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Banerjee S.,Gynaecology Unit | Kaye S.,Institute of Cancer Research
Current Oncology Reports | Year: 2011

Poly(ADP-ribose)polymerase (PARP) inhibitors are showing considerable promise for the treatment of BRCA mutation-associated ovarian and breast cancer. This approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in cancers that harbor mutations in the BRCA1 or BRCA2 genes. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic, high-grade serous ovarian cancers and other cancers including endometrial cancer. In this review, we discuss the clinical development of PARP inhibitors in ovarian cancer and explore challenges that need to be addressed if the full potential of these agents is to be realized. © 2011 Springer Science+Business Media, LLC.


Moschetta M.,Gynaecology Unit | George A.,Gynaecology Unit and Cancer Genetics Unit | Kaye S.B.,Gynaecology Unit | Banerjee S.,Gynaecology Unit
Annals of Oncology | Year: 2016

The significant activity of poly(ADP-ribose)polymerase (PARP) inhibitors in the treatment of germline BRCA mutation-associated ovarian cancer, which represents ~15% of HGS cases, has recently led to European Medicines Agency and food and drug administration approval of olaparib. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic ovarian cancers. Up to 50% of HGS ovarian cancer patients may exhibit homologous recombination deficiency (HRD) through mechanisms including germline BRCA mutations, somatic BRCA mutations, and BRCA promoter methylation. In this review, we discuss the role of somatic BRCA mutations and BRCA methylation in ovarian cancer. There is accumulating evidence for routine somatic BRCA mutation testing, but the relevance of BRCA epigenetic modifications is less clear. We explore the challenges that need to be addressed if the full potential of these markers of HRD is to be utilised in clinical practice. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Syrios J.,Gynaecology Unit | Banerjee S.,Gynaecology Unit | Kaye S.B.,Gynaecology Unit
Anticancer Research | Year: 2014

Ovarian cancer is the most frequent cause of death from gynaecological malignancy in the Western countries, and differences in outcome among different histological subtypes are being increasingly recognized. It is generally considered as chemosensitive, but resistant clones evolve in the majority of cases, at varying rates. In this brief review, we describe advances in conventional chemotherapy, particularly the use of weekly paclitaxel. We then focus on new promising agents that target certain pathways which drive the genesis and evolution of ovarian cancer; these include poly(ADP-ribose) polymerase (PARP) inhibitors targeting tumor cells deficient in homologous recombination. We also discuss other targets including the folate receptor. Ovarian cancer has also proved to be one of the most sensitive types of cancer to an anti-Angiogenic approach and we summarize recent experience using a range of agents.


Vicariotto F.,Gynaecology Unit | Del Piano M.,Gastroenterology Unit | Mogna L.,Biolab Research Srl | Mogna G.,Probiotical SpA
Journal of Clinical Gastroenterology | Year: 2012

