University of Texas, MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA. firstname.lastname@example.org.
Ovarian cancer is associated with an overall mortality of 75%, but can be cured in up to 90% of cases if diagnosed while still limited to the ovaries. Given the low prevalence of ovarian cancer in the general population, an effective screening strategy must not only have a high sensitivity for early-stage disease (>75%), but must also have a very high specificity (99.6%) to prompt no more than ten operations for each case of ovarian cancer diagnosed (positive predictive value [PPV] of 10%). Attempts to develop an effective screening strategy for ovarian cancer have utilized ultrasonography and serum tumor markers. Transvaginal sonography (TVS) and the serum marker CA125 have received the most attention to date. Used individually on a single occasion, neither of these approaches provides an adequate PPV and the cost of annual TVS is significant. Recent clinical trials have focused on serial monitoring of CA125 and the sequential use of a rising CA125 to prompt TVS in a limited number of women screened. Sequential monitoring of CA125 has significantly improved specificity of the assay in women over 50 years of age. The limited sensitivity of CA125 has, however, prompted a search for multiple serum markers that, in combination, would detect more than 90% of early-stage disease. Recent developments in genomic and proteomic research have identified a number of candidate biomarkers. Platforms have been developed that can assay more than 50 analytes in a few hundred microliters of serum. Panels of biomarkers have been discovered with high sensitivity and specificity for early-stage disease, but these require prospective validation. Several biomarkers have also been detected in urine, raising the possibility of a less expensive, more convenient screening test. Imaging techniques have been improved and mathematical methods developed that, in aggregate, promise to provide an effective screening strategy for ovarian cancer. In this review, we will assess the current status and describe future directions in ovarian cancer screening.
BMC Syst Biol. 2011 ;5 :144 21923952
Mandeep Kaur, Cameron R MacPherson, Sebastian Schmeier, Kothandaraman Narasimhan, Mahesh Choolani, Vladimir B Bajic
Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia.
BACKGROUND Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC) through the study of transcription regulation of genes affected by estrogen hormone. RESULTS The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs) that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers. CONCLUSIONS We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors.
Sci Pharm. 2011 Sep ;79 (3):493-505 21886899
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, 400076, MH, India.
Pathological changes in an organ or tissue may be reflected in proteomic patterns in serum. The early detection of cancer is crucial for successful treatment. Some cancers affect the concentration of certain molecules in the blood, which allows early diagnosis by analyzing the blood mass spectrum. It is possible that exclusive serum proteomic patterns could be used to differentiate cancer samples from non-cancer ones. Several techniques have been developed for the analysis of mass-spectrum curve, and use them for the detection of prostate, ovarian, breast, bladder, pancreatic, kidney, liver, and colon cancers. In present study, we applied data mining to the diagnosis of ovarian cancer and identified the most informative points of the mass-spectrum curve, then used student t-test and neural networks to determine the differences between the curves of cancer patients and healthy people. Two serum SELDI MS data sets were used in this research to identify serum proteomic patterns that distinguish the serum of ovarian cancer cases from non-cancer controls. Statistical testing and genetic algorithm-based methods are used for feature selection respectively. The results showed that (1) data mining techniques can be successfully applied to ovarian cancer detection with a reasonably high performance;(2) the discriminatory features (proteomic patterns) can be very different from one selection method to another.
Anal Chem. 2011 May 1;83 (9):3392-7 21449604
Highly sensitive detection of HER2 extracellular domain in the serum of breast cancer patients by piezoelectric microcantilevers.
LiNa Loo, Joseph A Capobianco, Wei Wu, Xiaotong Gao, Wan Y Shih, Wei-Heng Shih, Kambiz Pourrezaei, Matthew K Robinson, Gregory P Adams
Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States.
Rapid and sensitive detection of serum tumor biomarkers are needed to monitor cancer patients for disease progression. Highly sensitive piezoelectric microcantilever sensors (PEMS) offer an attractive tool for biomarker detection; however, their utility in the complex environment encountered in serum has yet to be determined. As a proof of concept, we have functionalized PEMS with antibodies that specifically bind to HER2, a biomarker (antigen) that is commonly overexpressed in the blood of breast cancer patients. The function and sensitivity of these anti-HER2 PEMS biosensors was initially assessed using recombinant HER2 spiked into human serum. Their ability to detect native HER2 present in the serum of breast cancer patients was then determined. We have found that the anti-HER2 PEMS were able to accurately detect both recombinant and naturally occurring HER2 at clinically relevant levels (>2 ng/mL). This indicates that PEMS-based biosensors provide a potentially effective tool for biomarker detection.
