WIH Researchers Examine Role of Hormone HE4 in Patient Responses to Ovarian Cancer Treatment

Researchers at Women & Infants’ Hospital of Rhode Island recently published the results of an investigation into the role of hormone HE4 in patient responses to ovarian cancer treatment.

Researchers at Women & Infants’ Hospital of Rhode Island recently published the results of an investigation into how we might better tailor therapy for ovarian cancer.

The work comes out of the molecular therapeutic laboratory directed by Richard G. Moore, M.D., of Women & Infants’ Program in Women’s Oncology. Entitled “HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation,” the research was recently published in the international science journal Scientific Reports, a Nature publishing group.

The goal of the study was to investigate the role of the hormone HE4 (Human epididymis protein 4) in modulating ovarian cancer’s response to hormones and hormonal therapies. HE4 is a biomarker that is elevated in ovarian cancer and is known to play a role in resistance to chemotherapy.

Richard G. Moore, M.D.

Richard G. Moore, M.D.

“There is little known about the biologic functions of HE4 but we did know that there were hormonal responsive elements within the promoter region of the HE4 gene, which regulates gene expression. For this reason, we hypothesized that steroid hormones could influence expression of HE4 in ovarian cancer,” Moore explains.

The study resulted in multiple findings:

  • Hormonal therapies like tamoxifen (Nolvadex) and fulvestrant (Faslodex) are effective because they bind the estrogen receptor. If cells have less estrogen receptor expression, these drugs can’t do their job. This, the researchers believe, is due to epigenetic modifications which modify the DNA structure but not the DNA sequence itself. Overexpression led to the epigenetic modification known as decreased DNA methylation in cell culture and in human tissue samples.
  • Treatment of ovarian cancer cells with tamoxifen and fulvestrant all cause HE4 to translocate to the cell nucleus, where it can then effect further gene expression in cancer cells.
  • Using the drug ivermectin (broad-spectrum antiparasitic agent), the researchers were able to inhibit the protein import in-4, which then inhibited HE4 from translocating to the nucleus. If HE4 can’t enter the nucleus, it cannot affect gene expression. The ability to block HE4 from entering the nucleus restored sensitivity to hormonal therapy.

“We are not certain but believe this might mean there could be a subset of women whose tumors are more likely to respond to hormonal therapy. Moreover, we might be able to eventually identify which tumors these are and target treatment,” Moore says.

Dr. Moore’s lab will continue to investigate the expression of estrogen receptors in both primary and recurrent ovarian cancers and how that relates to HE4 expression. In addition, Dr. Moore and other researchers will investigate how importin inhibitors may play a role in addressing chemoresistance to standard therapeutics, particularly in HE4 overexpressing tumors.

About Women & Infants Hospital

Women & Infants’ Hospital of Rhode Island, a Care New England hospital, is one of the nation’s leading specialty hospitals for women and newborns. The primary teaching affiliate of The Warren Alpert Medical School of Brown University for obstetrics, gynecology and newborn pediatrics, as well as a number of specialized programs in women’s medicine, Women & Infants’ is the eighth largest stand-alone obstetrical service in the country with nearly 8,400 deliveries per year.In 2009, Women & Infants opened the country’s largest, single-family room neonatal intensive care unit.

New England’s premier hospital for women and newborns, Women & Infants’ and Brown offer fellowship programs in gynecologic oncology, maternal-fetal medicine, urogynecology and reconstructive pelvic surgery, women’s mental health, neonatal-perinatal medicine, pediatric and perinatal pathology, gynecologic pathology and cytopathology, and reproductive endocrinology and infertility. It is home to the nation’s only mother-baby perinatal psychiatric partial hospital, as well as the nation’s only fellowship program in obstetric medicine.

Women & Infants’ Hospital has been designated as a Breast Center of Excellence from the American College of Radiography; a Center for In Vitro Maturation Excellence by SAGE In Vitro Fertilization; a Center of Biomedical Research Excellence by the National Institutes of Health; and a Neonatal Resource Services Center of Excellence. It is one of the largest and most prestigious research facilities in high risk and normal obstetrics, gynecology and newborn pediatrics in the nation, and is a member of the National Cancer Institute’s Gynecologic Oncology Group and the National Institutes of Health’s Pelvic Floor Disorders Network.

Sources:

  • Lokich E et al. “HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation.” Sci Rep. 2014 Jun 30;4:5500. doi: 10.1038/srep05500. [PMID:24975515] [PMCID:PMC4074789]

Related Posts:

  • Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer (March 15, 2009).
  • European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer (February 24, 2009).
  • Working Smarter, Not Harder: Use of Anti-Estrogen Therapy to Battle Recurrent Ovarian Cancer (August 18, 2008).

SU2C Announces the Formation of a New Translational Research Ovarian Cancer “Dream Team”

Ovarian Cancer Community Joins Forces to Fight Deadliest Gynecologic Cancer. The New Stand Up To Cancer Dream Team Will Launch in 2015.

The Ovarian Cancer Research Fund, The Ovarian Cancer National Alliance, and the National Ovarian Cancer Coalition Team Up to Fund New Translational Research Ovarian Cancer “Dream Team.”

 

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A groundbreaking collaboration is underway among three national ovarian cancer organizations: Ovarian Cancer Research Fund (OCRF), Ovarian Cancer National Alliance (OCNA), and National Ovarian Cancer Coalition (NOCC). In partnership with Stand Up To Cancer (SU2C), this group will fund a new Ovarian Cancer Dream Team dedicated to piloting leading-edge, ovarian cancer research that will help patients and save lives.

This partnership was announced tonight by actor Pierce Brosnan on the Stand Up To Cancer’s biennial telecast, and in recognition of National Ovarian Cancer Awareness Month. The SU2C-OCRF-OCNA-NOCC Translational Research Dream Team grant will provide funding, over a three-year period, for research associated with this insidious disease.

