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Author Ng, A.; Barker, N. url  openurl
  Title Ovary and fimbrial stem cells: biology, niche and cancer origins Type Journal Article
  Year 2015 Publication Abbreviated Journal Nat Rev Mol Cell Biol  
  Volume 16 Issue 10 Pages 625-638  
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  Abstract The mammalian ovary is covered by a single-layered epithelium that undergoes rupture and remodelling following each ovulation. Although resident stem cells are presumed to be crucial for this cyclic regeneration, their identity and mode of action have been elusive. Surrogate stemness assays and in vivo fate-mapping studies using recently discovered stem cell markers have identified stem cell pools in the ovary and fimbria that ensure epithelial homeostasis. Recent findings provide insights into intrinsic mechanisms and local extrinsic cues that govern the function of ovarian and fimbrial stem cells. These discoveries have advanced our understanding of stem cell biology in the ovary and fimbria, and lay the foundations for evaluating the contribution of resident stem cells to the initiation and progression of human epithelial ovarian cancer.  
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  Call Number UofT @ ankit.sinha @ Serial 44935  
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Author Hunter, S.M.; Anglesio, M.S.; Ryland, G.L.; Sharma, R.; Chiew, Y.E.; Rowley, S.M.; Doyle, M.A.; Li, J.; Gilks, C.B.; Moss, P.; Allan, P.E.; Stephens, A.N.; Huntsman, D.G.; deFazio, A.; Bowtell, D.D.; Australian, O.C.S.G.; Gorringe, K.L.; Campbell, I.G. url  openurl
  Title Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes Type Journal Article
  Year 2015 Publication Abbreviated Journal Oncotarget  
  Volume 6 Issue 35 Pages 37663-37677  
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  Abstract Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors.  
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  Call Number UofT @ ankit.sinha @ Serial 44942  
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Author Kampan, N.C.; Madondo, M.T.; McNally, O.M.; Quinn, M.; Plebanski, M. url  openurl
  Title Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Biomed Res Int  
  Volume 2015 Issue Pages 413076  
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  Abstract Paclitaxel, a class of taxane with microtubule stabilising ability, has remained with platinum based therapy, the standard care for primary ovarian cancer management. A deeper understanding of the immunological basis and other potential mechanisms of action together with new dosing schedules and/or routes of administration may potentiate its clinical benefit. Newer forms of taxanes, with better safety profiles and higher intratumoural cytotoxicity, have yet to demonstrate clinical superiority over the parent compound.  
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  Call Number UofT @ ankit.sinha @ Serial 45056  
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Author Wright, A.A.; Cronin, A.; Milne, D.E.; Bookman, M.A.; Burger, R.A.; Cohn, D.E.; Cristea, M.C.; Griggs, J.J.; Keating, N.L.; Levenback, C.F.; Mantia-Smaldone, G.; Matulonis, U.A.; Meyer, L.A.; Niland, J.C.; Weeks, J.C.; O’Malley, D.M. url  openurl
  Title Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal J Clin Oncol  
  Volume 33 Issue 26 Pages 2841-2847  
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  Abstract PURPOSE: A 2006 randomized trial demonstrated a 16-month survival benefit with intraperitoneal and intravenous (IP/IV) chemotherapy administered to patients who had ovarian cancer, compared with IV chemotherapy alone, but more treatment-related toxicities. The objective of this study was to examine the use and effectiveness of IP/IV chemotherapy in clinical practice. PATIENTS AND METHODS: Prospective cohort study of 823 women with stage III, optimally cytoreduced ovarian cancer diagnosed at six National Comprehensive Cancer Network institutions. We examined IP/IV chemotherapy use in all patients diagnosed between 2003 and 2012 (N = 823), and overall survival and treatment-related toxicities with Cox regression and logistic regression, respectively, in a propensity score-matched sample (n = 402) of patients diagnosed from 2006 to 2012, excluding trial participants, to minimize selection bias. RESULTS: Use of IP/IV chemotherapy increased from 0% to 33% between 2003 and 2006, increased to 50% from 2007 to 2008, and plateaued thereafter. Between 2006 and 2012, adoption of IP/IV chemotherapy varied by institution from 4% to 67% (P <.001) and 43% of patients received modified IP/IV regimens at treatment initiation. In the propensity score-matched sample, IP/IV chemotherapy was associated with significantly improved overall survival (3-year overall survival, 81% v 71%; hazard ratio, 0.68; 95% CI, 0.47 to 0.99), compared with IV chemotherapy, but also more frequent alterations in chemotherapy delivery route (adjusted rates discontinuation or change, 20.4% v 10.0%; adjusted odds ratio, 2.83; 95% CI, 1.47 to 5.47). CONCLUSION: Although the use of IP/IV chemotherapy increased significantly at National Comprehensive Cancer Network centers between 2003 and 2012, fewer than 50% of eligible patients received it. Increasing IP/IV chemotherapy use in clinical practice may be an important and underused strategy to improve ovarian cancer outcomes.  