Other papers by authors:
Clin Chem. 2012 Nov 30;: 23204222
Reflection on the Discovery of Carcinoembryonic Antigen, Prostate-Specific Antigen, and Cancer Antigens CA125 and CA19-9.
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada;
Autophagy. 2012 Apr ;8 (4):445-544 22966490
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Iban Seiliez, Oleksandr Seleverstov, Christian Sell, Jong Bok Seo, Duska Separovic, Vijayasaradhi Setaluri, Takao Setoguchi, Carmine Settembre, John J Shacka, Mala Shanmugam, Irving M Shapiro, Eitan Shaulian, Reuben J Shaw, James H Shelhamer, Han-Ming Shen, Wei-Chiang Shen, Zu-Hang Sheng, Yang Shi, Kenichi Shibuya, Yoshihiro Shidoji, Jeng-Jer Shieh, Chwen-Ming Shih, Yohta Shimada, Shigeomi Shimizu, Takahiro Shintani, Orian S Shirihai, Gordon C Shore, Andriy A Sibirny, Stan B Sidhu, Beata Sikorska, Elaine C M Silva-Zacarin, Alison Simmons, Anna Katharina Simon, Hans-Uwe Simon, Cristiano Simone, Anne Simonsen, David A Sinclair, Rajat Singh, Debasish Sinha, Frank A Sinicrope, Agnieszka Sirko, Parco M Siu, Efthimios Sivridis, Vojtech Skop, Vladimir P Skulachev, Ruth S Slack, Soraya S Smaili, Duncan R Smith, Maria S Soengas, Thierry Soldati, Xueqin Song, Anil K Sood, Tuck Wah Soong, Federica Sotgia, Stephen A Spector, Claudia D Spies, Wolfdieter Springer, Srinivasa M Srinivasula, Leonidas Stefanis, Joan S Steffan, Ruediger Stendel, Harald Stenmark, Anastasis Stephanou, Stephan T Stern, Cinthya Sternberg, Björn Stork, Peter Strålfors, Carlos S Subauste, Xinbing Sui, David Sulzer, Jiaren Sun, Shi-Yong Sun, Zhi-Jun Sun, Joseph J Y Sung, Kuninori Suzuki, Toshihiko Suzuki, Michele S Swanson, Charles Swanton, Sean T Sweeney, Lai-King Sy, Gyorgy Szabadkai, Ira Tabas, Heinrich Taegtmeyer, Marco Tafani, Krisztina Takács-Vellai, Yoshitaka Takano, Kaoru Takegawa, Genzou Takemura, Fumihiko Takeshita, Nicholas J Talbot, Kevin S W Tan, Keiji Tanaka, Kozo Tanaka, Daolin Tang, Dingzhong Tang, Isei Tanida, Bakhos A Tannous, Nektarios Tavernarakis, Graham S Taylor, Gregory A Taylor, J Paul Taylor, Lance S Terada, Alexei Terman, Gianluca Tettamanti, Karin Thevissen, Craig B Thompson, Andrew Thorburn, Michael Thumm, FengFeng Tian, Yuan Tian, Glauco Tocchini-Valentini, Aviva M Tolkovsky, Yasuhiko Tomino, Lars Tönges, Sharon A Tooze, Cathy Tournier, John Tower, Roberto Towns, Vladimir Trajkovic, Leonardo H Travassos, Ting-Fen Tsai, Mario P Tschan, Takeshi Tsubata, Allan Tsung, Boris Turk, Lorianne S Turner, Suresh C Tyagi, Yasuo Uchiyama, Takashi Ueno, Midori Umekawa, Rika Umemiya-Shirafuji, Vivek K Unni, Maria I Vaccaro, Enza Maria Valente, Greet Van den Berghe, Ida J van der Klei, Wouter van Doorn, Linda F van Dyk, Marjolein van Egmond, Leo A van Grunsven, Peter Vandenabeele, Wim P Vandenberghe, Ilse Vanhorebeek, Eva