To Fight Cancer, Know The Enemy

An Op-Ed entitled “To Fight Cancer, Know the Enemy” was published in The New York Times on August 6, 2009.  The author of the Op-Ed was James D. Watson, Ph.D.  James Watson co-discovered the DNA double helix structure; a discovery for which he received the 1962 Nobel Prize for Physiology or Medicine. In the article, Watson states his belief that beating cancer is now a realistic ambition, and he makes several suggestions designed to ensure that victory.

On August 6, 2009, an Op-Ed entitled To Fight Cancer, Know the Enemy was published in The New York Times (NYT).  The author of the article was James D. Watson, Ph.D. James Watson co-discovered the DNA double helix structure; a discovery for which he received the 1962 Nobel Prize for Physiology or Medicine.  Dr. Watson is the Chancellor Emeritus of Cold Spring Harbor Laboratory, and is generally considered the father of molecular biology. Throughout most of his career, James Watson’s novel scientific ideas generated great controversy among, and resistance from, many members of the scientific community.  The suggestions posed by James Watson in his August 6th NYT Op-Ed are likely no exception.

Watson begins the Op-Ed by suggesting an ambitious, yet optimistic, goal in the area of cancer research:

“The National Cancer Institute, which has overseen American efforts on researching and combating cancers since 1971, should take on an ambitious new goal for the next decade:  the development of new drugs that will provide lifelong cures for many, if not all, major cancers.  Beating cancer now is a realistic ambition because, at long last, we largely know its true genetic and chemical characteristics. …”

James D. Watson

James D. Watson, Ph.D. is the Chancellor Emeritus of the world-renowned Cold Spring Harbor Laboratory. Dr. Watson co-discovered DNA's double helix structure; a discovery for which he received the 1962 Nobel Prize for Physiology or Medicine. In an Op-Ed published in the New York Times on August 6, 2009, Dr. Watson states: "...Beating cancer now is a realistic ambition because, at long last, we largely know its true genetic and chemical characteristics."

Despite President Nixon’s declaration of  war on cancer in 1971, Watson states that the goal of “beating cancer” was not possible prior to the year 2000, because researchers did not possess the necessary scientific understanding of cancer molecular biology. Extensive details about specific cancers only became known after the 2003 completion of the Human Genome Project, says Watson. Researchers have identified most of the major cellular pathways through which cancer-inducing signals move through cells, and Watson notes that 20 or so signal-blocking drugs are in human clinical testing. By way of example, Watson highlights the breast cancer drug Herceptin, which is used to fight an aggressive form of breast cancer. Herceptin was approved initially by the U.S. Food & Drug Administration (FDA) in 1998, and today represents the standard of care in treating so-called “HER-2 positive” breast cancer.

With this scientific background, Dr. Watson outlines several suggested changes to the current U.S. cancer research paradigm. He believes that the various changes listed below will give the nation a fighting chance to win the war on cancer.

Change FDA Regulations To Allow Combination Testing of New Cancer Drugs Which Are Ineffective As Monotherapies.

Noting the lack of new cancer drugs that lead to lifelong cures, Watson explains that there are many types of cancer-causing “genetic drivers” within a single cancer cell. Although an analysis of several cancer genetic drivers may allow a doctor to prescribe more personalized chemotherapy treatments for the patient, Watson believes that use of drugs against one genetic cancer driver would simply lead to the emergence of increasingly destructive second and third drivers due to the inherent genetic instability of cancer cells.  Accordingly, Watson concludes that most anticancer drugs will not reach their full potential unless they are given in combination to shut down multiple cancer genetic drivers within a cancer cell simultaneously.

Dr. Watson, however, is quick to note that current FDA regulations effectively prohibit combination testing of new cancer drugs that, when administered alone, prove ineffective.  Thus, Watson concludes that current FDA regulations must be amended to allow combination testing of new cancer drugs that prove ineffective as monotherapies.

Better Understand The Chemical (Rather Than Genetic) Makeup of Cancer Cells

Dr. Watson believes that researchers should shift the current focus of cancer research away from decoding the genetic characteristics of cancer, and obtain a better understanding of the chemical reactions that occur within cancer cells. This suggestion, Watson explains, is based upon a 1924 discovery made by the German biochemist (and 1931 Nobel Laureate) Otto Warburg.  During experimentation, Warburg observed that cancer cells, irrespective of whether they grow in the presence or absence of oxygen, produce large amounts of lactic acid. Approximately one year ago, the significance of Warburg’s observation was revealed, says Watson. The metabolism of all proliferating cells (including cancer cells) is largely directed toward the synthesis of cellular building blocks from the breakdown of glucose. Based upon this recent discovery, Dr. Watson concludes that glucose breakdown runs faster in growing cells then in differentiated cells (i.e., cells that stop growing and perform specialized functions within the body).

The turbocharged breakdown of glucose in growing cells is attributable to growth-promoting signal molecules that effectively turn up the levels of transporter proteins which move glucose molecules into the cell, explains Watson. With this important discovery in hand, Watson suggests that researchers determine whether new drugs that specifically inhibit the key enzymes involved in the breakdown of glucose can produce an anticancer effect. Because this determination requires a better understanding of the chemical makeup of cancer cells, Watson believes that biochemists (rather than molecular biologists) will again move to the forefront of cancer research.

NCI Should Fund Smaller Biotechnology Companies & Increase Its Funding to Major Research-Oriented Cancer Centers

The next issue addressed by Dr. Watson relates to the lack of funding available to small biotechnology companies, which are generally engaged in highly innovative research. In the past, the requisite funding of these companies was provided by venture capitalists (VCs), Watson notes.  The level of VC funding required by small biotech companies is not currently available due to the severe U.S. economic downturn. To resolve this critical capital funding issue, Watson suggests that the National Cancer Institute (NCI) fund small biotech companies. This action, Watson believes, will allow the biotech companies to move drug discoveries from the laboratory into human clinical testing on an accelerated basis. In tandem with funding small biotech companies, Dr. Watson also requests NCI to increase its funding to major research-oriented cancer centers that engage in “low probability-high payoff” research projects, which are generally turned down by large pharmaceutical and biotech companies.

President Obama Should Appoint A Strong Leader To The Directorship of NCI

In 1971, the U.S. Congress provided the president, rather than the head of the National Institutes of Health, with the authority to appoint the NCI director.  Watson characterizes NCI in his Op-Ed as “an outpost of the White House” that has “… become a largely rudderless ship in dire need of a bold captain who will settle only for total victory.”  To resolve this issue, Dr. Watson advises President Barack Obama to appoint a strong leader, from among the nation’s best cancer researchers, to the directorship of NCI.  As part of this new leadership structure, Watson also recommends that NCI recruit a seasoned pharmaceutical developer who can radically increase the speed of anticancer drug development and human clinical testing.

Application Of Sun Tzu’s Strategies On The Art Of War To Cancer Research

Sun Tzu

A statue of the iconic Chinese military leader Sun Tzu. Sun Tzu wrote the earliest -- and still the most revered -- military treatise in the world. This 6th century BC masterpiece is best known to most of us as "The Art of War."