BACKGROUND:: Vulvovaginal candidiasis (VVC) is the second most common cause of vaginitis after bacterial vaginosis, and it is diagnosed in up to 40% of women with vaginal complaints in the primary care setting. Among Candida spp., Candida albicans is the most common infectious agent. The treatment of choice for uncomplicated VVC is achieved with single-dose or short-course therapy in over 90% of cases. Several topical and oral drugs are available, without evidence for superiority of any agent or route of administration. In any case, most classic treatments are unable to significantly offer a protection against possible recurrences. In recent years, probiotics are emerging as a new strategy to counteract VVC. In fact, they are well known for their ability to lower intravaginal pH, thus establishing a barrier effect against many types of yeasts. Some strains are also able to exert additional and more focused antagonistic activities mediated by specific molecules such as hydrogen peroxide and bacteriocins. For example, Lactobacillus fermentum LF5 (CNCM I-789) was successfully tested in 4 human trials involving a total of 340 women reporting VVC at enrollment. In any case, the way used to deliver probiotics to the vaginal environment represents a crucial point. The aim of this work was to first select 1 or more probiotic strains in vitro with an antagonistic activity on Candida yeasts and then to perform an in vivo human pilot study using an association of the most promising and active bacteria. METHODS:: For this purpose, 2 probiotic strains Probiotical S.p.A (Italy) were selected based on their strong in vitro inhibition activity toward 4 particular Candida species, namely C. albicans, Candida glabrata, Candida parapsilosis, and Candida krusei and subsequently tested in a human intervention pilot trial involving 30 women with VVC. The probiotics used, L. fermentum LF10 (DSM 19187) and Lactobacillus acidophilus LA02 (DSM 21717), were administered by means of slow release effervescent vaginal tablets (ActiCand 30 product). The main endpoint was the assessment of the establishment and maintenance of a barrier effect against Candida yeasts in women suffering from VVC. Thirty female subjects who were diagnosed with VVC by both microscopic examination and yeast culture were enrolled in the study and directed to apply a vaginal tablet once a day for 7 consecutive nights, followed by 1 tablet every 3 nights for a further 3-week application (acute phase) and, finally, 1 tablet per week to maintain a long-term vaginal colonization against possible recurrences. A medical examination of each patient was performed at enrollment (d0), at the end of the first 4 weeks of treatment (d28), and at the end of the second month of relapse prevention (d56). The visual and microscopic examination was always accompanied by microbiological analyses of vaginal swabs to assess the presence of Candida. A statistical comparison was made between d28, or d56, and d0, and between d56 and d28 to quantify the efficacy against possible recurrences. RESULTS:: The administration of the product ActiCand 30 was able to significantly solve Candida yeast symptoms after 28 days in 26 patients out of 30 (corresponding to 86.6%, P<0.001). At the end of the second month, recurrences were recorded, albeit not particularly serious, in only 3 out of 26 patients (11.5%, P=0.083) who were found to have fully healed at the end of the first month of treatment. This is a further confirmation of the long-term barrier effect exerted by the product. CONCLUSIONS:: VVC has a very high incidence as 70% to 75% of women report at least 1 episode during the life. Many treatments are currently available but, despite a relatively high effectiveness in the relief of symptoms typically associated with acute infections, they are generally unable to offer a long-term protective barrier against possible recurrences. This study demonstrated the ability of ActiCand 30 to not only solve Candida infections in a very high percentage of women, but also to exert a long-term physiological defense due to the colonization of vaginal microbiota and adhesion of the mucosa to the epithelial cells. The special formulation of ActiCand 30, consisting of slow release effervescent vaginal tablets, is able to mediate 2 types of barrier effects, the first represented by the formation of an anaerobic environment due to the release of CO2 and the second guaranteed by the colonization and adhesion to the vaginal epithelium of the 2 probiotics L. fermentum LF10 and L. acidophilus LA02. © 2012 by Lippincott Williams & Wilkins.


Lopez J.,Gynaecology Unit | Banerjee S.,Gynaecology Unit | Kaye S.B.,Gynaecology Unit | Kaye S.B.,Institute of Cancer Research and Royal Marsden NHS Trust
Annals of Oncology | Year: 2013

Over the past 40 years, the treatment of ovarian cancer has undoubtedly improved as a result of better multi-modality care and platinum-based chemotherapy. More recently, the introduction of anti-angiogenic therapy, PARP inhibitors and a weekly regimen for paclitaxel indicate that results are likely to improve further. However, major challenges remain and these will be reviewed in this article. We assess key issues in anti-angiogenic treatment including potential ways for addressing resistance; we review the current studies of PARP inhibitor treatment, which shows most promise in patients with germline BRCA mutations; we describe the potential for folate-receptor-directed therapy, given the high level of FR expression in ovarian cancer and we highlight the potential for molecular targeted therapy, focusing on specific subgroups of the disease with targets such as the PI3 K/AKT and RAS/RAF/MEK pathways and the ErbB family of oncogenes. We anticipate that progress will accelerate with a better understanding of the molecular pathogenesis of the various subtypes of ovarian cancer, leading to an increasingly personalized approach to treating women with this disease. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Mclachlan J.,Gynaecology Unit | Gore M.,Gynaecology Unit | Banerjee S.,Gynaecology Unit
Pharmacogenomics | Year: 2016

Until recently, there has been little change in the management of epithelial ovarian cancer with the majority of women receiving identical systemic therapy, regardless of histological subtype. The heterogeneity of epithelial ovarian cancer is now well established, with distinct subtypes characterized by specific molecular alterations and patterns of clinical behavior. Low-grade serous carcinoma is a rare subtype associated with an indolent biological behavior and inherent resistance to chemotherapy. The mitogen-activated protein kinase pathway plays a prominent role in the pathogenesis of low-grade serous carcinoma, and provides an attractive target for novel therapeutic agents. Selumetinib, a MEK1/2 inhibitor, demonstrates promising efficacy in women with relapsed low-grade serous carcinoma, and further trials of MEK-inhibition are underway. Translational research will be essential to identify predictive biomarkers for this treatment approach. © 2016 Future Medicine Ltd.