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  Call Number UofT @ ankit.sinha @ Serial 45060  
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Author Patch, A.M.; Christie, E.L.; Etemadmoghadam, D.; Garsed, D.W.; George, J.; Fereday, S.; Nones, K.; Cowin, P.; Alsop, K.; Bailey, P.J.; Kassahn, K.S.; Newell, F.; Quinn, M.C.; Kazakoff, S.; Quek, K.; Wilhelm-Benartzi, C.; Curry, E.; Leong, H.S.; Australian, O.C.S.G.; Hamilton, A.; Mileshkin, L.; Au-Yeung, G.; Kennedy, C.; Hung, J.; Chiew, Y.E.; Harnett, P.; Friedlander, M.; Quinn, M.; Pyman, J.; Cordner, S.; O’Brien, P.; Leditschke, J.; Young, G.; Strachan, K.; Waring, P.; Azar, W.; Mitchell, C.; Traficante, N.; Hendley, J.; Thorne, H.; Shackleton, M.; Miller, D.K.; Arnau, G.M.; Tothill, R.W.; Holloway, T.P.; Semple, T.; Harliwong, I.; Nourse, C.; Nourbakhsh, E.; Manning, S.; Idrisoglu, S.; Bruxner, T.J.; Christ, A.N.; Poudel, B.; Holmes, O.; Anderson, M.; Leonard, C.; Lonie, A.; Hall, N.; Wood, S.; Taylor, D.F.; Xu, Q.; Fink, J.L.; Waddell, N.; Drapkin, R.; Stronach, E.; Gabra, H.; Brown, R.; Jewell, A.; Nagaraj, S.H.; Markham, E.; Wilson, P.J.; Ellul, J.; McNally, O.; Doyle, M.A.; Vedururu, R.; Stewart, C.; Lengyel, E.; Pearson, J.V.; Waddell, N.; deFazio, A.; Grimmond, S.M.; Bowtell, D.D. url  openurl
  Title Whole-genome characterization of chemoresistant ovarian cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Nature  
  Volume 521 Issue 7553 Pages 489-494  
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  Abstract Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.  
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  Call Number UofT @ ankit.sinha @ Serial 45069  
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Author Drerup, J.M.; Liu, Y.; Padron, A.S.; Murthy, K.; Hurez, V.; Zhang, B.; Curiel, T.J. url  openurl
  Title Immunotherapy for ovarian cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Curr Treat Options Oncol  
  Volume 16 Issue 1 Pages 317  
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  Abstract OPINION STATEMENT: All work referenced herein relates to treatment of epithelial ovarian carcinomas, as their treatment differs from ovarian germ cell cancers and other rare ovarian cancers, the treatments of which are addressed elsewhere. Fallopian tube cancers and primary peritoneal adenocarcinomatosis are also generally treated as epithelial ovarian cancers. The standard of care initial treatment of advanced stage epithelial ovarian cancer is optimal debulking surgery as feasible plus chemotherapy with a platinum plus a taxane agent. If this front-line approach fails, as it too often the case, several FDA-approved agents are available for salvage therapy. However, because no second-line therapy for advanced-stage epithelial ovarian cancer is typically curative, we prefer referral to clinical trials as logistically feasible, even if it means referring patients outside our system. Immune therapy has a sound theoretical basis for treating carcinomas generally, and for treating ovarian cancer in particular. Advances in understanding the immunopathogenic basis of ovarian cancer, and the immunopathologic basis for prior failures of immunotherapy for it and other carcinomas promises to afford novel treatment approaches with potential for significant efficacy, and reduced toxicities compared with cytotoxic agents. Thus, referral to early phase immunotherapy trials for ovarian cancer patients that fail conventional treatment merits consideration.  
