Novel Mechanism Through Which Normal Stromal Cells Become Cancer-promoting Stromal Cells Identified

Nov 2012

PHILADELPHIA — New understanding of molecular changes that convert harmless cells surrounding ovarian cancer cells into cells that promote tumor growth and metastasis provides potential new therapeutic targets for this deadly disease, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.

“New approaches for treating patients with ovarian cancer are desperately needed,” said Ernst Lengyel, M.D., Ph.D., professor in the department of obstetrics and gynecology at the University of Chicago. “There have been no new approaches introduced into the clinic for quite some time, and we have seen no major improvements in patient survival over the years.”

According to Lengyel, greater understanding of the biology of ovarian cancer should provide new therapeutic targets. He and his colleagues set out to learn how normal stromal cells are transformed into cancer-associated fibroblasts, which are found in the tissue immediately surrounding the ovarian cancer cells. Intimate cross talk between cancer-associated fibroblasts and cancer cells boosts tumor growth and metastasis.

“The strength of our study lies in the fact that we used cells from patients, rather than cell lines,” said Lengyel. “This means that our model system reflects as closely as possible the clinical situation in patients.”

Initial analysis indicated that cancer-associated fibroblasts from patients with ovarian cancer had altered patterns of expression of small molecules called microRNAs compared with normal and tumor-adjacent fibroblasts.

MicroRNAs are important regulators of gene expression because they help direct that cell’s function. Thus, modified patterns of microRNA expression change cell function.

Lengyel and colleagues further studied the microRNA most upregulated in cancer-associated fibroblasts and the two microRNAs most significantly downregulated. When they changed the pattern of expression of these three microRNAs in normal fibroblasts to mimic the pattern they had seen in cancer-associated fibroblasts, they found that the normal fibroblasts were converted into cells with in-vitro characteristics of cancer-associated fibroblasts. Moreover, the cells reprogrammed to become cancer-associated fibroblasts by altering microRNA expression enhanced the growth of tumor cells in a mouse model of ovarian cancer.

Conversely, restoring the pattern of expression of the three microRNAs to normal in cancer-associated fibroblasts reduced their cancer-promoting characteristics.

“Therapeutic approaches targeting microRNAs in cancer cells are under development,” said Lengyel. “Our work suggests that it might be possible to modify microRNA expression in cancer-associated fibroblasts for therapeutic benefit.”

Lengyel added that treatments targeting microRNAs in cancer-associated fibroblasts may be particularly effective because these cells are genetically stable, unlike cancer cells, therefore, the risk that cancers will become unresponsive to these treatments is less than for treatments targeting cancer cells.

BioScience Tech

Lifetime of tea drinking can reduce risk of ovarian cancer

 Nov 2012

A lifetime of tea drinking can significantly reduce the risk of ovarian cancer in later life, according to the results of a new medical study.

Women who begin drinking tea at a young age and drink the beverage more often are less likely to get the disease, which affects around 7,000 Britons a year.

The results of the study were published in the journal Cancer Epidemiology and have been welcomed by the Tea Advisory Panel.

Health experts conducted a two-year study of 1,000 women with an average age of 59, half of which were diagnosed with ovarian cancer, while a controlled group of 500 were free of the disease.

They were questioned about their tea drinking habits from how often they made a cup, what kind of tea they drank and when they first started.

The researchers discovered that the women without cancer were more likely to be tea drinkers from an earlier age than those diagnosed with the illness.

The Telegraph

Optimal dose of dasatinib determined for advanced, recurrent ovarian cancer

Nov 2012

A phase I trial determined that dasatinib 150 mg daily is the optimum dose when dasatinib is combined with paclitaxel and carboplatin to treat patients with advanced or recurrent ovarian cancer.

Dasatinib is an oral SRC-family tyrosine kinase inhibitor. It has promising potential to treat advanced ovarian cancer because the SRC families play a role in the increased activation of cell migration, proliferation, survival, invasion, and angiogenesis. The SRC pathways are frequently dysregulated in solid tumors and can increase chemotherapy resistance.

Previous laboratory studies with ovarian cancer cell lines found that SRC inhibition enhanced the cytotoxic efficacy of both paclitaxel and cisplatin. Studies done in vivo found decreased tumor growth with SRC inhibition. This study sought to determine the maximum tolerated dose of dasatinib when it was combined with paclitaxel and cisplatin.