At the conclusion of his Op-Ed, Watson acknowledges that his views will provoke rebuttals from prominent scientists who believe that it is not the right time to wage war on cancer. Moreover, Watson anticipates that many scientists will recommend that, until victory is more certain, the U.S. should not expend large sums of money on cancer research. Watson admits that money alone will not win the war on cancer, but he emphasizes that victory over cancer will not come ” from biding our time.” As part of the Op-Ed title, Watson uses the phrase “know the enemy;” a phrase commonly attributed to the ancient Chinese military leader Sun Tzu. Sun Tzu wrote the earliest — and still the most revered — military treatise in the world.  This 6th century BC masterpiece is best known to most of us as The Art of War.  The clever use of the phrase “know the enemy” by Dr. Watson may suggest that the enemy is indeed cancer, and perhaps, ourselves as represented by the current U.S. cancer research paradigm.

In chapter III of The Art of War, entitled Attack by Stratagem, Sun Tzu describes the dual knowledge that one must possess to achieve ultimate victory in war:

“…If you know the enemy and know yourself, you need not fear the result of a hundred battles. If you know yourself but not the enemy, for every victory gained you will also suffer a defeat. If you know neither the enemy nor yourself, you will succumb in every battle. …”

To follow the advice of James Watson is to better know ourselves and the formidable enemy known as “cancer.” Will Watson’s advice allow us to achieve ultimate victory in the war on cancer? Perhaps. Only time (and appropriate research funding) will tell.

Source: To Fight Cancer, Know The Enemy, by James D. Watson, Op-Ed, The New York Times, August 6, 2009.

UA Research Team Designing Holographic Imaging System For Ovarian Cancer

University of Arizona researchers Jennifer Barton and Ray Kostuk have received a five-year, $2.4 million grant from the National Institutes of Health to build the instrument that they hope will one day be used to monitor women at high risk for ovarian cancer.

Hologram of Human Ovary

Human ovary image captured with the use of the prototype holographic imaging system the team developed. (Photo: Univ. of Arizona News)

Hologram of An Orange

For comparison, an onion is imaged with the use of the prototype system the team developed. (Photo: Univ. of Arizona News)

Two University of Arizona [UA] researchers have formed a research team to design, build and evaluate two versions of an ovarian cancer medical imaging and screening instrument that will use holographic components in a new type of optical microscope.

Raymond Kostuk and Jennifer Barton have secured a five-year, $2.4 million grant from the National Institutes of Health to build the instrument that they hope will one day be used to monitor women at high risk for ovarian cancer. Kostuk is the Kenneth Von Behren Professor of Electrical and Computer Engineering and professor of optical sciences. Barton heads the UA department of biomedical engineering and is assistant director of the BIO5 Institute.

The system is unique in that it will for the first time project multiple spatial images from different depths within a tissue sample and simultaneously provide spectral information from optical markers in order to better identify cancerous cells.

This combined spectral spatial imaging technique shows potential to be much more effective in identifying cancerous tissue sites than by separately using spatial or spectral information.

The grant was issued following the successful two-year development of a prototype system the team built. It tests the validity of using holographic technology for subsurface imaging without having to perform surgery and take tissue samples.

According to the National Institutes of Health, there is, to date, no single effective screening test for ovarian cancer, so ovarian cancer is rarely diagnosed in its early stages. The result is that in more than 50 percent of women with ovarian cancer are diagnosed in the late stages of the disease when the cancer has already advanced.

  • About 76 percent percent of women with ovarian cancer survive one year after diagnosis.
  • About 45 percent live longer than 5 years after diagnosis.

Barton said ovarian cancer provides a compelling case to test holographic imaging and its efficacy in detecting cancers. At the present time the preferred treatment is surgery, which is also often needed to diagnose ovarian cancer. The procedure includes taking tissue samples, which may threaten the woman’s ability to have children in the future.

Jennifer Barton, UA

Jennifer Barton, Professor & Chair, Department of Biomedical Engineering; Assistant Director, BIO5 Institute. (Photo: Univ of Arizona News)

“Ovarian cancer has no symptoms until it is highly advanced making the five-year prognosis extremely poor. Those at high risk – with a family history of ovarian cancer or those who carry genetic mutations in the BRCA1 and BRCA2 genes, which normally help protect against both breast and ovarian cancer – may be counseled to have their ovaries removed through laparoscopic surgery,” Barton said. “Now imagine if you are an 18-year-old woman who has this history – ovaries are an important part of your overall health. They produce hormones you need over and above the notion that you would need your ovaries should you want to have children in the future.”

Thus, new technology capable of reliably diagnosing ovarian cancer in earlier stages could reduce the morbidity, high mortality and economic impact of this disease.

The system will work like a high-powered microscope that can be used to study tissue samples already removed. In addition, an endoscopic version is in the design stage to safely scan the ovaries for cancer during laparoscopic screenings in high-risk women, or as an adjunct to other laparoscopic procedures in all women.

The team will work with Dr. Kenneth D. Hatch, president of the Society of Pelvic Surgeons, and a professor of obstetrics and gynecology and director of female pelvic medicine and reconstructive surgery at the UA College of Medicine.

Through Hatch and a partnership with his patients who consent, Barton and Kostuk will be able to identify abnormal spatial and spectral markers of cancerous ovarian tissue.

Ray Kostuk

Ray Kostuk, Kenneth Von Behren Professor of Electrical and Computer Engineering & Professor of Optical Sciences, University of Arizona (Photo: Univ. of Arizona News)

The new imaging system will be tested on high-risk patients who are willing to participate and provide some future benefit to other patients who find themselves in a similar situation, Barton said.

Kostuk and Barton’s aim is to design the imaging system so that it is easy to use, requiring very little training, and also be cost effective.

“The system will image like an MRI or a CT scan but with much higher resolution than an ultrasonic image and will be a lot less expensive than an MRI. As an additional benefit no radiation will be used or exposed to sensitive ovary areas during the cancer screenings,” Kostuk said.

During the past 25 years Kostuk has researched different aspects of holography and holographic materials for use as optical elements.

The holographic imaging system being designed combines an optical technique that creates images capable of detecting subtle tissue microstructure changes. Together with fluorescence spectroscopy methods, the system has demonstrated capability for early cancer detection.

Another member of the team, UA research professor Marek Romanowski, with the UA department of biomedical engineering and the BIO5 Institute, is working on the development of targeted fluorescent dyes that will be used on tissue samples to identify or confirm suspected cancerous areas shown in the spatial image.

The multidisciplinary approach to the design of the hologram-based imaging system is a testament to the complexity of treating cancers.

“One of the advantages of being part of the UA is the ability to interact collaboratively with people in other disciplines,” Kotuk said. “Jennifer is a wonderful colleague who can identify important medical applications for new techniques and is able to bridge the gap between traditional engineering and medicine. Her skill and knowledge is critical to the success of the program,” he said.

“To solve the really interesting problems of today, no one person has all the expertise needed,” Barton added.