C Vaquero, Guillermo Velasco, Tibor Vellai, Jose Miguel Vicencio, Richard D Vierstra, Miquel Vila, Cécile Vindis, Giampietro Viola, Maria Teresa Viscomi, Olga V Voitsekhovskaja, Clarissa von Haefen, Marcela Votruba, Keiji Wada, Richard Wade-Martins, Cheryl L Walker, Craig M Walsh, Jochen Walter, Xiang-Bo Wan, Aimin Wang, Chenguang Wang, Dawei Wang, Fan Wang, Fen Wang, Guanghui Wang, Haichao Wang, Hong-Gang Wang, Horng-Dar Wang, Jin Wang, Ke Wang, Mei Wang, Richard C Wang, Xinglong Wang, Xuejun Wang, Ying-Jan Wang, Yipeng Wang, Zhen Wang, Zhigang Charles Wang, Zhinong Wang, Derick G Wansink, Diane M Ward, Hirotaka Watada, Sarah L Waters, Paul Webster, Lixin Wei, Conrad C Weihl, William A Weiss, Scott M Welford, Long-Ping Wen, Caroline A Whitehouse, J Lindsay Whitton, Alexander J Whitworth, Tom Wileman, John W Wiley, Simon Wilkinson, Dieter Willbold, Roger L Williams, Peter R Williamson, Bradly G Wouters, Chenghan Wu, Dao-Cheng Wu, William K K Wu, Andreas Wyttenbach, Ramnik J Xavier, Zhijun Xi, Pu Xia, Gengfu Xiao, Zhiping Xie, Zhonglin Xie, Da-zhi Xu, Jianzhen Xu, Liang Xu, Xiaolei Xu, Ai Yamamoto, Akitsugu Yamamoto, Shunhei Yamashina, Michiaki Yamashita, Xianghua Yan, Mitsuhiro Yanagida, Dun-Sheng Yang, Elizabeth Yang, Jin-Ming Yang, Shi Yu Yang, Wannian Yang, Wei Yuan Yang, Zhifen Yang, Meng-Chao Yao, Tso-Pang Yao, Behzad Yeganeh, Wei-Lien Yen, Jia-jing Yin, Xiao-Ming Yin, Ook-Joon Yoo, Gyesoon Yoon, Seung-Yong Yoon, Tomohiro Yorimitsu, Yuko Yoshikawa, Tamotsu Yoshimori, Kohki Yoshimoto, Ho Jin You, Richard J Youle, Anas Younes, Li Yu, Long Yu, Seong-Woon Yu, Wai Haung Yu, Zhi-Min Yuan, Zhenyu Yue, Cheol-Heui Yun, Michisuke Yuzaki, Olga Zabirnyk, Elaine Silva-Zacarin, David Zacks, Eldad Zacksenhaus, Nadia Zaffaroni, Zahra Zakeri, Herbert J Zeh 3rd, Scott O Zeitlin, Hong Zhang, Hui-Ling Zhang, Jianhua Zhang, Jing-Pu Zhang, Lin Zhang, Long Zhang, Ming-Yong Zhang, Xu Dong Zhang, Mantong Zhao, Yi-Fang Zhao, Ying Zhao, Zhizhuang J Zhao, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Cong-Zhao Zhou, Changlian Zhu, Wei-Guo Zhu, Xiao-Feng Zhu, Xiongwei Zhu, Yuangang Zhu, Teresa Zoladek, Wei-Xing Zong, Antonio Zorzano, Jürgen Zschocke, Brian Zuckerbraun
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. email@example.com
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
Cancer Lett. 2012 Aug 14;: 22902993
Paclitaxel Inhibits Ovarian Tumor Growth by Inducing Epithelial Cancer Cells to Benign Fibroblast-like cells.
Departments of Pathology and Gynecology, The Affiliated People's Hospital of Inner Mongolia Medical College, Inner Mongolia Autonomous Region, China; Department of Obstetrics and Gynecology, The Affiliated People's Hospital of Inner Mongolia Medical College, Inner Mongolia Autonomous Region, China.