Administering dasatinib with paclitaxel did not alter the effects of either drug, according to the study's results. Further, dasatinib may be better used in combination with chemotherapy agents for a synergistic effect.

“It may also be better to combine dasatinib with only one cytotoxic therapy to improve tolerability,” study co-author Robert M. Wenham, MD, of the Moffitt Cancer Center explained.

The researchers concluded that finding biomarkers to direct the use of targeted therapies is of the utmost importance. Although SRC gene expression was not correlated with response, the research team found several differentially regulated genes between responders and those with stable disease.

“Unfortunately, a biomarker was unable to be identified to demonstrate which women are most likely to benefit from dasatinib,” said study contributor Johnathan M. Lancaster, MD, PhD, also of Moffitt Cancer Center. “Further study should explore relevant biomarkers and identify a patient population most likely to benefit from the addition of dasatinib.”

This study was published in Clinical Cancer Research (2012; doi:10.1158/1078-0432.CCR-12-0507).

Oncology Nurse Advisor

Ovarian cancer stem cell like side populations are enriched following chemotherapy and overexpress EZH2

2011

Siân Rizzo,¹ Jenny M. Hersey,¹ Paul Mellor,¹ Wei Dai,² Alessandra Santos-Silva,¹ Daniel Liber,²Louisa Luk,^2,3 Ian Titley,⁴ Craig P Carden,¹ Garry Box,⁵ David L. Hudson,¹ Stanley B. Kaye,¹ andRobert Brown^1,2

^Abstract

^{Platinum-based chemotherapy, with cytoreductive surgery, is the cornerstone of treatment of advanced ovarian cancer, however acquired drug resistance is a major clinical obstacle. It has been proposed that subpopulations of tumour cells with stem-cell like properties, such as so-called side populations (SP) which over-express ABC drug-transporters, can sustain the growth of drug resistant tumour cells, leading to tumour recurrence following chemotherapy. The histone methyltransferase EZH2 is a key component of the Polycomb Repressive Complex 2 (PRC2) required for maintenance of a stem cell state and overexpression has been implicated in drug resistance and shorter survival of ovarian cancer patients. We observe higher percentage SP in ascites from patients that have relapsed following chemotherapy compared to chemonaive patients, consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, ABCB1 (P-glycoprotein) and EZH2 are consistently over-expressed in SP compared to non-SP from patients’ tumour cells. SiRNA knockdown of EZH2 leads to loss of SP in ovarian tumour models, reduced anchorage-independent growth and reduced tumour growth in vivo. Together these data support a key role for EZH2 in the maintenance of a drug-resistant tumour-sustaining subpopulation of cells in ovarian cancers undergoing chemotherapy. As such, EZH2 is an important target for anticancer drug development.}

^NIH

Rethinking Ovarian Cancer: Recommendations for Improving Outcomes

2012

Sebastian Vaughan,¹ Jermaine I. Coward,¹ Robert C. Bast Jr., Andy Berchuck, Jonathan S. Berek,James D. Brenton, George Coukos, Christopher C. Crum, Ronny Drapkin, Dariush Etemadmoghadam, Michael Friedlander, Hani Gabra, Stan B. Kaye, Chris J. Lord, Ernst Lengyel,Douglas A. Levine, Iain A. McNeish, Usha Menon, Gordon B. Mills, Kenneth P. Nephew, Amit M. Oza, Anil K. Sood, Euan A. Stronach, Henning Walczak, David D. Bowtell,^2,3 and Frances R. Balkwill²

There have been major advances in our understanding of the cellular and molecular biology of the human malignancies collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Perspective.

Patient prognosis has improved significantly for many solid cancer types. However, survival of women with epithelial ovarian cancer has changed little since platinum-based treatment was introduced over 30 years ago. Invasive epithelial ovarian cancer is widely viewed and treated as a single disease entity with little stratification of histological or molecular subtypes. At a recent Helene Harris Memorial Trust (HHMT) meeting of leading ovarian cancer researchers and clinician-scientists, sponsored and organised by Ovarian Cancer Action (Box 1), we asked the question ‘what actions can we take to improve the outcome for women with ovarian cancer?’ A consensus regarding the major barriers to success and the most pressing questions led delegates to propose nine priorities for action, which we describe in this Perspective.