Ovarian cancer is the deadliest of all the gynecologic cancers. Almost 22,000 American women will be diagnosed with ovarian cancer in 2014, and more than 14,000 women will lose their lives to the disease. By collaborating to fund an Ovarian Cancer Dream Team, OCRF, OCNA and NOCC, with SU2C, will further research in the field that can lead to new treatments and improved patient outcomes.

Later this month, SU2C, through its science partner the American Association for Cancer Research (AACR), will issue a “Call for Ideas” from researchers and scientists worldwide. The selected Dream Team will be announced next spring, with research beginning in July 2015.

OCRF“Ovarian Cancer Research Fund has been the leading nonprofit funder of ovarian cancer research for years, and this new collaboration is a wonderful way to mark our 20th anniversary,” said Audra Moran, CEO of Ovarian Cancer Research Fund. “We are excited that the Dream Team grant will continue our long tradition of supporting the most innovative research in the field, while providing scientists with a vital new source of financial support.”

OCNA1Calaneet Balas, CEO of the Ovarian Cancer National Alliance, said: “I am so thrilled that our three organizations are coming together to fight the disease we all care so much about. I believe the Ovarian Cancer Dream Team will be paradigm-shifting for our community, and I cannot wait to see what comes from this new initiative. We’re proud of the work the Alliance has done to secure federal research funding on behalf of all women, but the Dream Team gives us new opportunities for collaboration and innovation.”

NOCC - Logo“We are both proud and excited to join in supporting the Ovarian Cancer Dream Team, the first-ever collaboration of such efforts,” said David Barley, CEO of the National Ovarian Cancer Coalition. “We are looking forward to being instrumental in furthering ovarian cancer research. The impacts on families and communities continue to make ovarian cancer “More Than a Woman’s Disease®.” By working together we hope to make a difference in the lives of everyone we touch.”

About the Ovarian Cancer Research Fund
The Ovarian Cancer Research Fund (OCRF), founded in 1994, is the oldest and largest charity in the United States funding ovarian cancer research, and ranks third in overall ovarian cancer research funding only after the National Cancer Institute (NCI) and the U.S. Department of Defense (DOD). Its mission is to fund scientific research that leads to more effective identification, treatment, and ultimately a cure for ovarian cancer, as well as related educational and support initiatives. OCRF has invested nearly $60 million in ovarian cancer research through 217 grants to scientists at 65 leading medical centers in the United States. OCRF continues to take the lead in funding the best and most promising ovarian cancer research while supporting women and their loved ones affected by this terrible disease in our quest to end it. For more information, please visit www.ocrf.org.

About the Ovarian Cancer National Alliance
The Ovarian Cancer National Alliance is a powerful voice for everyone touched by ovarian cancer. We connect survivors, women at risk, caregivers, and health providers with the information and resources they need. We ensure that ovarian cancer is a priority for lawmakers and agencies in Washington, DC, and throughout the country. We help our community raise their voices on behalf of every life that has been affected by this disease. For more information, please visit: www.ovariancancer.org

About the National Ovarian Cancer Coalition
Since its inception in 1995, the National Ovarian Cancer Coalition (NOCC) has been committed to raising awareness, promoting education, and funding research in support of women, families, and communities touched by ovarian cancer. NOCC is well-established as an important national advocate for patients and families struggling with ovarian cancer. NOCC remains steadfast in its mission to save lives by fighting tirelessly to prevent and cure ovarian cancer, and to improve the quality of life for survivors. For more information, please visit: www.ovarian.org.

About Stand Up To Cancer
Stand Up To Cancer (SU2C) raises funds to accelerate the pace of research to get new therapies to patients quickly and save lives now. SU2C, a program of the Entertainment Industry Foundation (EIF) and a 501(c)(3) charitable organization, was established in 2008 by film and media leaders who utilize the industry’s resources to engage the public in supporting a new, collaborative model of cancer research, and to increase awareness about cancer prevention as well as progress being made in the fight against the disease. For more information, please visit: www.standup2cancer.org

U.S. President Barack Obama Proclaims September 2014 As National Ovarian Cancer Awareness Month — What Should You Know?

Today, U.S. President Barack Obama designated September 2014 as National Ovarian Cancer Awareness Month. “This month, our Nation stands with everyone who has been touched by this disease, and we recognize all those committed to advancing the fight against this cancer through research, advocacy, and quality care. Together, let us renew our commitment to reducing the impact of ovarian cancer and to a future free from cancer in all its forms.”

WhiteHouse-LogoToday, U.S. President Barack Obama designated September 2014 as National Ovarian Cancer Awareness Month. The Presidential Proclamation is reproduced in full below.

During National Ovarian Cancer Awareness Month, Libby’s H*O*P*E*™ will continue to honor the women who have lost their lives to the disease (including our own Elizabeth “Libby” Remick), support those who are currently battling the disease, and celebrate with those who have beaten the disease. This month, medical doctors, research scientists, and ovarian cancer advocates renew their commitment to develop a reliable early screening test, improve current treatments, discover new groundbreaking therapies, and ultimately, defeat the most lethal gynecologic cancer.

Let us begin this month with several important facts relating to ovarian cancer. Please take time to review these facts — they may save your life or that of a loved one.

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Ovarian Cancer Facts

Lethality. Ovarian cancer causes more deaths than any other cancer of the female reproductive system.

Statistics. In 2014, the American Cancer Society (ACS) estimates that there will be approximately 21,980 new ovarian cancer cases diagnosed in the U.S. ACS estimates that 14,270 U.S. women will die from the disease, or about 39 women per day or 1-to-2 women every hour. This loss of life is equivalent to 28 Boeing 747 jumbo jet crashes with no survivors — each and every year.