Paclitaxel is commonly used to treat multiple human malignancies, but its mechanism of action is still poorly defined. Human ovarian cancer SKOV3 cells (parental SKOV3) were treated with paclitaxel (1 μM) for 2 days, and the morphologic changes in the cells were monitored for more than 4 months. Parental SKOV3 underwent a markedly morphologic transition from the epithelial to fibroblast-like phenotype following treatment with paclitaxel; the resulting cells were designated as SKOV3-P. The SKOV3-P cells' proliferative ability was assessed via a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. The molecular characteristics of these cells were assessed via immunocytochemical staining and Western blot analysis. Their invasiveness and tumor formation ability was evaluated via wound-scratch and colony formation assays. The tumorigenicity of SKOV3-P cells was assessed in vivo after subcutaneous injection of tumor cells between injections of parental and paclitaxel-treated cells in nude mice. SKOV3-P cells have decreased the proliferation and invasion ability, decreased colony-forming ability when cultured in Matrigel and lost their tumor formation as compared with parental SKOV3 cells when injected in nude mice. SKOV3-P cells have decreased expression of E-cadherin, cytokeratin, Snail, PI3K, and P-Akt-Ser473, and increased expression of fibronectin, vimentin, Slug, P27, and PTEN. These results demonstrated that paclitaxel can inhibit tumor growth by inducing ovarian cancer epithelial cells toward a benign fibroblast-like phenotype through dysregulation of previously known pathways involved in the regulation of epithelial to mesenchymal transition (EMT), which may represent a novel mechanism for paclitaxel-induced tumor suppression.
PLoS One. 2012 ;7 (7):e41170 22829924
Xiao-Feng Le, Maria I Almeida, Weiqun Mao, Riccardo Spizzo, Simona Rossi, Milena S Nicoloso, Shu Zhang, Yun Wu, George A Calin, Robert C Bast Jr
Department of Experimental Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3'-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.
BMC Cancer. 2012 Jun 13;12 (1):243 22695491
Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome.
Jia Xu, Priya B Shetty, Weiwei Feng, Carol Chenault, Robert C Bast Jr, Jean-Pierre J Issa, Susan G Hilsenbeck, Yinhua Yu
ABSTRACT: BACKGROUND: Aberrant promoter CpG island hypermethylation is associated with transcriptional silencing. Tumor suppressor genes are the key targets of hypermethylation in breast cancer and therefore may lead to malignancy by deregulation of cell growth and division. Our previous pilot study with pairs of malignant and normal breast tissues identified correlated methylation of two pairs of genes - HIN-1/RASSFIA and RIL/CDH13 - with expression of estrogen receptors (ER), progesterone receptors (PR), and HER2 (HER2). To determine the impact of methylation on clinical outcome, we have conducted a larger study with breast cancers for which time to first recurrence and overall survival are known. METHODS: Tumors from 193 patients with early stage breast cancer who received no adjuvant systemic therapy were used to analyze methylation levels of RIL, HIN-1, RASSF1A and CDH13 genes for associations with known predictive and prognostic factors and for impact on time to first recurrence and overall survival. RESULTS: In this study, we found that ER was associated with RASSF1A methylation (p < 0.001) and HIN-1 methylation (p = 0.002). PR was associated with RIL methylation (p = 0.012), HIN-1 (p = 0.002), and RASSF1A methylation (p = 0.019). Tumor size was associated with RIL and CDH13 methylation (both p = 0.002), and S-phase was associated with RIL methylation (p = 0.036). Only RASSF1A was associated with worse time to first recurrence (p = 0.045) and worse overall survival (p = 0.016) after adjusting for age, tumor size, S-phase, estrogen receptor and progesterone receptor. CONCLUSIONS: Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancers was associated with clinical characteristics, but only RASSF1A methylation was associated with time to first recurrence and overall survival. Our data suggest that RASSF1A methylation could be a potential prognostic biomarker.