^NIH

Copy-Number and Expression Alterations of miRNAs in the Ovarian Cancer Cell Line OVCAR-3: Impact on Kallikrein 6 Protein Expression.

Nov 2012

Bayani J, Kuzmanov U, Saraon P, Fung WA, Soosaipillai A, Squire JA, Diamandis EP.

Source

Department of Laboratory Medicine and Pathobiology, University of Toronto, and.

Abstract

BACKGROUND: Kallikrein-related peptidase 6 (KLK6), a member of the serine protease family of kallikrein (KLK) genes, is dysregulated in ovarian carcinomas (OCa) and its overexpression is associated with poor prognosis. Regulation of its expression is poorly understood and is likely to be influenced by multiple mechanisms. The KLK locus is subject to copy-number changes and heterogeneity in serous OCas. These copy-number imbalances generally correlate with KLK6 protein expression; however, this is not always the case. In this study we explored the role of miRNAs in the posttranscriptional control of KLK6 expression and the contributions of copy numbers, not only of the KLK locus, but also of the miRNAs predicted to regulate it.

METHODS AND RESULTS: By miRNA profiling of the KLK6-overexpressing OCa cell line, OVCAR-3, we identified overexpressed and underexpressed miRNAs. Publically available miRNA databases identified the human miRNA lethal 7 (hsa-let-7) family members as putative regulating miRNAs, from which hsa-let-7a was chosen for functional analysis. The transient transfection of hsa-let-7a to OVCAR-3 resulted in a decrease of KLK6 secreted protein. Moreover, such transfection was also able to weakly affect the expression of another member of the KLK gene family, KLK10 (kallikrein-related peptidase 10). Cytogenomic analysis, including array comparative genomic hybridization, fluorescence in situ hybridization, and spectral karyotyping revealed the overall net copy-number losses of hsa-let-7a and other miRNAs predicted to target KLK6.

CONCLUSIONS:The hsa-let-7 family member hsa-let-7a is a modulator of KLK6 protein expression that is independent of the KLK6 copy-number status.

Clinical Chemistry

Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer.

Nov 2012

Monk BJ, Dalton H, Farley JH, Chase DM, Benjamin I.

Source

Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, United States. Electronic address: Bradley.Monk@DignityHealth.org.

Abstract

Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted.

Oncology Hematology

Ovarian Cancer, Version 3.2012.

Nov 2012

Morgan RJ, Alvarez RD, Armstrong DK, Burger RA, Castells M, Chen LM, Copeland L, Crispens MA, Gershenson D,Gray H, Hakam A, Havrilesky LJ, Johnston C, Lele S, Martin L, Matulonis UA, O'Malley DM, Penson RT, Remmenga SW,Sabbatini P, Santoso JT, Schilder RJ, Schink J, Teng N, Werner TL, Hughes M, Dwyer MA.

Source

From 1City of Hope Comprehensive Cancer Center; 2University of Alabama at Birmingham Comprehensive Cancer Center; 3The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 4Fox Chase Cancer Center; 5Dana-Farber/Brigham and Women's Cancer Center; 6UCSF Helen Diller Family Comprehensive Cancer Center; 7The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; 8Vanderbilt-IngramCancer Center; 9The University of Texas MD Anderson Cancer Center; 10University of Washington Medical Center/SeattleCancer Care Alliance; 11Moffitt Cancer Center; 12Duke Cancer Institute; 13University of Michigan Comprehensive CancerCenter; 14Roswell Park Cancer Institute; 15Massachusetts General Hospital Cancer Center; 16UNMC Eppley CancerCenter at The Nebraska Medical Center; 17Memorial Sloan-Kettering Cancer Center; 18St. Jude Children's Research Hospital/University of Tennessee Cancer Institute; 19Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 20Stanford Cancer Institute; 21Huntsman Cancer Institute at the University of Utah; and 22National Comprehensive Cancer Network.