Signs & Symptoms. Ovarian cancer is not a “silent” disease; it is a “subtle” disease. Recent studies indicate that women with ovarian cancer are more like to experience four persistent, nonspecific symptoms as compared with women in the general population, such as (i) bloating, (ii) pelvic or abdominal pain, (iii) difficulty eating or feeling full quickly, or (iv) urinary urgency or frequency. Women who experience such symptoms daily for more than a few weeks should seek prompt medical evaluation. Note: Several other symptoms have been commonly reported by women with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain with intercourse, constipation and menstrual irregularities. However, these additional symptoms are not as useful in identifying ovarian cancer because they are also found in equal frequency in women within the general population who do not have the disease.

Age. Although the median age of a woman with ovarian cancer at initial diagnosis is 63, the disease cancer can afflict adolescent, young adult, and mature women. Ovarian cancer does not discriminate based upon age.

Prevention. Pregnancy, breastfeeding, long-term use of oral contraceptives, and tubal ligation reduce the risk of developing ovarian cancer.

Risk Factors.

  • BRCA Gene Mutations. Women who have had breast cancer, or who have a family history of breast cancer or ovarian cancer may have increased risk. Women who test positive for inherited mutations in the BRCA-1 or BRCA-2 gene have an increased lifetime risk of breast and ovarian cancer. A women can inherit a mutated BRCA gene from her mother or father. Women of Ashkenazi (Eastern European) Jewish ancestry are at higher risk (1 out of 40) for inherited BRCA gene mutations. Studies suggest that preventive surgery to remove the ovaries and fallopian tubes in women possessing BRCA gene mutations can decrease the risk of ovarian cancer.
  • Lynch Syndrome. An inherited genetic condition called “hereditary nonpolyposis colorectal cancer” (also called “Lynch syndrome“), which significantly increases the risk of colon/rectal cancer (and also increases the risk of other types of cancers such as endometrial (uterine), stomach, breast, small bowel (intestinal), pancreatic, urinary tract, liver, kidney, and bile duct cancers), also increases ovarian cancer risk.
  • Hormone Therapy. The use of estrogen alone menopausal hormone therapy may increase ovarian cancer risk. The longer estrogen alone replacement therapy is used, the greater the risk may be. The increased risk is less certain for women taking both estrogen and progesterone, although a large 2009 Danish study involving over 900,000 women suggests that combination hormone therapy may increase risk. Because some health benefits have been identified with hormone replacement therapy, a women should seek her doctor’s advice regarding risk verses benefit based on her specific factual case.
  • Smoking. Smoking has been linked to an increase in mucinous epithelial ovarian cancer.

Early Detection. There is no reliable screening test for the detection of early stage ovarian cancer. Pelvic examination only occasionally detects ovarian cancer, generally when the disease is advanced. A Pap smear cannot detect ovarian cancer. However, the combination of a thorough pelvic exam, transvaginal ultrasound, and a blood test for the tumor marker CA-125 may be offered to women who are at high risk of ovarian cancer and to women who have persistent, unexplained symptoms like those listed above. This early detection strategy has shown promise in a 2013 University of Texas M.D. Anderson Cancer Center early detection study involving over 4,000 women. Importantly, another large ovarian cancer screening trial that is using similar early detection methods is under way in the United Kingdom, with results expected in 2015. The U.K. study is called “UKCTOCS” (UK Collaborative Trial of Ovarian Cancer Screening) and involves over 200,000 women aged 50-74 years.

Treatment.

  • Treatment includes surgery and usually chemotherapy.
  • Surgery usually includes removal of one or both ovaries and fallopian tubes (salpingo-oophorectomy), the uterus (hysterectomy), and the omentum (fatty tissue attached to some of the organs in the belly), along with biopsies of the peritoneum (lining of the abdominal cavity) and peritoneal cavity fluid.
  • In younger women with very early stage tumors who wish to have children, removal of only the involved ovary and fallopian tube may be possible.
  • Among patients with early ovarian cancer, complete surgical staging has been associated with better outcomes.
  • For women with advanced disease, surgically removing all abdominal metastases larger than one centimeter (debulking) enhances the effect of chemotherapy and helps improve survival.
  • For women with stage III ovarian cancer that has been optimally debulked, studies have shown that chemotherapy administered both intravenously and directly into the abdomen (intraperitoneally) improves survival.
  • Patients can enter clinical trials at the start of, during the course of, and even after, their ovarian cancer treatment(s).
  • New types of treatment are being tested in ovarian and solid tumor clinical trials, including “biological therapy” and “targeted therapy.” For example, these types of treatment can exploit biological/molecular characteristics unique to an ovarian cancer patient’s specific tumor classification, or better “train” the patient’s own immune system to identify and attack her tumor cells, without harming normal cells.

Survival. 

  • If diagnosed at the localized stage, the 5-year ovarian cancer survival rate is 92%; however, only about 15% of all cases are detected at an early stage, usually fortuitously during another medical procedure. The majority of cases (61%) are diagnosed at a distant or later stage of the disease.
  • Overall, the 1-, 5-, and 10-year relative survival of ovarian cancer patients is 75%, 44%, and 34%, respectively.
  • The 10-year relative survival rate for all disease stages combined is only 38%.
  • Relative survival varies by age; women younger than 65 are twice as likely to survive 5 years (56%) following diagnosis as compared to women 65 and older (27%).

Help Spread the Word to “B-E-A-T” Ovarian Cancer

Please help us “B-E-A-T” ovarian cancer by spreading the word about the early warning signs & symptoms of the disease throughout the month of September.

beatlogo_308x196B = bloating that is persistent and does not come and go

E = eating less and feeling fuller

A =abdominal or pelvic pain

T = trouble with urination (urgency or frequency)

Women who have these symptoms almost daily for more than a few weeks should see their doctor. Prompt medical evaluation may lead to detection at the earliest possible stage of the disease. As noted above, early stage diagnosis is associated with an improved prognosis.