Cancer Discov. 2012 Jan ;2 (1):16-8 22585163
Department of Experimental Therapeutics and Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. firstname.lastname@example.org
Epithelial ovarian cancers exhibit marked heterogeneity and can be divided into low-grade type I and more prevalent high-grade type II lesions that differ in stage at diagnosis, rate of growth, and susceptibility to platinum-based chemotherapy. Activation of the phosphatidylinositol 3' kinase (PI3K) pathway occurs in a significant fraction of both types of ovarian cancer, driven predominantly by mutations in type I and amplification in type II. Available cell lines do not often reflect the genotype of type II ovarian cancers, but studies with cell lines driven by mutation suggest that blocking activated AKT is necessary, but not sufficient to inhibit cancer cell growth. Inhibition of multiple signaling pathways will likely be required to achieve effective personalized therapy for patients whose cancers exhibit "PI3Kness."
University of Texas MD Anderson Cancer Center, Houston, TX, USA. email@example.com
More than 200,000 women undergo exploratory surgery for a pelvic mass in the United States each year and 13%-21% of pelvic lesions are found to be malignant. Individual reports and meta-analysis indicate better outcomes when cancer surgery is performed by gynecologic oncologists. Despite the advantages provided by more thorough staging and cytoreductive surgery, only 30%-50% of women with ovarian cancer are referred to surgeons with specialized training in the United States. Imaging, menopausal status and biomarkers can aid in distinguishing malignant from benign pelvic masses to inform decisions regarding appropriate referral. The risk of malignancy index (RMI) uses ultrasound, menopausal status and CA125 and has been utilized in the United Kingdom for two decades, providing sensitivity that has ranged from 71%-88% and specificity it from 97%-74% for identifying patients with malignant disease. Criteria have been established by the Society of Gynecology Oncology and American College of Obstetrics and Gynecology for referral to a gynecologic oncologist, but these have lower sensitivity and specificity than the RMI. Recently, two new algorithms have been developed to identify women at sufficiently high risk to prompt referral to a specialized surgeon. The OVA1 multivariate index incorporates imaging, menopausal status, CA125 and four other proteomic biomarkers. Use of OVA1 provides 85%-96% sensitivity at 28%-40% specificity depending upon menopausal status. The negative predictive value for women judged to be at low risk is 94%-96%. The risk of malignancy algorithm (ROMA) includes CA125, human epididymal protein 4 and menopausal status, but not imaging results. The ROMA has yielded 93%-94% sensitivity at 75% specificity with a negative predictive value of 93%-98%. In a direct comparison, ROMA has achieved greater sensitivity (94%) than the RMI (75%) at 75% specificity. OVA1 has not been compared directly to ROMA, but is likely to be as sensitive, but substantially less specific. Both algorithms have high negative predictive values 94%-98%. Although a difference in specificity should not affect patient outcomes, it could affect distribution of medical resources.
Programmable bio-nano-chip systems for serum CA125 quantification: toward ovarian cancer diagnostics at the point-of-care.
Archana Raamanathan, Glennon W Simmons, Nicolaos Christodoulides, Pierre N Floriano, Wieslaw B Furmaga, Spencer W Redding, Karen H Lu, Robert C Bast Jr, John T McDevitt
Departments of Bioengineering and Chemistry, Rice University, Houston, TX 77005, USA.
Point-of-care (POC) implementation of early detection and screening methodologies for ovarian cancer may enable improved survival rates through early intervention. Current laboratory-confined immunoanalyzers have long turnaround times and are often incompatible with multiplexing and POC implementation. Rapid, sensitive, and multiplexable POC diagnostic platforms compatible with promising early detection approaches for ovarian cancer are needed. To this end, we report the adaptation of the programmable bio-nano-chip (p-BNC), an integrated, microfluidic, and modular (programmable) platform for CA125 serum quantitation, a biomarker prominently implicated in multimodal and multimarker screening approaches. In the p-BNCs, CA125 from diseased sera (Bio) is sequestered and assessed with a fluorescence-based sandwich immunoassay, completed in the nano-nets (Nano) of sensitized agarose microbeads localized in individually addressable wells (Chip), housed in a microfluidic module, capable of integrating multiple sample, reagent and biowaste processing, and handling steps. Antibody pairs that bind to distinct epitopes on CA125 were screened. To permit efficient biomarker sequestration in a three-dimensional microfluidic environment, the p-BNC operating variables (incubation times, flow rates, and reagent concentrations) were tuned to deliver optimal analytical performance under 45 minutes. With short analysis times, competitive analytical performance (inter- and intra-assay precision of 1.2% and 1.9% and limit of detection of 1.0 U/mL) was achieved on this minisensor ensemble. Furthermore, validation with sera of patients with ovarian cancer (n = 20) showed excellent correlation (R(2)= 0.97) with gold-standard ELISA. Building on the integration capabilities of novel microfluidic systems programmed for ovarian cancer, the rapid, precise, and sensitive miniaturized p-BNC system shows strong promise for ovarian cancer diagnostics.
Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.
Siqing Fu, Bryan T Hennessy, Chaan S Ng, Zhenlin Ju, Kevin R Coombes, Judith K Wolf, Anil K Sood, Charles F Levenback, Robert L Coleman, John J Kavanagh, David M Gershenson, Maurie Markman, Kristine Dice, Adrienne Howard, Jane Li, Yang Li, Katherine Stemke-Hale, Mary Dyer, Edward Atkinson, Ed Jackson, Vikas Kundra, Razelle Kurzrock, Robert C Bast Jr, Gordon B Mills
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; Department of Gynecologic Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
OBJECTIVES On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. RESULTS Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9months and 4.5months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5months, and another patient with a PIK3CA mutation had stable disease (SD) for 4months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with (18)F-FDG-PET responses. CONCLUSIONS Patients tolerated perifosine 150mg PO daily plus docetaxel at 75mg/m(2) every 4weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.
M.D. Anderson Cancer Center, Translational Research, Houston, Texas 77030, USA.
More than 90% of ovarian cancers have been thought to arise from epithelial cells that cover the ovarian surface or, more frequently, line subserosal cysts. Recent studies suggest that histologically similar cancers can arise from the fimbriae of Fallopian tubes and from deposits of endometriosis. Different histotypes are observed that resemble epithelial cells from the normal Fallopian tube (serous), endometrium (endometrioid), cervical glands (mucinous), and vaginal rests (clear cell) and that share expression of relevant HOX genes which drive normal gynecological differentiation. Two groups of epithelial ovarian cancers have been distinguished: type I low-grade cancers that present in early stage, grow slowly, and resist conventional chemotherapy but may respond to hormonal manipulation; and type II high-grade cancers that are generally diagnosed in advanced stage and grow aggressively but respond to chemotherapy. Type I cancers have wild-type p53 and BRCA1/2, but have frequent mutations of Ras and Raf as well as expression of IGFR and activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Virtually all type II cancers have mutations of p53, and almost half have mutation or dysfunction of BRCA1/2, but other mutations are rare, and oncogenesis appears to be driven by amplification of several growth-regulatory genes that activate the Ras/MAPK and PI3K pathways. Cytoreductive surgery and combination chemotherapy with platinum compounds and taxanes have improved 5-yr survival, but less than 40% of all stages can be cured. Novel therapies are being developed that target high-grade serous cancer cells with PI3Kness or BRCAness as well as the tumor vasculature. Both in silico and animal models are needed that more closely resemble type I and type II cancers to facilitate the identification of novel targets and to predict response to combinations of new agents.
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Eiji Kobayashi, Yutaka Ueda, Shinya Matsuzaki, Takuhei Yokoyama, Toshihiro Kimura, Kiyoshi Yoshino, Masami Fujita, Tadashi Kimura, Takayuki Enomoto
1Obstetrics and Gynecology, Osaka University.
Serum tumor markers have a major role in the screening, diagnosis and monitoring of most gynecologic cancers. Ovarian cancer is one of the deadliest of the group because it is so frequently asymptomatic until it has advanced to an untreatable stage. Even CA 125, clinically one of the most reliable serum markers for ovarian cancer, is elevated in only half of early-stage still-treatable tumors. Because of the very low prevalence of ovarian cancer in the general population, at present there is no cost-effective imaging or simple microscopic screening test for ovarian cancer, as there is for breast and cervical cancers. However, recent proteomics and nucleic acid -based analyses have shown great promise for the discovery of new and more useful serum biomarkers, that cumulatively might provide such a screening tool. In this review we will discuss both the currently utilized serum tumor markers for screening, diagnosis, monitoring of ovarian cancer and the novel biomarkers that are now under investigation and validation.