Abstract

These NCCN Guidelines Insights focus on the major updates for the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer by describing how and why the new recommendations were made. The 6 update topics were selected based on recent important updates in the guidelines and on debate among panel members about recent clinical trials, and include: 1) screening, 2) diagnostic tests for assessing pelvic masses, 3) primary treatment using neoadjuvant chemotherapy, 4) primary adjuvant treatment using bevacizumab in combination with chemotherapy, 5) therapy for recurrent disease, and 6) management of drug/hypersensitivity reactions. These NCCN Guidelines Insights also discuss why some recommendations were not made (eg, panel members did not feel the new data warranted changing the guideline). See "Updates" in the NCCN Guidelines for Ovarian Cancer for a complete list of all the recent revisions.

JNCCN

Ovarian Cancer Stem Cells: Working Towards the Root of Stemness.

Nov 2012

Foster R, Buckanovich RJ, Rueda BR.

Source

Vincent Center for Reproductive Biology; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital.

Abstract

Despite medical advances made over the past decade, ovarian cancer remains one of the more lethal gynecologic cancers in the United States. While current therapeutic strategies are relatively effective, there is a high incidence of recurrent chemoresistant disease. This has been attributed, in part, to a regenerative tumor cell sub-population that has acquired stem cell properties which allow these cells to escape standard chemotherapeutics and drive recurrent disease. To date, a number of laboratories have identified these cancer stem cell (CSC) sub-populations in ovarian cancer cell lines, tumors or ascites and the collective findings suggest ovarian CSC are likely to be as heterogeneous as the disease itself. Moreover, the multiple ovarian histophenotypes and possible sites of disease origin together with the potential for differential hierarchal contributions of multiple CSC populations represent significant challenges to the identification, functional characterization and therapeutic targeting of ovarian CSC. This review will highlight the markers and methodology currently used to identify and isolate these cells. We will discuss some of the underlying ovarian CSC biology, the signaling pathways implicated in their survival, replication and differentiation and potential therapeutic targeting strategies.

Elsevier

Population prevalence of first- and second-degree family history of breast and ovarian cancer.

2011

Moghimi-Dehkordi B, Safaee A, Vahedi M, Pourhoseingholi MA, Pourhoseingholi A, Zali MR.

Source

Research Center of Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran.

Abstract

BACKGROUND:

Family cancer history is an important risk factor for common cancers, thus, recognizing pattern of familial cancer can help us to identify individuals who may have higher chance to develop specified cancers.

METHODS:

This cross-sectional survey assessed family history of cancer in first- and second degree relatives. Totally, 7,300 persons aged > or = 20 years selected by random sampling from Tehran general population. Age- and sex-specified prevalence of breast and ovarian cancer in respondent's family was calculated.

RESULTS:

Of all, 279(4.3%) individuals reported a history of breast or ovarian cancer in their relatives. The prevalence of breast cancer family history was 1.8% among first-degree relatives and 2.5% among second- degree relatives. For ovarian cancer, first- and second-degree prevalence ranged from 0.05 to 0.12%. Those with family history of cancer were more often young and female.

CONCLUSIONS:

Overall, the estimates of prevalence presented here are likely to be conservative compared with actual current prevalence because of some limitations. While family history is an important risk factor for common cancers such as breast cancer, recognizing pattern of familial cancer that signify increased risk can help us to identify individuals who may have higher chance to develop specified cancers.

PubMed

Identifying women with undetected ovarian cancer: independent and external validation of QCancer(®) (Ovarian) prediction model.

 Nov 2012

Collins GS, Altman DG.

Source

Centre for Statistics in Medicine, Wolfson College Annexe, University of Oxford, Oxford, UK.

Abstract

Early identification of ovarian cancer is an unresolved challenge and the predictive value of single symptoms is limited. We evaluated the performance of QCancer(®) (Ovarian) prediction model for predicting the risk of ovarian cancer in a UK cohort of general practice patients. A total of 1.1 million patients registered with a general practice surgery between 1 January 2000 and 30 June 2008, aged 30-84 years with 735 ovarian cancer cases, were included in the analysis. Ovarian cancer was defined as incident diagnosis of ovarian cancer during the 2 years after study entry. The results from this independent and external validation of QCancer(®) (Ovarian) prediction model demonstrated good performance on a large cohort of general practice patients. QCancer(®) (Ovarian) had very good discrimination with an area under the receiver operating characteristic curve of 0.86 and explained 59.9% of the variation. QCancer(®) (Ovarian) was well calibrated across all tenths of risk and over all age. The 10% of women with the highest predicted risks included 64% of all ovarian cancer diagnoses over the next 2 years. QCancer(®) (Ovarian) appears to be a useful tool for identifying undetected cases of ovarian cancer in primary care in the UK for early referral and investigation.