__________________________________________________________

The White House

Office of the Press Secretary

For Immediate Release August 29, 2014

BY THE PRESIDENT OF THE UNITED STATES OF AMERICA

A PROCLAMATION

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Ovarian cancer is the most deadly of all female reproductive system cancers. This year nearly 22,000 Americans will be diagnosed with this cancer, and more than 14,000 will die from it. The lives of mothers and daughters will be taken too soon, and the pain of this disease will touch too many families. During National Ovarian Cancer Awareness Month, we honor the loved ones we have lost to this disease and all those who battle it today, and we continue our work to improve care and raise awareness about ovarian cancer.

When ovarian cancer is found in its early stages, treatment is most effective and the chances for recovery are greatest. But ovarian cancer is difficult to detect early — there is no simple and reliable way to screen for this disease, symptoms are often not clear until later stages, and most women are diagnosed without being at high risk. That is why it is important for all women to pay attention to their bodies and know what is normal for them. Women who experience unexplained changes — including abdominal pain, pressure, and swelling — should talk with their health care provider. To learn more about the risk factors and symptoms of ovarian cancer, Americans can visit www.Cancer.gov.

Regular health checkups increase the chance of early detection, and the Affordable Care Act expands this critical care to millions of women. Insurance companies are now required to cover well-woman visits, which provide women an opportunity to talk with their health care provider, and insurers are prohibited from charging a copayment for this service.

For the thousands of women affected by ovarian cancer, the Affordable Care Act also prohibits insurance companies from denying coverage due to a pre-existing condition, such as cancer or a family history of cancer; prevents insurers from denying participation in an approved clinical trial for any life-threatening disease; and eliminates annual and lifetime dollar limits on coverage. And as we work to ease the burden of ovarian cancer for today’s patients, my Administration continues to invest in the critical research that will lead to earlier detection, improved care, and the medical breakthroughs of tomorrow.

Ovarian cancer and the hardship it brings have affected too many lives. This month, our Nation stands with everyone who has been touched by this disease, and we recognize all those committed to advancing the fight against this cancer through research, advocacy, and quality care. Together, let us renew our commitment to reducing the impact of ovarian cancer and to a future free from cancer in all its forms.

NOW, THEREFORE, I, BARACK OBAMA, President of the United States of America, by virtue of the authority vested in me by the Constitution and the laws of the United States, do hereby proclaim September 2014 as National Ovarian Cancer Awareness Month. I call upon citizens, government agencies, organizations, health care providers, and research institutions to raise ovarian cancer awareness and continue helping Americans live longer, healthier lives. I also urge women across our country to talk to their health care providers and learn more about this disease.

IN WITNESS WHEREOF, I have hereunto set my hand this twenty-ninth day of August, in the year of our Lord two thousand fourteen, and of the Independence of the United States of America the two hundred and thirty-ninth.

BARACK OBAMA

__________________________________________________________

Sources:

  • Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014 [PDF file].
  • Presidential Proclamation — National Ovarian Cancer Awareness Month, 2013, Office of the Press Secretary, The White House, August 29, 2014.

National Women’s Health Week — Learn, Spread the Word & Join!

National Women’s Health Week begins on Mother’s Day each year. During this week, individuals, families, communities, and others work to help women learn how to achieve longer, healthier, and safer lives.

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Beginning with Mother’s Day on Sunday, May 11, we celebrate National Women’s Health Week by encouraging the women in our lives – our mothers, grandmothers, aunts, sisters, cousins, friends, and colleagues – to take steps to live healthier, happier lives.

We know that women are often the ones who make sure that everyone – everyone else, that is – in our families are cared for. But too often, women put their own health last.

But the reality is unless you take care of yourself, you cannot really take care of your family. That means eating right, exercising, quitting smoking, and getting the care necessary to stay healthy. In fact, you can now use websites, apps, and mobile devices to help you track and manage your health.

Preventive services are critical to helping us stay healthy, but unfortunately they have not always been affordable. Thanks to the Affordable Care Act, it is a new day for women’s health by making it easier for women to take control of their own health.

For many women, preventive services like mammograms, birth control, smoking cessation services, and annual well-woman visits are now available without any out-of-pocket costs. Also, as of 2014, the Affordable Care Act requires most insurers to cover maternity benefits as part of the package of essential health benefits.

And insurers can no longer refuse women coverage just because they’re battling cancer or have another pre-existing condition – and they won’t be allowed to charge women more just because they’re women. Being a woman is no longer a pre-existing condition.

It’s not just women with job-based insurance who are benefitting from the Affordable Care Act. The law has greatly expanded access to quality, affordable health coverage to uninsured women and men. More than 8 million Americans – more than 4.3 million of whom are women – have enrolled in affordable health insurance through the Health Insurance Marketplace. Open enrollment begins again in November.

Learn

On Sunday, May 11, 2014, President Barrack Obama proclaimed May 11 through 17, National’s Women’s Health Week. National Women’s Health Week is an observance led by the U.S. Department of Health and Human Services Office on Women’s Health (OWH). The goal is to empower women to make their health a priority. National Women’s Health Week also serves as a time to help women understand what it means to be well.

What does it mean to be a well woman?

It’s a state of mind. It’s being as healthy as you can be. And, most importantly, it’s about taking steps to improve your physical and mental health:

Check out the National Women’s Health Week infographics.

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Download OWH’s National Women’s Health Week infographics.

How can you celebrate National Women’s Health Week?

The OWH invites women across the country to join in the celebration:

Download a copy of the National Women’s Health Week fact sheet.

Spread the Word

Spread the word about National Women’s Health Week to your mom, sisters, daughters, friends, and coworkers! Invite them to join in the celebration by using the resources below.

Join

Join or plan a Meetup

Join us in celebrating National Women’s Health Week by hosting or attending an event in your area. This year, we’re asking you to register your National Women’s Health Week event with Meetup Everywhere.