Banerjee S.,Gynaecology Unit | Kaye S.B.,Gynaecology Unit
Clinical Cancer Research | Year: 2013

The treatment of ovarian cancer is set to undergo rapid changes, as strategies incorporating molecular targeted therapies begin to take shape. These are based on a better appreciation of approaches targeting the tumor microenvironment as well as specific subtypes of the disease, with distinct molecular aberrations. Targeting the VEGF pathway through bevacizumab is clearly effective, with positive randomized trials at all disease stages; targeting defective homologous recombination repair pathways with PARP inhibitors is also proving successful in a substantial proportion of patients with high-grade serous ovarian cancer. In this article, we will review progress in these two leading areas and also discuss the potential for targeting other pathways and receptors that may be activated in ovarian cancer, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor. Here, single-agent therapy may play a role in selected cases but essential components of future strategies should include combination treatments aimed at dealing with the key problem of drug resistance, together with rational approaches to patient selection. © 2012 American Association for Cancer Research.


McLachlan J.,Gynaecology Unit | Banerjee S.,Gynaecology Unit
Expert Opinion on Pharmacotherapy | Year: 2016

Introduction: Despite recent advances in the management of epithelial ovarian cancer, overall survival rates remain poor, and there is a pressing need to develop novel therapeutic agents and maintenance strategies to improve outcomes for women with this disease. Olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, has demonstrated antitumor activity in women with ovarian cancer, associated with homologous recombination deficiency.Areas covered: This review outlines the rationale for PARP inhibitor therapy in ovarian cancer and summarizes the efficacy and tolerability data for olaparib to date. Ongoing phase III clinical trials of olaparib in ovarian cancer will be discussed.Expert opinion: There are a number of issues regarding the optimal use of olaparib in ovarian cancer, including the identification of a homologous recombination deficiency signature to predict treatment response, establishment of the optimal treatment setting (maintenance or relapsed disease), and evaluation of cost-effectiveness. Finally, the long term consequences of PARP inhibitors, including the risk of myelodysplasia and acute myeloid leukemia need to be quantified in ongoing large phase III clinical trials. © 2016 Informa UK Limited.


Miller R.E.,Gynaecology Unit | Banerjee S.,Gynaecology Unit
Expert Opinion on Investigational Drugs | Year: 2013

Introduction: Pemetrexed is a multitargeted antifolate drug that has shown benefit in several clinical trials in solid tumors. It is currently approved for the treatment of nonsmall cell lung cancer (NSCLC) and mesothelioma, and is being explored in epithelial ovarian cancer. Areas covered: In this article, the clinical development of pemetrexed in relation to ovarian cancer is discussed. Early phase clinical trials using pemetrexed monotherapy or in combination with other cytotoxic or target agents are reviewed. The safety profile of pemetrexed will also be evaluated. Expert opinion: A number of Phase I and II clinical trials have evaluated the use of pemetrexed in patients with ovarian cancer. Thus far, there are no randomized studies that address the role of pemetrexed compared to current, standard treatments. The activity of single agent pemetrexed in platinum-resistant patients is worth exploring. Biomarker-driven randomized, clinical trials and patient selection are key for the future development of pemetrexed. © 2013 Informa UK, Ltd.


McLachlan J.,Gynaecology Unit | Banerjee S.,Gynaecology Unit
Expert Review of Anticancer Therapy | Year: 2015

The majority of women with ovarian cancer present with advanced disease, and ultimately relapse following primary surgery and platinum-taxane chemotherapy. Despite recent advances in the development of targeted agents in ovarian cancer, survival rates remain poor. The promising activity of bevacizumab, a VEGF receptor inhibitor, has stimulated research on the use of additional anti-angiogenic agents in ovarian cancer. Pazopanib, an oral tyrosine kinase inhibitor, targets VEGF receptor-1, -2 and -3, platelet-derived growth factor receptor-and -β and c-kit; resulting in the inhibition of angiogenesis and tumor proliferation. Early phase studies have demonstrated promising efficacy and tolerability. To date, there has been one Phase III trial of pazopanib in ovarian cancer, demonstrating a progression-free survival benefit in women treated with maintenance pazopanib following primary surgery and systemic therapy. This article summarizes the preclinical and clinical data of pazopanib in ovarian cancer, highlighting future research options for this agent. © 2015 Informa UK, Ltd.

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