Blackwell - PubMed

NFCR Scientists Discover Surprising New Target for Ovarian Cancer

NFCR Scientists Discover Surprising New Target for Ovarian Cancer

National Foundation for Cancer Research Makes New Step Toward Enhancing Anti-Cancer Drugs

The National Foundation for Cancer Research (NFCR) has opened a large window of opportunity to improve the effectiveness of existing chemotherapies against ovarian cancer. For the first time, the protein Salt Inducible Kinase 2 (SIK2) has been found to play a critical role in cell division and regulating the response of ovarian cancer to chemotherapy. This discovery means that scientists have a new pathway to explore to increase the sensitivity of ovarian cancer cells to anti-cancer drugs.

This research was reported in the August issue of Cancer Cell by NFCR scientists, Robert C. Bast, Jr., M.D. and Ahmed Ashour Ahmed, M.D., Ph.D. Dr. Bast and Ahmed are with the University of Texas MD Anderson Cancer Center and the University of Oxford.

Only about half of women with ovarian cancer will respond to a taxane, which is a standard type of chemotherapy agent. This dramatic lack of response resulted in an urgent call to researchers to find a new treatment to fight this cancer.

NFCR researchers, Ahmed and Bast, answered the call by using nearly 780 pools of siRNAs, (strands of genetic material involved in decoding DNA instructions) to knock down different proteins that might alter cell sensitivity to the chemotherapy agent. One of the most promising proteins, the enzyme SIK2, was an unlikely candidate, as it is normally associated only with cell metabolism. However, Dr. Ahmed and Bast discovered that SIK2 also plays a key role in the beginning stages of cell division.

Dr. Ahmed and Bast demonstrated that depleting SIK2 from ovarian cancer cells in laboratory models also sensitized the cells to taxanes, which are known to inhibit cell division. This may lead to enhancement of taxane-based drugs to make them more effective in inhibiting or even stopping the cancer's growth in a larger fraction of patients. These findings demonstrate once again that combination therapies targeting different phases of the cell division cycle are vital for new and better approaches to treating cancer.

"The discovery that SIK2 plays a role in cell cycle regulation is groundbreaking, since, to date, it has only been linked to cellular metabolism and energy balance," Dr. Ahmed said. "In addition to improving the response of some cancers to a taxane, our findings add support to emerging evidence that cancer cell metabolism and cell division functions are coupled."

Dr. Bast, Vice President for Translational Research at MD Anderson, credits this discovery to NFCR's long-standing support of their research. For ten years, NFCR has supported Dr. Bast in his search for more effective ways to treat ovarian cancer. "NFCR understands that it is only through this type of long-term support of research that we will unlock the intricate and complex mysteries of cancer to benefit patients with this disease," said Bast.

Finding drugs that inhibit SIK2 could improve cancer treatment significantly. Such drugs do not yet exist, but, thanks to NFCR scientists, the critical first step of identifying a promising target has been achieved.

"This research breakthrough will set in motion the drug discovery process to identify inhibitors of SIK2," said Dr. Michael Wang, NFCR Chief Science Officer. "Ovarian cancer patients are in great need of new approaches that allow us to be more effective than anything we now have available. This new understanding of how treatment may be enhanced looks very promising."

About the National Foundation for Cancer Research

The National Foundation for Cancer Research (NFCR) is a leading cancer research charity dedicated to funding cancer research and public education relating to cancer prevention, earlier diagnosis, better treatments and, ultimately, a cure for cancer. NFCR promotes and facilitates collaboration among scientists to accelerate the pace of discovery from bench to bedside.

Since 1973, NFCR has provided over $288 million in support of discovery-oriented cancer research focused on understanding how and why cells become cancerous, and on public education relating to cancer prevention, detection, and treatment. NFCR scientists are discovering cancer's molecular mysteries and translating these discoveries into therapies that hold the hope for curing cancer. NFCR is about Research for a Cure-cures for all types of cancer. For more information, please visit www.NFCR.org.

 NFCR