Join the President’s Challenge

The President’s Challenge is the premier program of the President’s Council on Fitness, Sports, and Nutrition administered through a co-sponsorship agreement with the Amateur Athletic Union. The President’s Challenge helps people of all ages and abilities increase their physical activity and improve their fitness through research-based information, easy-to-use tools, and friendly motivation.

NWHW-infographic-well-woman-visitCelebrate National Women’s Checkup Day 

National Women’s Checkup Day is led by OWH. Our goal is to encourage women to schedule an annual well-woman visit.

A well-woman visit is a checkup. It’s a time to see your health care provider to:

  • Discuss your health habits and family history.
  • Get or schedule necessary screenings and exams.
  • Set health goals.
  • Schedule your well-woman visit every year.

Thanks to the Affordable Care Act, it’s considered a preventive service and must be covered by most health plans at no cost to you. During your well-woman visit, you can receive many screenings free of charge, such as screenings for blood pressure, cholesterol, cervical cancer, and more. And if your health care provider says you need more than one well-woman visit in a year, the additional visits are also covered.

When is National Women’s Checkup Day?

The 12th annual National Women’s Checkup Day is today, Monday, May 12, 2014, during National Women’s Health Week.

Why is it important for women to participate in this effort?

Well-woman visits help you get the preventive care you need, including screenings. Screenings can find diseases early, when they are easier to treat. Screenings can also identify other problems and help lower your risk for many conditions, such as heart disease. Under the Affordable Care Act, many women can receive these services without paying a deductible or copay.

How can you participate in this important event?

There are several ways to participate in National Women’s Checkup Day:

 

Glutamine Ratio is Key Ovarian Cancer Indicator

Glutamine plays an important role in cellular growth in several cancers. A Rice University-led study shows how ovarian cancer metabolism changes between early and late stages. In this study, a further link between glutamine dependency and tumor invasiveness is established in ovarian cancer.

A Rice University-led analysis of the metabolic profiles of hundreds of ovarian tumors has revealed a new test to determine whether ovarian cancer cells have the potential to metastasize, or spread to other parts of the body. The study also suggests how ovarian cancer treatments can be tailored based on the metabolic profile of a particular tumor.

The research, which appears online this week in Molecular Systems Biology, was conducted at the Texas Medical Center in Houston by researchers from Rice University, the University of Texas M.D. Anderson Cancer Center, and the Baylor College of Medicine.

Deepak Nagrath

Deepak Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice University

“We found a striking difference between the metabolic profiles of poorly aggressive and highly aggressive ovarian tumor cells, particularly with respect to their production and use of the amino acid glutamine,” said lead researcher Deepak Nagrath Ph.D. of Rice University. “For example, we found that highly aggressive ovarian cancer cells are glutamine-dependent, and in our laboratory studies, we showed that depriving such cells of external sources of glutamine — as some experimental drugs do — was an effective way to kill late-stage cells.

“The story for poorly aggressive cells was quite different,” said Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice. “These cells use an internal metabolic pathway to produce a significant portion of the glutamine that they consume, so a different type of treatment — one aimed toward internal glutamine sources — will be needed to target cells of this type.”

The research is part of a growing effort among cancer researchers worldwide to create treatments that target the altered metabolism of cancer cells. It has long been known that cancer cells adjust their metabolism in subtle ways that allow them to proliferate faster and survive better. In 1924, Otto Warburg showed that cancer cells produced far more energy from glycolysis than did normal cells. The Nobel Prize-winning discovery became known as the “Warburg effect,” and researchers long believed that all cancers behaved in this way. Intense research in recent decades has revealed a more nuanced picture.

“Each type of cancer appears to have its own metabolic signature,” Nagrath said. “For instance, kidney cancer does not rely on glutamine, and though breast cancer gets some of its energy from glutamine, it gets even more from glycolysis. For other cancers, including glioblastoma and pancreatic cancer, glutamine appears to be the primary energy source.”

Rice University Researchers

Researchers at Rice University’s Laboratory for Systems Biology of Human Diseases analyzed the metabolic profiles of hundreds of ovarian tumors and discovered a new test to determine whether ovarian cancer cells have the potential to metastasize. Study co-authors include, from left, Julia Win, Stephen Wahlig, Deepak Nagrath, Hongyun Zhao, Lifeng Yang and Abhinav Achreja.

Nagrath, director of Rice University’s Laboratory for Systems Biology of Human Diseases, said the new metabolic analysis indicates that ovarian cancer may be susceptible to multidrug cocktails, particularly if the amounts of the drugs can be tailored to match the metabolic profile of a patient’s tumor.

The research also revealed a specific biochemical test that pathologists could use to guide such treatments. The test involves measuring the ratio between the amount of glutamine that a cell takes up from outside and the amount of glutamine it makes internally.

“This ratio proved to be a robust marker for prognosis,” said University of Texas M.D. Anderson Cancer Center co-author Anil Sood, M.D., Professor of Gynecologic Oncology and Reproductive Medicine and co-director of the Center for RNA Interference and Non-Coding RNA. “A high ratio was directly correlated to tumor aggression and metastatic capability. Patients with this profile had the worst prognosis for survival.”

The three-year study included cell culture studies at Rice as well as a detailed analysis of gene-expression profiles of more than 500 patients from the Cancer Genome Atlas and protein-expression profiles from about 200 M.D. Anderson patients.

“The enzyme glutaminase is key to glutamine uptake from outside the cell, and glutaminase is the primary target that everybody is thinking about right now in developing drugs,” Nagrath said. “We found that targeting only glutaminase will miss the less aggressive ovarian cancer cells because they are at a metabolic stage where they are not yet glutamine-dependent.”

