1120 arm (16 vs 10%, all gd 3; no gd 4 events). Elevated liver enzymes occurred in 43% (BIBF 1120) vs. 6.3% (placebo). CONCLUSIONS: Our trial suggests that maintenance BIBF 1120 could delay disease progression in OC pts who had previously responded to chemotherapy. A large phase III trial is needed to confirm the efficacy of this drug. [Table: see text].
Ledermann JA, Rustin GJ, Hackshaw A, et al., 2009, A randomized phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC), 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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- Citations: 8
McKie A, Okon I, Vaughan S, et al., 2009, The OPCML tumor suppressor negatively regulates expression and activity of HER2 and EGFR, and may predict ovarian and breast cancer response to Lapatinib, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472
Tan DSP, Lambros MBK, Rayter S, et al., 2009, PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas, CLINICAL CANCER RESEARCH, Vol: 15, Pages: 2269-2280, ISSN: 1078-0432
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- Citations: 133
Janczar S, Graham JS, Paige AJW, et al., 2009, Targeting locoregional peritoneal dissemination in ovarian cancer, Expert Review of Obstetrics and Gynecology, Vol: 4, Pages: 133-147
Gabra H, 2009, CAN WE PREDICT CHEMOTHERAPY RESISTANCE? WHAT ARE THE CLINICAL PARAMETERS?, IUBMB LIFE, Vol: 61, Pages: 292-292, ISSN: 1521-6543
Sharma R, Graham J, Mitchell H, et al., 2009, Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer, British Journal of Cancer, Vol: 100, Pages: 707-712, ISSN: 0007-0920
There is increasing evidence of the efficacy of dose-dense therapy in the management of platinum-resistant/refractory ovarian cancer. We report our experience of extended weekly carboplatin and paclitaxel in this population group. Twenty patients with platinum-resistant/refractory ovarian cancer received carboplatin AUC 3 and paclitaxel 70 mg m−2 on day 1, 8, 15 q 4 weekly for six planned cycles. Toxicity was assessed using Common Toxicity Criteria. Response was evaluated using radiological and CA125 criteria. Median age was 61 years (range 40–74 years). Median number of prior therapies is three (range 1–8). Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anaemia (5%). One patient experienced grade 4 neutropenia. No grade 3/4 thombocytopaenia was reported. Fatigue, nausea and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months and overall survival was 13.3 months. The dynamics of response to dose-dense therapy were as rapid as with front-line therapy within the same patient. This dose-dense regimen can be extended to at least 18 weekly cycles over 6 months and is well tolerated with high response rates in heavily pre-treated, platinum-resistant ovarian cancer. It forms a highly active and tolerable cytotoxic scaffold to which molecular-targeted therapies can be added in platinum-resistant ovarian cancer.
Kitchener HC, Trimble EL, 2009, Endometrial Cancer State of the Science Meeting, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 19, Pages: 134-140, ISSN: 1048-891X
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- Citations: 77
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