University of Pittsburgh, Pittsburgh, PA, USA. firstname.lastname@example.org
Recent discoveries in the field of biomarkers for screening and early detection of ovarian cancer (OC) identified current needs for biomarkers capable of recognizing preclinical disease. The suggested approaches are (1) development of highly analytically sensitive CA 125 assays capable of detecting CA 125 released from small cancerous and preneoplastic lesions;(2) identification of biomarkers effective in CA 125-negative cases; and (3) performing biomarker discovery in samples obtained from patients with prophylactic bilateral salpingo-oophorectomy with pathologically confirmed preneoplastic lesions, or in appropriate animal models of ovarian cancer.
Molecular Diagnostics Program, Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA. email@example.com
Human epididymis protein 4 (HE4) shows promise as a serum marker that complements CA125 in the early detection of epithelial ovarian cancer, either as a first-line screen or as a second-line screen in a multimodal strategy. Incorporation of symptoms in a screening strategy that includes CA125 and HE4 may warrant further research.
Tumour Biol. 2011 Aug ;32 (4):831-8 21625941
Janneta Tcherkassova, Carolina Abramovich, Rafael Moro, Chen Chen, Ralph Schmit, Angela Gerber, Ricardo Moro
Pacific Biosciences Research Centre, Richmond, BC, Canada.
Ovarian cancer can be cured in up to 90% of cases if diagnosed early. CA125, the most studied ovarian cancer biomarker, exhibits poor sensitivity for detecting early disease stages and low specificity to malignancy. RECAF, the alpha-fetoprotein receptor, is a wide-spectrum oncofetal antigen with clinical potential for cancer diagnosis, screening, and monitoring. This study evaluated the performance of RECAF as a diagnostic tool and the sensitivity of a combination of RECAF and CA125 to detect early stages of ovarian cancer at a cutoff resulting in 100% specificity among healthy women. This retrospective case-control study was designed to measure the serum levels of RECAF and CA125 in normal individuals (n=106) and cancer patients stages I/II (RECAF, n=32; CA125, n=35) and III/IV (RECAF, n=49; CA125, n=51). A competitive chemiluminescence assay was developed to measure the circulating RECAF. To eliminate any false positives, we classified as positive any patient with a RECAF or a CA125 value higher than their respective 100% specificity cutoff. We have shown that RECAF discriminated cancer and healthy donors better than CA125, particularly in the early stages (AUC(RECAF)=0.96 and AUC(CA125)=0.805). CA125 sensitivity was lower in the early stages than in the advance stages; RECAF sensitivity was high at all stages. A combination of CA125 and RECAF detected three out of four early-stage patients, with no false positives. In conclusion, the combination of RECAF and CA125 serum values provides the specificity and the sensitivity necessary to screen for ovarian cancer and in particular, to detect early stages of the disease.
J Oncol. 2011 ;2011 :475983 21577260
Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
This paper reviews current screening techniques as well as novel biomarkers and their potential role in early detection of ovarian cancer. Ovarian cancer is one of the most common reproductive cancers and has the highest mortality rate amongst gynecologic cancers. Because most ovarian cancer diagnoses occur in the late stages of the disease, five-year survival rates fall below 20%. To improve survival rates and to lower mortality rates for ovarian cancer, improved detection at early stages of the disease is needed. Current screening approaches include tumor markers, ultrasound, or a combination. Efforts are underway to discover new biomarkers of ovarian cancer in order to surmount the obstacles in early-stage diagnosis. Among serum protein markers, HE4 and mesothelin can augment CA125 detection providing higher sensitivity and specificity due to the presence of these proteins in early-stage ovarian cancer. Detection testing that includes methylation of the MCJ gene and increased expression of vascular endothelial growth factor is correlated to poor prognosis and may predict patient survival outcome. Detection testing of biomarkers with long-term stability and combination panels of markers, will likely lead to effective screening strategies with high specificity and sensitivity for early detection of ovarian cancer.