Sources:

NCCN Updates Infection Guidelines To Include Information About H1N1 Virus (Swine Flu)

NCCN [National Comprehensive Cancer Network] recently updated the NCCN Clinical Practice Guidelines in Oncology™ for the Prevention and Treatment of Cancer-Related Infections to include information about the H1N1 virus, also known as “swine flu”. The NCCN Guidelines provide specific recommendations on the prevention, diagnosis, and treatment of the major common and opportunistic infections that afflict patients with cancer.

National Comprehensive Cancer Network logoInfectious diseases are important causes of morbidity and mortality in patients with cancer. In certain cases, the malignancy itself can predispose patients to severe or recurrent infections. The National Comprehensive Cancer Network (NCCN) recognizes the importance of providing the latest information on treating these infections and has developed the NCCN Clinical Practice Guidelines in Oncology™ for the Prevention and Treatment of Cancer-Related Infections. The NCCN Guidelines were recently updated to include information about the effect that the H1N1 virus, or “swine flu,” may have on the diagnosis and treatment of cancer treatment-related infections.

The NCCN Guidelines on Prevention and Treatment of Cancer-Related Infections characterize the major categories of immunologic deficits in persons with cancer and the major pathogens to which they are susceptible. Specific recommendations are provided on the prevention, diagnosis, and treatment of the major common and opportunistic infections that afflict patients with cancer.

The H1N1 reference is located in the section of the NCCN Guidelines that lists recommendations for treating lung infiltrates in febrile neutropenic patients. The updated NCCN

This image of the newly identified H1N1 influenza virus ("Swine Flu") was taken in the Centers For Disease Control & Prevention (CDC) Influenza Laboratory.

This image of the newly identified H1N1 influenza virus ("Swine Flu") was taken in the Centers For Disease Control & Prevention (CDC) Influenza Laboratory.

Guidelines note that certain tests and antiviral treatments that are effective in more common strains of influenza and viruses may not be applicable to the H1N1 strain as well as other seasonal or pandemic strains.

Additional noteworthy updates to the NCCN Guidelines include the addition of doripenem (Doribax®, Ortho-McNeil-Janssen Pharmaceuticals, Inc.) to the Antibacterial Agents Tables and tenofovir disoproxil fumarate (Viread®, Gilead Sciences, Inc.) to the Antiviral Agents Tables.

NCCN Clinical Practice Guidelines in Oncology™ are developed and updated through an evidence-based process with explicit review of the scientific evidence integrated with expert judgment by multidisciplinary panels of physicians from NCCN Member Institutions. The most recent version of this and all the NCCN Guidelines are available free of charge at NCCN.org.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit NCCN.org.

Sources:

FDA Issues Final Rules to Help Patients Gain Access to Investigational Drugs

The U.S. Food and Drug Administration (FDA) published two rules [on August 12, 2009] …that seek to clarify the methods available to seriously ill patients interested in gaining access to investigational drugs and biologics when they are not eligible to participate in a clinical trial and don’t have other satisfactory treatment options.

U.S. Food & Drug Administration

U.S. Food & Drug Administration

The U.S. Food and Drug Administration (FDA) published two rules [on August 12, 2009] …that seek to clarify the methods available to seriously ill

Margaret Hamburg, M.D., Comissioner of Food & Drugs, U.S. Food & Drug Administration

Margaret A. Hamburg, M.D., Commissioner of Food & Drugs, U.S. Food & Drug Administration

patients interested in gaining access to investigational drugs and biologics when they are not eligible to participate in a clinical trial and don’t have other satisfactory treatment options.

To support the effort to help these patients, the agency also is launching a new Web site where patients and their health care professionals can learn about options for investigational drugs. In general, these options include being treated with a drug that has been approved by FDA, being given an investigational drug as part of a clinical trial, or obtaining access to an investigational drug outside of a clinical trial.

The new rule, “Expanded Access to Investigational Drugs for Treatment Use,” makes investigational drugs more widely available to patients by clarifying procedures and standards. The other rule, “Charging for Investigational Drugs Under an Investigational New Drug Application,” clarifies the specific circumstances and the types of costs for which a manufacturer can charge patients for an investigational drug when used as part of a clinical trial or when used outside the scope of a clinical trial.

“With these initiatives, patients will have the information they need to help them decide whether to seek investigational products,” said Margaret A. Hamburg, M.D., Commissioner of Food and Drugs. “For patients seeking expanded access to investigational drugs and biologics, the new rules make the process easier to understand.”

Clinical trials are studies of drugs and biologics that are still in development and have not yet been approved by the FDA. Many patients enroll in clinical trials to gain access to investigational therapies and contribute to finding out how well an investigational therapy works, and how safe it is for patients. Obtaining a drug or biologic under an expanded access program may be an option for some patients who are not able to enroll in clinical trials.

The FDA has allowed expanded access to experimental drugs and biologics since the 1970s. That access has allowed tens of thousands of patients with HIV/AIDS, cancer, and other conditions to receive promising therapies when no approved alternative is available.

“The final rules balance access to promising new therapies against the need to protect patient safety and seek to ensure that expanded access does not discourage participation in clinical trials or otherwise interfere with the drug development process,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Clinical trials are the most important part of the drug development process in determining whether new drugs are safe and effective, and how to best use them.”

Source: FDA Issues Final Rules to Help Patients Gain Access to Investigational Drugs, FDA News Release, News & Events, U.S. Food & Drug Administration, 12 Aug. 09.

Additional Information:

Women Often Opt to Surgically Remove Their Breasts, Ovaries to Reduce Cancer Risk

Many women at high risk for breast or ovarian cancer are choosing to undergo surgery as a precautionary measure to decrease their cancer risk, according to a report in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

PHILADELPHIA – Many women at high risk for breast or ovarian cancer are choosing to undergo surgery as a precautionary measure to decrease their cancer risk, according to a report in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Gareth

Dr. Gareth Evans is an international authority on cancer genetics. Dr. Evans is the Chairman of the National Institute For Health & Clinical Excellence (NICE) familial breast cancer group; Chairman, Cancer Genetics Group & Council Member, British Society of Human Genetics; Consultant, Genesis Prevention Center, Univ. Hospital of South Manchester NHS Trust; Professor, Univ. of Manchester, UK

“Women have their breasts or ovaries removed based on their risk.

Claudine_2009_July_(photo_credit_Phil_Humnicky,_Georgetown)

Dr. Claudine Isaacs is an Associate Professor of Medicine, Director of the Familial Cancer Registry Shared Resource, Director of the Clinical Breast Cancer Program, and the Co-Medical Director of the Fisher Center for Familial Cancer Research at the Lombardi Comprehensive Cancer Center, Georgetown Univ., Washington, D.C. (photo credit: Phil Humnicky, Georgetown Univ.)

It does not always happen immediately after counseling or a genetic test result and can take more than seven years for patients to decide to go forward with surgery,” said lead researcher D. Gareth Evans, M.D. Evans is a consultant in clinical genetics at the Genesis Prevention Center, University Hospital of South Manchester NHS Trust and a professor at the University of Manchester, United Kingdom.