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  Call Number UofT @ ankit.sinha @ Serial 45091  
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Author Sharma, P.; Allison, J.P. url  openurl
  Title Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential Type Journal Article
  Year 2015 Publication Abbreviated Journal Cell  
  Volume 161 Issue 2 Pages 205-214  
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  Abstract Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.  
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  Call Number UofT @ ankit.sinha @ Serial 45097  
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Author Butterfield, L.H. url  openurl
  Title Cancer vaccines Type Journal Article
  Year 2015 Publication Abbreviated Journal Bmj  
  Volume 350 Issue Pages h988  
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  Abstract Cancer vaccines are designed to promote tumor specific immune responses, particularly cytotoxic CD8 positive T cells that are specific to tumor antigens. The earliest vaccines, which were developed in 1994-95, tested non-mutated, shared tumor associated antigens that had been shown to be immunogenic and capable of inducing clinical responses in a minority of people with late stage cancer. Technological developments in the past few years have enabled the investigation of vaccines that target mutated antigens that are patient specific. Several platforms for cancer vaccination are being tested, including peptides, proteins, antigen presenting cells, tumor cells, and viral vectors. Standard of care treatments, such as surgery and ablation, chemotherapy, and radiotherapy, can also induce antitumor immunity, thereby having cancer vaccine effects. The monitoring of patients’ immune responses at baseline and after standard of care treatment is shedding light on immune biomarkers. Combination therapies are being tested in clinical trials and are likely to be the best approach to improving patient outcomes.  
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  Call Number UofT @ ankit.sinha @ Serial 45100  
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Author Urbanska, K.; Powell, D.J. url  openurl
  Title Advances and prospects in adoptive cell transfer therapy for ovarian cancer Type Journal Article
  Year 2015 Publication Abbreviated Journal Immunotherapy  
  Volume 7 Issue 5 Pages 473-476  
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  Call Number UofT @ ankit.sinha @ Serial 45106  
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Author Hasan, N.; Ohman, A.W.; Dinulescu, D.M. url  openurl
  Title The promise and challenge of ovarian cancer models Type Journal Article
  Year 2015 Publication Abbreviated Journal Transl Cancer Res  
  Volume 4 Issue 1 Pages 14-28  
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  Abstract The complexity and heterogeneity of ovarian cancer cases are difficult to reproduce in in vitro studies, which cannot adequately elucidate the molecular events involved in tumor initiation and disease metastasis. It has now become clear that, although the multiple histological subtypes of ovarian cancer are being treated with similar surgical and therapeutic approaches, they are in fact characterized by distinct phenotypes, cell of origin, and underlying key genetic and genomic alterations. Consequently, the development of more personalized treatment methodologies, which are aimed at improving patient care and prognosis, will greatly benefit from a better understanding of the key differences between various subtypes. To accomplish this, animal models of all histotypes need to be generated in order to provide accurate in vivo platforms for research and the testing of targeted treatments and immune therapies. Both genetically engineered mouse models (GEMMs) and xenograft models have the ability to further our understanding of key mechanisms facilitating tumorigenesis, and at the same time offer insight into enhanced imaging and treatment modalities. While genetic models may be better suited to examine oncogenic functions and interactions during tumorigenesis, patient-derived xenografts (PDXs) are likely a superior model to assess drug efficacy, especially in concurrent clinical trials, due to their similarity to the tumors from which they are derived. Genetic and avatar models possess great clinical utility and have both benefits and limitations. Additionally, the laying hen model, which spontaneously develops ovarian tumors, has inherent advantages for the study of epithelial ovarian cancer (EOC) and recent work champions this model especially when assessing chemoprevention strategies. While high-grade ovarian serous tumors are the most prevalent form of EOC, rarer ovarian cancer variants, such as small cell ovarian carcinoma of the hypercalcemic type and transitional cell carcinoma, or non-epithelial tumors, including germ cell tumors, will also benefit from the generation of improved models to advance our understanding of tumorigenic mechanisms and the development of selective therapeutic options.  
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  Call Number UofT @ ankit.sinha @ Serial 45119  
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