Lifeng

Lifeng Yang, Study Lead Author & Graduate Student, Systems Biology of Human Diseases, Rice University

Rice University graduate student Lifeng Yang, lead author of the study, designed a preclinical experiment to test the feasibility of a multidrug approach, involving the use of a JAK inhibitor and a glutaminase inhibitor. This “drug cocktail” approach inhibited the early stage production of internal glutamine, while also limiting the uptake of external glutamine.

“That depleted all sources of glutamine for the cells, and we found that cell proliferation decreased significantly,” Yang said.

Nagrath said the study also revealed another key finding — a direct relationship between glutamine and an ovarian cancer biomarker called “STAT3” (Signal Transducer And Activator Of Transcription 3).

“A systems-level understanding of the interactions between metabolism and signaling is vital to developing novel strategies to tackle cancer,” said M.D. Anderson co-author Prahlad Ram Ph.D., Associate Professor of Systems Biology and co-director of the M.D. Anderson Cancer Center’s Systems Biology Program. “STAT3 is the primary marker that is used today to ascertain malignancy, tumor aggression and metastasis in ovarian cancer.”

Nagrath said, “The higher STAT3 is, the more aggressive the cancer. For the first time, we were able to show how glutamine regulates STAT3 expression through a well-known metabolic pathway called the TCA cycle, which is also known as the ‘Krebs cycle.’”

Nagrath said the research is ongoing. Ultimately, Dr. Nagrath hopes the investigations will lead to new treatment regimens for cancer as well as a better understanding of the role of cancer-cell metabolism in metastasis and drug resistance.

Co-authors include Hongyun Zhao, Stephen Wahlig, Abhinav Achreja and Julia Win (all affiliated with Rice University); Tyler Moss, Lingegowda Mangala, Guillermo Armaiz-Pena, Dahai Jiang, Rajesha Roopaimoole, Cristian Rodriguez-Aguayo, Imelda Mercado-Uribe, Gabriel Lopez-Berestein and Jinsong Liu (all affiliated with M.D. Anderson Cancer Center); Juan Marini of Baylor College of Medicine; and Takashi Tsukamoto of Johns Hopkins University.

The research was supported by seed funding from (i) the Collaborative Advances in Biomedical Computing Program at Rice Univesity’s Ken Kennedy Institute for Information Technology, (ii) Rice University’s John and Ann Doerr Fund for Computational Biomedicine, (iii) the Odyssey Fellowship Program at the MD Anderson Cancer Center, (iv) the estate of C.G. Johnson Jr., (v) the National Institutes of Health, (vi) the Cancer Prevention and Research Institute of Texas, (v) the Ovarian Cancer Research Fund, (vi) the Blanton-Davis Ovarian Cancer Research Program, (vii) the Gilder Foundation, and (viii) the MD Anderson Cancer Center.

Sources: 

Ovarian Cancer Cells Are More Aggressive On Soft Tissues

When ovarian cancer spreads from the ovaries it almost always does so to a layer of fatty tissue that lines the gut. A new study has found that ovarian cancer cells are more aggressive on these soft tissues due to the mechanical properties of this environment. The finding is contrary to what is seen with other malignant cancer cells that seem to prefer stiffer tissues.

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Professor Michelle Dawson and graduate student Daniel McGrail used traction force microscopy to measure the forces exerted by cancer cells on soft and stiff surfaces. (Photo Credit: Rob Felt, Georgia Institute of Technology)

“What we found is that there are some cancer cells that respond to softness as opposed to stiffness,” said Michelle Dawson, an assistant professor in the School of Chemical and Biomolecular Engineering at the Georgia Institute of Technology. “Ovarian cancer cells that are highly metastatic respond to soft environments by becoming more aggressive.”

Ovarian cancer cells spread, or metastasize, by a different method than other cancer cells. Breast cancer cells, for example, break off from a solid tumor and flow through the blood until they arrest in small blood vessels. The cancer cells then penetrate the vessel surface to form a tumor. Because ovarian tumors are in the abdomen, these cancer cells are shed into the surrounding fluid and not distributed through the blood. They must be able to adhere directly to the fatty tissue that lines the gut, called the omentum, to begin forming a tumor. The new study discovered details about how ovarian cancer cells seem to prefer the mechanical properties of this soft tissue.

The study was published in a recent advance online edition of the Journal of Cell Science and was sponsored by the National Science Foundation and the Georgia Tech and Emory Center for Regenerative Medicine.

The research team, led by Daniel McGrail, a graduate student in the Dawson lab, found that ovarian cancer cells in vitro were more adherent to a layer of soft fat cells than a layer of stiffer bone cells, and that this behavior was also repeated using gels of similar rigidities.

“All the behaviors that we associate with breast cancer cells on these more rigid environments are flipped for ovarian cancer cells,” Dawson said.

After adhering to these soft surfaces, metastatic ovarian cancer cells became more aggressive. Their proliferation increased and they were less responsive to chemotherapeutics. The ovarian cancer cells were also more motile on soft surfaces, moving nearly twice as fast as on rigid surfaces.

The team also found that less aggressive cells that do not metastasize do not exhibit any of these changes.

The researchers used techniques that haven’t been traditionally used in the study of ovarian cancer. They measured the force exerted by the cells by tracking the displacement of beads in the environment around the cells. The researchers found that the metastatic cells increased their traction forces – used to generate motion – by three-fold on soft surfaces, but no such change was present in the less aggressive cells.

“We think the behavior that metastatic ovarian cancer cells exert on these soft surfaces is representative of the mechanical tropism that they have for these softer tissues in the gut,” Dawson said.

In future work, the researchers will investigate whether ovarian cancer cells have some natural inclination towards this uniquely more aggressive behavior in softer environments.

“We’re trying to find out whether there is some internal programming that leads to this aggressive behavior,” Dawson said.

This research is supported by the National Science Foundation under award number 1032527, and the Georgia Tech and Emory Center for Regenerative Medicine under award number 1411304. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the sponsoring agencies.