Evans and colleagues assessed the increase in risk-reduction surgery among women with breast cancer and evaluated the impact of cancer risk, timing and age.

Rate of increase was measured among 211 women with known unaffected BRCA1 or BRCA2 mutation carriers. BRCA1 and BRCA2 are hereditary gene mutations that indicate an increased risk for developing breast cancer. Additionally, more than 3,500 women at greater than 25 percent lifetime risk of breast cancer without mutations also had a documented increase in risk-reduction surgery.

Women who had a biopsy after undergoing risk evaluation were twice as likely to choose a risk-reducing mastectomy. Forty percent of the women who were mutation carriers underwent bilateral risk-reducing mastectomy; 45 percent had bilateral risk-reducing salpingo-oophorectomy (surgical removal of ovaries). These surgeries are widely used by carriers of BRCA1 and BRCA2 gene mutations to reduce the risk for breast and ovarian cancer.

Evaluated by gene type, bilateral risk-reducing salpingo-oophorectomy was more common in women who were BRCA1 gene carriers – 52 percent had the surgery compared with 28 percent of the women who were BRCA2 gene carriers.

“We found that older women were much less likely to have a mastectomy, but were more likely to have their ovaries removed,” said Evans.

Most of the women, specifically those aged 35 to 45 years, opted for surgery within the first two years after the genetic mutation test, but some did not make a decision until seven years later.

“This is a very interesting study. It fleshes out some of what we know about adoption of risk reduction strategies in high-risk women who have participated in a very comprehensive and well thought-out genetic counseling, testing and management program,” said Claudine Isaacs, M.D., an associate professor of medicine and co-director of the Fisher Center for Familial Cancer Research, Lombardi Comprehensive Cancer Center at Georgetown University.

BRCA1 and BRCA2 mutation carriers have a very high lifetime risk of cancer, and for BRCA1 carriers there are unfortunately no clearly proven non-surgical prevention strategies, according to Isaacs. These women face a 50 to 85 percent lifetime risk of breast cancer, and mastectomy is currently the most effective prevention method available.

The findings confirm the expectations that when a woman has a biopsy, even if benign, most are more likely to opt for risk-reduction surgery.

“Screening should be conducted at a place with expertise in an effort to minimize false-positive results, which often lead to biopsy. This will minimize the anxiety that comes along with such a diagnosis. Patients should consult with an expert in advance and stay in contact with them to see how the science may be changing over time,” she advised. “This is an ongoing conversation that needs to be addressed and individualized for each patient.”

Likewise, Evans suggested that additional studies are needed to help evaluate the communication efforts and methods between doctors and/or counselors and women at risk for breast cancer. Questions to be raised should include how is the communication method occurring, are the doctors sympathetic and is there an ongoing dialogue?

“Careful risk counseling does appear to influence women’s decision for surgery although the effect is not immediate,” the researchers wrote.

References:

Young Early-Stage Ovarian Cancer Patients Can Preserve Fertility

A new study finds that young women with early-stage ovarian cancer can preserve future fertility by keeping at least one ovary or the uterus without increasing the risk of dying from the disease. The study is published in the September 15, 2009 issue of CANCER, a peer-reviewed journal of the American Cancer Society.

A new study finds that young women with early-stage ovarian cancer can preserve future fertility by keeping at least one ovary or the uterus without increasing the risk of dying from the disease. The study is published in the September 15, 2009 issue of CANCER, a peer-reviewed journal of the American Cancer Society.

fertility

... “Given the potential reproductive and nonreproductive benefits of ovarian and uterine preservation, the benefits of conservative surgical management should be considered in young women with ovarian cancer” ...

Most cases of ovarian cancer are diagnosed at later stages and in older women. However, up to 17 percent of ovarian tumors occur in women 40 years of age or younger, many of whom have early stage disease. Surgery for ovarian cancer usually involves complete removal of the uterus (hysterectomy) and ovaries, which not only results in the loss of fertility, but also subjects young women to the long-term consequences of estrogen deprivation.

Jason Wright

Jason Wright, M.D., Assistant Professor, OB/GYN, Columbia University College of Physicians & Surgeons, New York City, NY

Researchers led by Jason Wright, M.D., of Columbia University College of Physicians and Surgeons in New York City conducted a study to examine the safety of fertility-conserving surgery in premenopausal women with ovarian cancer. This type of surgery conserves at least one ovary or the uterus.

The investigators analyzed data from women 50 years of age or younger who were diagnosed with early stage (stage I) ovarian cancer between 1988 and 2004 and who were registered in the National Cancer Institute’s Surveillance, Epidemiology and End Results database, a population-based cancer registry that includes approximately 26 percent of the US population. Patients who had both of their ovaries removed were compared with those who had only the cancerous ovary removed. A second analysis examined uterine conservation verus hysterectomy.

For their first analysis, the researchers identified 1,186 ovarian cancer patients. While most had both ovaries removed, about one in three (36 percent) had one ovary conserved. They found those in whom one ovary was saved had similar survival for up to at least five years.

To examine the effect of uterine preservation, the investigators studied a total of 2,911 women. While most of the women underwent hysterectomy, about one in four (23 percent) had uterine preservation. Uterine preservation also had no effect on survival.

Women who were younger, who were diagnosed in more recent years, and who resided in the eastern or western United States were more likely to undergo ovarian or uterine conservation.

These results are promising for the many young women who are diagnosed with ovarian cancer each year. An estimated 21,650 women in the United States were diagnosed with the disease in 2008. “Given the potential reproductive and nonreproductive benefits of ovarian and uterine preservation, the benefits of conservative surgical management should be considered in young women with ovarian cancer,” the authors concluded.

Source:  Wright JD, Shah M, Mathew L, et. al.  Fertility preservation in young women with epithelial ovarian cancer. CANCER; Published Online: August 10, 2009 (DOI: 10.1002/cncr.24461); Print Issue Date: September 15, 2009.

Comment: The key to this study is the concept that fertility preservation “should be considered in young women with ovarian cancer.”  As part of this consideration, the patient’s subtype of ovarian cancer may play an important role as well.  For example, a diagnosis of ovarian clear cell adenocarcinoma (OCCA) in a young adult woman should create a moment of pause in regard to fertility-sparing. The OCCA subtype of epithelial ovarian cancer can be extremely chemoresistant (even during first-line treatment), especially if the tumor histology indicates that the tumor possesses a dominant clear cell component or is a pure form of OCCA.  In addition, OCCA is a rare form of epithelial ovarian cancer in women worldwide (with the exception of Japanese foreign nationals). My hypothetical does not mean that fertility sparing should not be considered in the event of a OCCA diagnosis, it simply means that each woman should carefully discuss fertility-sparing with her board-certified gynecologic oncologist based upon the specific facts of her case, including tumor histology.