Juan Ren, Hui Cai, Yi Li, Xiaozhi Zhang, Zi Liu, Jian-Sheng Wang, Yi Lisa Hwa, Yuelang Zhang, Ya Yang, Yu Li, Shi-Wen Jiang
Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China. firstname.lastname@example.org
The overall mortality rate for ovarian cancer is 75%, but when diagnosed at stage I, 90% of patients can be cured. Strategies for early detection require high sensitivity (>75%) and extremely high specificity (99.6%) to attain a positive predictive value of at least 10%. When functioning alone, conventional markers fall short of this required sensitivity or specificity. Greater specificity can be achieved by combining multiple markers. Meanwhile, technological developments offer the potential identification of new candidate markers. Panels of new markers have been discovered with improved sensitivity and specificity for early-stage detection, but these require prospective validation. Through empirical development of: biotechnology (including monoclonal antibodies, gene expression, cloning of gene families and proteomics); statistical methods; and guidelines from specialized institutions, more candidate markers might be discovered and validated with systematic, efficient and cost-effective screenings.
Carole & Ray Neag Comprehensive Cancer Center, University of Connecticut Health Center, Obstetrics & Gynecology, Farmington, CT 05030, USA.
One of the most challenging issues in gynecologic oncology is the high mortality rate of ovarian cancer, largely due to detection of disease in advanced stages. Women with early-stage disease have a significantly improved survival rate and may not require chemotherapy. Thus, the issues to examine are whether there are methods to improve early detection, thereby resulting in a reduction in mortality. Several large, randomized, clinical trials have recently completed evaluating CA 125 and transvaginal sonography as effective strategies to accomplish this goal. These issues and the results of the recent trials will be reviewed in this article.
Prim Care. 2009 Sep ;36 (3):623-39 19616158
Division of Geriatric Medicine, Department of Family and Community Medicine, Jefferson Medical College, Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107, USA. Lauren.Collins@jefferson.edu
Lung and ovarian cancers are two of the most common and deadly cancers affecting men and women in the United States. The potential impact of an effective screening modality for early detection of these cancers is enormous. Yet, to date, no screening tool has been proven to reduce mortality in asymptomatic individuals, and no major organization endorses current modalities for screening for these cancers. Novel approaches, potentially relying on genomics and proteomics, may be the future for early detection of these deadly cancers.
Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China. email@example.com
OBJECTIVE To find new serum tumor markers for ovarian epithelial cancers by 2-DE DIGE and MALDI-TOF/TOF proteomic methods, in order to improve the diagnostic sensitivity and specificity. METHODS Serum samples from 103 cases of ovarian epithelial cancers, 60 cases of healthy women, 63 cases of benign ovarian tumors and 63 cases of benign pelvic diseases were collected. Sera of 20 cases of ovarian epithelial cancers (A), 20 cases of ovarian benign tumors (B), 20 cases of pelvic benign diseases (C) and 20 cases of health control (D) were matched by age and pooled, respectively. After depletion of high abundance serum albumin and IgG, the samples were assayed by 2-DE DIGE. The test was repeated three times. Analysis with DeCyder software revealed significant differential protein spots which were identified by MAIDI-TOF/TOF. Western blot and ELISA were used to validate the candidate serum markers. RESULTS 1) There were 41 proteins having significant differences between the groups. MAIDI-TOF/TOF successfully identified 28 proteins. Haptoglobin (Hp) was the most significantly up-regulated protein, and transferrin (Tf) was the most significantly down-regulated protein. 2) Western blot and ELISA proved that there were significant differences in Hp and Tf between ovarian epithelial cancers and normal controls (P = 0.000), between ovarian epithelial cancers and ovarian benign tumors (P = 0.000), between ovarian epithelial cancers and benign pelvic disease sera (P = 0.000). 3) CA125 + Hp + Tf combined detection of ovarian cancer had higher sensitivity and specificity than CA125, Hp or Tf detection alone. CONCLUSION Hp and Tf are differently expressed in the sera of patients with ovarian epitheliual cancers. They can be used as serum biomarkers for ovarian epithelial cancers. CA125 + Hp + Tf combined detection may improve the sensitivity and specificity of diagnosis of ovarian epithelial cancers.