Source:  McGrail DJ, et al., The malignancy of metastatic ovarian cancer cells is increased on soft matrices through a mechanosensitive Rho-ROCK pathway. (Journal of Cell Science, 2014). http://dx.doi.org/10.1242/?jcs.144378.

World Ovarian Cancer Day: One Voice for Every Woman

Each year, nearly a quarter of a million women around the world are diagnosed with ovarian cancer and the disease is responsible for 140,000 deaths annually. Statistics show that just 45% of women with ovarian cancer are likely to survive for five years compared with 89% of women with breast cancer. We ask that you join us on World Ovarian Cancer Day (May 8th) in the fight against the most lethal form of gynecologic cancer.

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LEARN: World Ovarian Cancer Day — May 8, 2014

On May 8, join the global movement to raise awareness about ovarian cancer by pledging to spread the word about the most serious gynecological cancer during the second annual World Ovarian Cancer Day (WOCD). The pledge to pass on the awareness message to at least five friends will bring to life this year’s theme One Voice for Every Woman.

“The number one objective of World Ovarian Cancer Day is to increase awareness of this disease and to connect people internationally with the resources available to educate others,” says Elisabeth Baugh, chair of the WOCD international organizing committee and CEO of Ovarian Cancer Canada. “In our inaugural year, 28 cancer organizations from 18 countries participated in getting the word out, largely through social media. In 2014, we are not only inviting cancer organizations, but all interested groups internationally to register and partner with us. With our pledge, we are also involving individuals worldwide, and empowering them with information about ovarian cancer and a quick and easy way to pass on the word about the disease.”

All of those who sign the World Ovarian Cancer Day pledge at www.ovariancancerday.org will receive an e-card on May 8 with ovarian cancer risk and symptom information. This card is to be passed along to at least five friends, who in turn will be encouraged to pass it along to their friends.

Each year, nearly a quarter of a million women around the world are diagnosed with ovarian cancer and the disease is responsible for 140,000 deaths annually. Statistics show that just 45% of women with ovarian cancer are likely to survive for five years compared with 89% of women with breast cancer. Women in developed and developing countries are similarly affected by ovarian cancer. There is no test for the early detection of ovarian cancer, a disease characterized around the world by a lack of awareness of symptoms and late stage diagnosis.

WOCD’s social media campaign includes the WOCD website, Facebook, Twitter and Pinterest. To help raise awareness and show international involvement in the inaugural year, partner organizations and individuals from many countries wore teal and posed for photos in front of well-known landmarks holding signs featuring the WOCD “world embrace” logo.

These photographs were shared around the world. Other activities included public awareness events at train and subway stations, and information tables and education sessions at hospitals and cancer centers. These activities will continue to grow on May 8, 2014 along with governmental proclamations and “lighting the world in teal” – the color that represents ovarian cancer. Committee members Annwen Jones, Chief Executive of Target Ovarian Cancer, and Alison Amos, CEO, Ovarian Cancer Australia agree this is a wonderful opportunity. “World Ovarian Cancer Day is an important day for ovarian cancer organizations and communities around the world to unite and speak with one voice to raise awareness of ovarian cancer. We’re proud to be involved with this global initiative and will be passing the awareness message out among those we work with. This activity supports our vision to save lives and ensure that no woman with ovarian cancer walks alone.” “For women living with the disease and their families and friends, World Ovarian Cancer Day has tremendous meaning,” says Baugh. “Through this important day, we will continue to build momentum and a sense of solidarity in the fight against ovarian cancer. Every woman is at some risk for ovarian cancer and awareness remains our best defence.”

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EDUCATE: Ovarian Cancer Facts:

Libby’s H*O*P*E* is dedicated to my 26-year old cousin, Elizabeth “Libby” Remick, who died from ovarian cancer in July 2008. Our mission is to educate ovarian cancer survivors and their families, as well as the general public, about ovarian cancer under the principle that “information is power.” The key to a significant reduction in deaths from ovarian cancer is early detection. Early detection is best achieved by having women listen to their bodies for the subtle, yet persistent, early warning signs & symptoms of the disease as described below. Together, we can raise money for a reliable early detection test, and ultimately a cure, for ovarian cancer.

Please take time to educate yourself with respect to the important ovarian cancer awareness facts provided below.

–Ovarian cancer causes more deaths than any other cancer of the female reproductive system.

–In 2014, the American Cancer Society (ACS) estimates that there will be approximately 21,980 new ovarian cancer cases diagnosed in the U.S. ACS estimates that 14,270 U.S. women will die from the disease, or about 40 women per day. The loss of life is equivalent to 28 Boeing 747 jumbo jet crashes with no survivors every year.

–Ovarian cancer is not a “silent” disease; it is a “subtle” disease. Recent studies indicate that some women may experience persistent, nonspecific symptoms, such as (i) bloating, (ii) pelvic or abdominal pain, (iii) difficulty eating or feeling full quickly, or (iv) urinary urgency or frequency. Women who experience such symptoms daily for more than a few weeks should seek prompt medical evaluation.

–Ovarian cancer can afflict adolescent, young adult, and mature women.

–Pregnancy and the long-term use of oral contraceptives reduce the risk of developing ovarian cancer.

–Women who have had breast cancer, or who have a family history of breast cancer or ovarian cancer may have increased risk. Inherited mutations in BRCA1/BRCA2 genes increase risk. Women of Ashkenazi Jewish ancestry are at higher risk for BRCA gene mutations.

–There is no reliable screening test for the detection of early stage ovarian cancer. Pelvic examination only occasionally detects ovarian cancer, generally when the disease is advanced. A Pap smear is used to detect cervical cancer, not ovarian cancer. However, the combination of a thorough pelvic exam, transvaginal ultrasound, and a blood test for the tumor marker CA125 may be offered to women who are at high risk of ovarian cancer and to women who have persistent, unexplained symptoms like those listed above.