Novel Targeted Gene Therapies Use Diphtheria Toxin To Fight Ovarian Cancer; One Clinical Trial Underway

Two separate research teams reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer. … A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells. Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

Targeted Gene Therapy In the Fight Against Ovarian Cancer

The peritoneal cavity is a common site of ovarian cancer and accompanying ascites caused by the disease. Ascites is an abnormal buildup of fluid in the peritoneal cavity that causes swelling.  Malignant tumor cells may be found in the ascites fluid in connection with late stage ovarian cancer.  Massive ascites and the related abdominal distention can cause anorexia, nausea, vomiting and respiratory difficulties, and negatively impact the patient’s quality of life. Ovarian cancer patients frequently experience disease involvement of the pelvic and retroperitoneal lymph nodes as well. The standard primary treatment of patients with advanced stage ovarian cancer is cytoreductive surgery followed by platinum drug and taxane drug doublet chemotherapy. Despite this aggressive approach, there is a high rate of disease recurrence. Although discovery of several other active nonplatinum cytotoxic agents has improved outcome, long-term survival rates are low. Success of traditional chemotherapy has been limited by drug resistance and lack of specificity with respect to disease formation and progression. Thus, novel “targeted” ovarian cancer therapies that achieve improved long-term disease control with lower toxicity are desperately needed.

A so-called “targeted therapy” utilizes drugs or other medically manufactured substances (e.g., small molecule drugs or monoclonal antibodies) to block the growth and spread of cancer by interfering with specific molecules involved in cancer tumor growth and progression.  By identifying and selectively focusing upon molecular and cellular changes or unique genetic characteristics that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy, and less harmful to normal cells.

It is possible for a targeted therapy to incorporate a gene therapy. Gene therapy is an experimental treatment that involves the introduction of genetic material (DNA or RNA) into a human cell to fight a disease such as cancer.  When both therapeutic approaches are combined by researchers, a “targeted gene therapy” is the result.  A targeted gene therapy is an attractive approach to controlling or killing human cancer cells only if the therapy can selectively identify and exploit the genetic and epigenetic alterations in cancer cells, without harming normal cells that do not possess such alternations.

Two separate research groups reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer.  The toxin is produced by a deadly bacterium (Corynebacterium diphtheriae).  A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells.  Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

MIT-Lankenau Institute Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The MSLN & HE4 Ovarian Cancer Genes.

anderson

Daniel Anderson, Ph.D., Research Associate, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

The first study, which appears in the August 1 issue of the journal Cancer Research, was conducted by a team of researchers from the Massachusetts Institute of Technology (MIT) and the Lankenau Institute of Medical Research (Lankenau Institute). In this study, the researchers used a nanoparticle as a delivery vehicle (or vector) for DNA that encodes a diphtheria toxin suicide protein (DT-A).  The novel nanoparticles are made with positively charged, biodegradable polymers known as poly(beta-amino esters). When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue.

The nanoparticle carrying the DT-A is designed to target overexpression of two genes (mesothelin (MSLN) and HE4 (or WFDC2)) that are highly active in ovarian tumor cells, but not in normal cells. Once inside an ovarian cancer tumor cell, the DT-A disrupts the tumor cell’s ability to manufacture critical life sustaining proteins, thereby causing cell death.  Accordingly, the choice of the DT-A fragment of a diptheria toxin gene ensures high ovarian cancer cell killing activity.  It also avoids unintended toxicity to normal cells because the DT-A released from destroyed ovarian cancer cells is not able to enter normal neighboring tissue cells in the absence of the DT-B fragment which was excluded from the original nanoparticle delivery system or vector.

As part of this study, researchers administered DT-A nanoparticles directly into the peritoneal cavity – which encases abdominal organs such as the stomach, liver, spleen, ovaries and uterus – of mice xenografted with primary and metastatic ovarian tumors.  Ovarian cancer is known to initially spread throughout the peritoneal cavity, and current therapeutic approaches in humans include direct injection into the peritoneal space, thereby targeting the therapy to the ovaries and nearby tissues where tumors may have spread.

“… [The researchers] discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. …”

langerrobert

Robert S. Langer is the David H. Koch Institute for Integrative Cancer Research Professor (there are 14 Institute Professors at MIT; being an Institute Professor is the highest honor that can be awarded to a faculty member). Dr. Langer has written approximately 1,050 articles. He also has approximately 750 issued and pending patents worldwide. Dr. Langer’s patents have been licensed or sublicensed to over 220 pharmaceutical, chemical, biotechnology and medical device companies. He is the most cited engineer in history.

Sawicki

Janet Sawicki, Ph.D., Professor, Lankenau Institute of Medical Research. Dr. Sawicki also serves as an Associate Professor at the Kimmel Cancer Center of Thomas Jefferson University. Her ovarian cancer research is funded by the National Institutes of Health, the U.S. Department of Defense, the Sandy Rollman Foundation, the Teal Ribbon Ovarian Cancer Foundation, and the Kaleidoscope of Hope Foundation.

Daniel Anderson, Ph.D., research associate in the David H. Koch Institute for Integrative Cancer Research at MIT and a senior author of the paper, and others from MIT, including Institute Professor Robert Langer, along with researchers from the Lankenau Institute, led by Professor Janet Sawicki, discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. Furthermore, the novel therapy did not have the toxic side effects of chemotherapy because the diptheria toxin gene is engineered to function in ovarian cells but is inactive in normal cell types.

Based upon these finding, the MIT and Lankenau Institute researchers concluded that IP administration of DT-A nanoparticles, combined with designed targeting of those nanoparticles against ovarian tumor cell gene (MSLN & HE4) expression, holds promise as an effective therapy for advanced-stage ovarian cancer. According to Anderson, human clinical trials could start, after some additional preclinical studies, in about 1 to 2 years.  Currently ovarian cancer patients undergo surgery followed by chemotherapy. In many cases, the cancer returns after treatment.  Disease recurrence is problematic because there are no curative therapies for advanced-stage tumors.

For several years, the MIT-Lankenau Institute team worked to develop the DT-A nanoparticles as an alternative to viruses, which are associated with safety risks. In addition to ovarian cancer, these nanoparticles have demonstrated treatment potential for a variety of diseases, including prostate cancer and viral infection. “I’m so pleased that our research on drug delivery and novel materials can potentially contribute to the treatment of ovarian cancer,” Langer said. In future studies, the team plans to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including brain, lung and liver cancers.

Other MIT authors of the paper are recent MIT Ph.D. recipients Gregory Zugates and Jordan Green (now a professor at John’s Hopkins University), and technician Naushad Hossain. The research was funded by the Department of Defense and the National Institutes of Health.

Israeli Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The H19 Ovarian Cancer Gene.

The second study was conducted by Israeli researchers and was published August 6 online ahead of print in the Journal of Translational Medicine.

In the provisional study report, the researchers note that based upon earlier studies from their team and others, the H19 gene has emerged as a candidate for cancer gene therapy. The H19 gene is expressed at substantial levels in ovarian cancer tumor cells, but is nearly undetectable in surrounding normal tissue cells.  Although the Israeli research team acknowledges that the exact function of H19 is the subject of past debate, it notes that recent data suggests a role for H19 in promoting cancer progression, angiogenesis and metastasis.

As a first step, Israeli researchers tested H19 gene expression in ovarian cancer cells obtained from the ascites fluid of 24 patients, and established that H19 expression levels were detected in 90% of the tested patients. Of those patients with positive H19 expression, 76% showed a moderate or high level of expression, while 24% showed a low level of expression.

Next, the researchers created a DT-A nanoparticle similar to the one created by the MIT/Lankenau research team as described above, except the Israeli nanoparticle was designed to target H19 overexpression within ovarian cancer cells.  The therapeutic effect of the DT-A/H19 nanoparticles was first tested in vitro against various ovarian cancer cell lines and cells obtained from patient ascites fluid.  The researchers determined that the DT-A/H19 nanoparticle therapy caused ovarian cancer cell death.  The therapeutic effect of the DT-A nanoparticles was tested in vivo by injecting the DT-A nanoparticles into mice xenografted with ovarian cancer tumors. The researchers estimate that the DT-A nanoparticle therapy reduced ovarian cancer tumor growth in the treated mice by 40%.

Based upon these finding, the researchers note that although the study report issued is provisonal, it is their working hypothesis that intraperitoneal administration of DT-A/H19 nanoparticles holds the potential to (1) reach ascites tumor cells, (2) deliver its intracellular toxin without targeting normal tissue cells, and (3) reduce tumor burden & fluid accumulation; and therefore, improve the patient’s quality of life, and hopefully, prolong her survival.

  • DT-A/H19 Nanoparticle Therapy Administered To An Israeli Patient On A Compassionate Use Trial Basis

In the provisional study report, the researchers state that the targeted gene therapy was administered to an Israeli patient with advanced, recurrent ovarian cancer, who qualified for compassionate use treatment under Israeli regulatory rules.  Specifically, the patient’s intraperitoneal ovarian cancer metastases and ascites were treated with the DT-A/H19 nanoparticle therapy after the failure of conventional chemotherapy. The results of the single patient compassionate use trial suggest that the drug caused no serious adverse events at any drug dosage level.  Moreover, the patient experienced (1) a 50% decrease in serum cancer marker protein CA-125, (2) a significant decrease in the number of cancerous cells in the ascites, and (3) a clinical improvement as reported by her doctors.  It is reported that the patient’s quality of life increased during the course of treatment and her condition continues to be stable, with no new cancerous growths.

  • Phase I/II Clinical Trial To Test DT-A/H19 Nanoparticle Therapy (BC-819) In the U.S. & Israel

The DT-A/H19 nanoparticle therapy is being developed commercially by BioCancell Therapeutics, Inc (BioCancell) Recently, BioCancell announced the opening of a clinical trial to test the DT-A/H19 nanoparticle therapy (also referred to as BC-819) in patients with advanced stage ovarian cancer.  The clinical trial is entitled, Phase 1/2a, Dose-Escalation, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Intraperitoneal Administration of DTA-H19 in Subjects With Advanced Stage Ovarian Cancer, and the trial investigators are recruiting patients in the U.S. and Israel as indicated below.

University of Pennsylvania Medical Center [Abramson Cancer Center] (Recruiting)
Philadelphia, Pennsylvania, United States, 19104-6142
Contact: Lana E. Kandalaft, Pharm.D, PhD – 215-537-4782 (lknd@mail.med.upenn.edu)
Principal Investigator: George Coukos, M.D., Ph.D.

Massey Cancer Center (Not yet recruiting)
Richmond, Virginia, United States, 23298-0037
Contact: Jane W. Baggett, RN 804-628-2360 (jbaggett@mcvh-vcu.edu)
Principal Investigator: Cecelia H. Boardman, M.D.

The Edith Wolfson Medical Center (Recruiting)
Holon, Israel
Contact: Pnina Nir (972)-52-8445143 (pninanir@wolfson.health.gov.il)
Principal Investigator: Tally Levy, M.D.

Hadassah University Hospital (Recruiting)
Jerusalem, Israel
Contact: Zoya Bezalel (972)-2-6776725 (zoyab@hadassah.org.il)
Principal Investigator: David Edelman, MD

Meir Hospital (Recruiting)
Kfar Saba, Israel
Contact: Tal Naderi 09-7472213 (Ta.INadiri@clalit.org.il)
Principal Investigator: Ami Fishman, MD

In the provisional study report, the Israeli researchers discuss the importance of collecting data regarding the correlation between the level of ovarian cancer cell H19 expression and the efficacy of the treatment as part of the clinical trial discussed above.  Based upon accrued future clinical trial data, the researchers believe that they will be able to identify in advance patients that will respond to this novel therapy, as well as non-responders who are resistant to all known therapies, thereby avoiding treatment failure and unnecessary suffering and cost.

References:

Ovary Removal May Increase Lung Cancer Risk

Women who have premature menopause because of medical interventions are at an increased risk of developing lung cancer, according to a new study published in the International Journal of Cancer.  The startling link was made by epidemiologists from the Université de Montréal, the Research Centre of the Centre Hospitalier de l’Université de Montréal and the INRS—Institut Armand-Frappier. …

Ovary removal may increase lung cancer risk

Press Release, Monday, 20 July 2009

lungsWomen who have premature menopause because of medical interventions are at an increased risk of developing lung cancer, according to a new study published in the International Journal of Cancer.  The startling link was made by epidemiologists from the Université de Montréal, the Research Centre of the Centre Hospitalier de l’Université de Montréal and the INRS—Institut Armand-Frappier.

“We found that women who experienced non-natural menopause are at almost twice the risk of developing lung cancer compared to women who experienced natural menopause,” says Anita Koushik, a researcher at the Université de Montréal’s Department of Social and Preventive Medicine and a scientist at the Research Centre of the Centre Hospitalier de l’Université de Montréal. “This increased risk of lung cancer was particularly observed among women who had non-natural menopause by having had both their ovaries surgically removed.”

The scientists studied 422 women with lung cancer and 577 control subjects at 18 hospitals across Montreal, Quebec, Canada. They assessed socio-demographic characteristics, residential history, occupational exposures, medical and smoking history, and (among women) menstruation and pregnancy histories.

Koushiki

Anita Koushik, researcher, Université de Montréal's Department of Social & Preventive Medicine; scientist, Research Centre of the Centre Hospitalier de l'Université de Montréal.

“A major strength of this study was the detailed smoking information which we obtained from all study participants; this is important because of the role of smoking in lung cancer and because smokers generally have lower estrogen levels than non-smokers,” says Dr. Koushik. “Although smoking is the dominant cause of lung cancer, we know other factors can play an important role in enhancing the impact of tobacco carcinogens; this research suggests that in women hormonal factors may play such a role.”

Women were considered menopausal if their menstrual periods had stopped naturally, surgically (by hysterectomy with bilateral surgical ovary removal) or because of radiation or chemotherapy.  Women who had at least one remaining ovary and who still had their menstrual periods at the time of diagnosis/interview were classified as premenopausal.  Among participants with natural menopause, the median age for attaining menopause was 50 years old; among those with non-natural menopause, it was at 43 years.