–If diagnosed at the localized stage, the 5-year ovarian cancer survival rate is 92%; however, only about 19% of all cases are detected at this stage, usually fortuitously during another medical procedure.

–The 10-year relative survival rate for all disease stages combined is only 38%.

Please help us spread the word about the early warning signs & symptoms of ovarian cancer and raise money for ovarian cancer research. The life you save may be your own or that of a loved one.

FIGHT: The “Holy Trinity” of Major U.S. Ovarian Cancer Organizations

There are three major U.S. ovarian cancer organizations that are working to increase ovarian cancer awareness, and/or raise money to fight the disease. They are listed below. Please consider making a donation to one of these critically important nonprofit organizations.

  • Ovarian Cancer Research Fund

The Ovarian Cancer Research Fund (OCRF) is the largest independent organization in the U.S. that is dedicated exclusively to funding ovarian cancer research– and to finding a cure. Through its three research programs, OCRF funds many of the best researchers and the most innovative projects.

Since 1998, OCRF has awarded 63 leading medical centers 195 grants for ovarian cancer research: an investment totaling over $50 million. OCRF researchers are taking on ovarian cancer from many angles:

– Developing innovative strategies for early detection;

– Discovering genetic polymorphisms that increase risk for ovarian cancer;

– Understanding the underlying genetics and molecular biology of ovarian cancer;

– Identifying new, better targets for treatment;

– Determining how to super-charge a woman’s immune response to better fight ovarian cancer; and

– Deciphering how and why ovarian cancer spreads, and how to stop it.

You can click here to make a donation to OCRF through the Libby’s H*O*P*E*’s donation page.

  • Ovarian Cancer National Alliance

The Ovarian Cancer National Alliance (OCNA) is one of the foremost advocates for women with ovarian cancer in the U.S. To advance the interests of women with ovarian cancer, OCNA advocates at a national level for increases in research funding for the development of an early detection test, improved health care practices, and life-saving treatment protocols. OCNA also educates health care professionals and raises public awareness of the risks and symptoms of ovarian cancer.

To make a donation to OCNA, click here.

  • National Ovarian Cancer Coalition

The mission of the National Ovarian Cancer Coalition (NOCC) is to raise awareness and promote education about ovarian cancer. NOCC is committed to improving the survival rate and quality of life for women with ovarian cancer.

Through national programs and local Chapter initiatives, the NOCC’s goal is to make more people aware of the early symptoms of ovarian cancer. In addition, the NOCC provides information to assist the newly diagnosed patient, to provide hope to survivors, and to support caregivers.

To make a donation to NOCC, click here.

INSPIRE: Everyday Heroes in the Fight Against Ovarian Cancer.

Nearly a quarter million women are diagnosed with ovarian cancer every year around the world, and the disease also affects their families and friends. Please take time to visit the WOCD website and read inspirational stories about survivors, volunteers, and family members who are overcoming ovarian cancer, as well as the endeavors people are taking on to raise awareness about the disease.

At Libby’s H*O*P*E*, we are amazed each and every day by the inspirational ovarian cancer survivors and family members that we hear about, correspond with, or meet. The stories below represent a small sample of incredible individuals who have successfully fought the disease, as well as those who are currently fighting the disease with courage and grace. There are also stories about women who have died from ovarian cancer, but contributed to ovarian cancer awareness in a unique and special way during life. In addition, there are stories about doctors, advocates, and other inspirational individuals who are clearly making a difference in the fight against the disease.

“Bald is Beautiful,” March 20, 2008.

“Patty Franchi Flaherty Loses Battle to Ovarian Cancer, But Deserves a Long Standing Ovation,” August 19, 2008.

“Oscar Winner Kathy Bates Is an Inspirational Ovarian Cancer Survivor,” February 25, 2009.

– “Rare Form of Ovarian Cancer Not Getting Inspirational 13 Yr. Old Down; You Can Help!,” February 26, 2009.

– “Meet Laurey Masterton, 20-Year Ovarian Cancer Survivor Extraordinaire,” March 20, 2009.

– “The Rock Band ‘N.E.D.': Their Medical Skills Save Many; Their Music Could Save Thousands,” March 29, 2009.

“A Wish To Build A Dream On,” May 3, 2009.

“Husband’s Love For Wife Inspires A 9,000 Mile Bike Trek To Raise Money For Ovarian Cancer Awareness & Cancer Prevention,” May 14, 2009.

“Gloria Johns Was Told ‘Ovarian Cancer Patients Don’t Live Long Enough … To Have Support Groups;’ She Proved Otherwise,” June 5, 2009.

“Vox Populi:* How Do Your Define “Tragedy?“, January 22, 2010.

– “Smile, Open Your Eyes, Love and Go On,” July 28, 2010.

“PBS Documentary, ‘The Whisper: The Silent Crisis of Ovarian Cancer,'” September 21, 2010.

“Determined Teen Loses Ovarian Cancer Battle, But Her Courage Inspires An Entire Community,” December 28, 2010.

“Mrs. Australia Quest Finalist Veronica Cristovao Is Raising Ovarian Cancer Awareness ‘Down Under'”, February 28, 2011.

– “Whither Thou Goest, I Will Go …”, July 28, 2012.

– “Crowd Funding:” Paying Medical Bills With a Little Help From Your Friends (and Strangers Too!), January 17, 2013.

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For more information on World Ovarian Cancer Day visit: www.ovariancancerday.org

Facebook: www.facebook.com/WorldOvarianCancerDay

Twitter: @OvarianCancerDY

Pinterest: @OvarianCancerDY

Each participating country is linked through the dedicated website which has been established for World Ovarian Cancer Day. To find out more about activities in each country, please contact the local organization directly through the website at http://www.ovariancancerday.org/get-involved/