“Non-natural menopause, particularly surgical menopause, may represent an increased risk with younger age at menopause given that surgery is usually done before natural menopause occurs. It’s possible that vulnerability to lung cancer is caused by early and sudden decrease in estrogen levels or potentially long-term use of hormone replacement therapy and further research is needed to explore these hypotheses,” says Jack Siemiatycki a professor at the Université de Montréal’s Department of Social and Preventive Medicine and a scientist at the Research Centre of the Centre Hospitalier de l’Université de Montréal.

Siemiatycki

Jack Siemiatycki, professor, Université de Montréal's Department of Social & Preventive Medicine; scientist, Research Centre of the Centre Hospitalier de l'Université de Montréal


About the Study
The article “Characteristics of menstruation and pregnancy and the risk of lung cancer in women,” published in the International Journal of Cancer, was authored by Anita Koushik and Jack Siemiatycki of the Université de Montréal and Research Centre of the Centre Hospitalier de l’Université de Montréal and Marie-Elise Parent of the INRS—Institut Armand-Frappier.

Partners in Research
This study was funded by the Canadian Institutes of Health Research, the Fonds de la recherche en santé du Québec and the Guzzo-SRC Chair in Environment and Cancer.

Source: Ovary Removal May Increase Lung Cancer Risk, Press Release, University of Montreal, 20 Jul. 09 [summarizing the findings of Koushik A, Parent ME, Siemiatycki J. Characteristics of menstruation and pregnancy and the risk of lung cancer in women. Int J Cancer. 2009 May 11. (Epub ahead of print)].

Beyond BRCA1 & BRCA2: U.K. Researchers Identify Genetic Defect That Could Increase Risk of Ovarian Cancer Up To 40%

Scientists have located a region of DNA which – when altered – can increase the risk of ovarian cancer according to research published in Nature Genetics today. An international research group led by scientists based at the Cancer Research UK Genetic Epidemiology Unit, at the University of Cambridge and UCL (University College London) searched through the genomes of 1,810 women with ovarian cancer and 2,535 women without the disease from across the UK. …The scientists estimate that there is a 40 per cent increase in lifetime risk for women carrying the DNA variation on both copies of chromosome nine compared with someone who doesn’t carry it on either chromosome. The risk for women carrying the variation on both chromosomes is 14 in 1000 – compared with [10] ten in 1000 [in the general population]. … The lifetime risk for a woman carrying the DNA variant on one copy of the chromosome is increased by 20 per cent from ten in 1000 to 12 in 1000. …

Genetic link to ovarian cancer found

Cancer Research UK

SUNDAY 2 AUGUST 2009

Cancer Research UK Press Release

Scientists have located a region of DNA which – when altered – can increase the risk of ovarian cancer according to research published in Nature Genetics today.

An international research group led by scientists based at the Cancer Research UK Genetic Epidemiology Unit, at the University of Cambridge and UCL (University College London) searched through the genomes of 1,810 women with ovarian cancer and 2,535 women without the disease from across the UK. They analysed 2.5 million variations in DNA base pairs – the letters which spell out the genetic code – to identify common spelling ‘errors’ linked to ovarian cancer risk.

The scientists identified the genetic ‘letters’- called single nucleotide polymorphisms (SNPs) – which when spelled slightly differently increase ovarian cancer risk in some women. This is the first time scientists have found a SNP linked uniquely to risk of ovarian cancer and is the result of eight years of investigations. With the help of the international Ovarian Cancer Association Consortium (OCAC), they then looked at more than 7,000 additional women with ovarian cancer and 10,000 women without disease from around the world to confirm this finding.

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The region of risk DNA is located on chromosome nine – there are 23 pairs of each chromosome in humans, one of each pair inherited from each parent. The scientists estimate that there is a 40 per cent increase in lifetime risk for women carrying the DNA variation on both copies of chromosome nine compared with someone who doesn’t carry it on either chromosome. The risk for women carrying the variation on both chromosomes is 14 in 1000 – compared with [10] ten in 1000 [in the general population].

Approximately 15 per cent of women in the UK population carry two copies of the variant DNA.

The lifetime risk for a woman carrying the DNA variant on one copy of the chromosome is increased by 20 per cent from ten in 1000 to 12 in 1000. Approximately 40 per cent of women in the UK carry one copy.

Senior author Dr. Simon Gayther, whose work is supported by Cancer Research UK and The Eve Appeal charity which fundraises for the gynaecological cancer research team based at UCL, said: “The human DNA blueprint contains more than 10 million genetic variants. These are part and parcel of our characteristics and make-up – but a handful will also increase the chances of some women getting ovarian cancer and we have found the first one of these.”

“There is now a genuine hope that as we find more, we can start to identify the women at greatest risk and this could help doctors to diagnose the disease earlier when treatment has a better chance of being successful.”

Dr. Andrew Berchuck, head of the international Ovarian Cancer Association Consortium steering committee, said: “This study confirms that ovarian cancer risk is partly determined by genetic variants present in a large number of women. This initial discovery and others that will likely follow in the future lay the groundwork for individualised early detection and prevention approaches to reduce deaths from ovarian cancer.”

Ovarian cancer is the fifth most common cancer in women in the UK with around 6,800 new cases diagnosed each year in the UK – 130 women every week. It is the fourth most common cause of cancer death in women in the UK with around 4,300 deaths from the disease in the UK each year.

BRCA1 and BRCA2 are high risk genes which cause breast cancer and are already known to significantly increase the risk of ovarian cancer- but faults in these genes are rare and probably cause less than five per cent of all cases of ovarian cancer.

Lead author, Professor Dr Paul Pharoah, a Cancer Research UK senior research fellow at the University of Cambridge, said: “We already know that people with mistakes in the BRCA1 and BRAC2 genes have a greater risk of ovarian cancer – but on their own they don’t account for all of the inherited risk of the disease. “It is likely that the remaining risk is due to a combination of several unidentified genes – which individually carry a low to moderate risk. Now we have ticked one off, the hunt is on to find the rest.”

Rose Lammy, the mother of David Lammy MP [Member of Parliament] for Tottenham and Minister for Higher Education and Intellectual Property, died of ovarian cancer in 2008. Rose Lammy’s DNA sample was included in the study, and she carried both risk alleles of the new genetic marker that researchers have identified.

David Lammy said: “I am pleased that Mum’s sample was included in this study as it is one step towards earlier diagnosis of ovarian cancer when treatment is more successful. We now know the fact that she had this altered DNA meant that her lifetime risk had risen from 10 in 1,000 to 14 in 1,000, an increase of 40 per cent compared to those women who don’t carry this DNA variation. Dr Lesley Walker, director of cancer information at Cancer Research UK, added: “This is an important discovery. Our researchers have worked as part of a huge collaboration to establish the regions of DNA that can increase someone’s risk of developing ovarian cancer. “This research paves the way for scientists to discover even more genes linked to ovarian cancer and could lead to new approaches to treat or prevent the disease – crucially it will help doctors manage women who are at increased risk.”

Source: Genetic link to ovarian cancer found, Cancer Research U.K. Press Release & Video, 02 Aug. 09.

Reference: Honglin Song et al. (2009). A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 Nature Genetics 10.1038/ng.424.

New Study Shows Four-Year Window for Early Detection of Ovarian Cancer

A new study by Howard Hughes Medical Institute researchers shows that most early stage ovarian tumors exist for years at a size that is a thousand times smaller than existing tests can detect reliably.  But the researchers say their findings also point to new opportunities for detecting ovarian cancer—a roughly four-year window during which most tumors are big enough to be seen with a microscope, but have not yet spread.

Tiny Early-Stage Ovarian Tumors Define Early Detection Challenge

Currently available tests detect ovarian cancer when it is about the size of the onion in the photograph. To reduce ovarian cancer mortality by 50 percent, an early detection test would need to be able to reliably detect tumors the size of the peppercorn. (Photo Source:  Patrick O. Brown, Howard Hughes Medical Institute Investigator, Research News Release, July 28, 2009)

Currently available tests detect ovarian cancer when it is about the size of the onion in the photograph. To reduce ovarian cancer mortality by 50 percent, an early detection test would need to be able to reliably detect tumors the size of the peppercorn. (Photo Source: Patrick O. Brown, Howard Hughes Medical Institute Investigator, Research News Release, July 28, 2009)

A new study by Howard Hughes Medical Institute researchers shows that most early stage ovarian tumors exist for years at a size that is a thousand times smaller than existing tests can detect reliably.

But the researchers say their findings also point to new opportunities for detecting ovarian cancer—a roughly four-year window during which most tumors are big enough to be seen with a microscope, but have not yet spread.

“Our work provides a picture of the early events in the life of an ovarian tumor, before the patient knows it’s there,” says Howard Hughes Medical Institute researcher Patrick O. Brown. “It shows that there is a long window of opportunity for potentially life-saving early detection of this disease, but that the tumor spreads while it is still much too small to be detected by any of the tests that have been developed or proposed to date.”

According to the American Cancer Society, some 15,000 women in the United States and 140,000 women worldwide die from ovarian cancer each year. The vast majority of these deaths are from cancers of the serous type, which are usually discovered only after the cancer has spread.

“Instead of typically detecting these cancers at a very advanced stage, detecting them at an early stage would be enormous in terms of saving lives,” says Brown, who is at Stanford University School of Medicine. Early detection would enable surgeons to remove a tumor before it spreads, he adds.

The article—co-authored by Chana Palmer of the Canary Foundation, a nonprofit organization focused on early cancer detection—was published July 28, 2009, in the open access journal PLoS Medicine.

“Like almost everything with cancer … the more closely you look at the problem, the harder it looks,” Brown says. “That’s not to say that I don’t believe it’s a solvable problem. It’s just a difficult one.” — Patrick O. Brown, M.D. Ph.D.

Patrick O. Brown, M.D. Ph.D., Howard Hughes Medical Institute Investigator, Stanford University School of Medicine

Patrick O. Brown, M.D. Ph.D., Howard Hughes Medical Institute Investigator, Stanford Univ. School of Medicine

“Like almost everything with cancer … the more closely you look at the problem, the harder it looks,” Brown says. “That’s not to say that I don’t believe it’s a solvable problem. It’s just a difficult one.”

In the quest to develop early detection methods for ovarian cancer, Brown says, science hasn’t had a firm grasp on its target. So he and Palmer took advantage of published data on ovarian tumors to generate a better understanding of how the cancer progresses in its earliest stages.

The team analyzed data on serous-type ovarian tumors that were discovered when apparently healthy women at high genetic [BRCA1 gene mutation] risk for ovarian cancer had their ovaries and fallopian tubes removed prophylactically. Most of the tumors were microscopic in size; they were not detected when the excised tissue was examined with the naked eye.

The analysis uncovered a wealth of unexplored information. Thirty-seven of the early tumors had been precisely measured when they were excised – providing new details about the size of the tumors when they were developing prior to intervention, Brown says. By extrapolating from this “occult” size distribution to the size distribution of larger, clinically evident tumors, the researchers were able to develop a model of how the tumors grew and progressed. “We are essentially trying to build a story for how these tumors progress that fits the data,” Brown explains.

Among the study’s findings:

  • Serous ovarian tumors exist for at least four years before they spread.
  • The typical serous cancer is less than three millimeters across for 90 percent of this “window of opportunity for early detection.”
  • These early tumors are twice as likely to be in the fallopian tubes as in the ovaries.
  • To cut mortality from this cancer in half, an annual early-detection test would need to detect tumors five millimeters in diameter or less – about the size of a black peppercorn and less than a thousandth the size at which these cancers are typically detected today.

Brown’s lab is now looking for ways to take advantage of that window of opportunity to detect the microscopic tumors and intervene before the cancer spreads.

One strategy the laboratory is pursuing is to examine tissues near the ovaries, in the female reproductive tract, for protein or other molecular markers that could signify the presence of cancer. Brown says answering another question might also prove helpful: whether there is any reliable flow of material from the ovaries and fallopian tubes through the uterus and cervix into the vagina—material that might be tested for a specific cancer marker.

Despite science’s broad understanding of cancer at a molecular level, it has been challenging to identify simple molecular markers that signal the presence of early disease. One current blood marker, CA-125, has proven useful in monitoring later-stage ovarian cancer, but it has not been helpful for early detection. So Brown’s lab is also looking for biomarkers that are present only in ovarian tumors and not in healthy cells, instead of relying on tests that look for unusually high levels of a molecule that is part of normal biology (like CA-125).

The researchers are doing extensive sequencing of all messenger RNA molecules (which carry information for the production of specific proteins) in ovarian cancer cells, searching for evidence of proteins in these cells that would never be found in non-cancer cells. These variant molecules could be produced as a result of chromosome rearrangements—when the genome is cut and spliced in unusual ways—in ovarian cancers. “It’s a long shot,” says Brown, “but it’s important enough to try.”

Source: Tiny Early-Stage Ovarian Tumors Define Early Detection Challenge, Research News, Howard Hughes Medical Institute, July 29, 2009 [summarizing Brown PO, Palmer C, 2009 The Preclinical Natural History of Serous Ovarian Cancer: Defining the Target for Early Detection. PLoS Med 6(7): e1000114. doi:10.1371/journal.pmed.1000114].

Trojan Horse* For Ovarian Cancer–Nanoparticles Turn Immune System Soldiers Against Tumor Cells

In a feat of trickery, Dartmouth Medical School immunologists have devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumor. Using nanoparticles–ultra small bits– the team has reprogrammed a protective cell that ovarian cancers have corrupted to feed their growth, turning the cells back from tumor friend to foe. Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades …

Hanover, N.H.—In a feat of trickery, Dartmouth Medical School immunologists have devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumor.

Using nanoparticles–ultra small bits– the team has reprogrammed a protective cell that ovarian cancers have corrupted to feed their growth, turning the cells back from tumor friend to foe. Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades.

Dr. Jose Conejo-Garcia (right) with graduate student Juan Cubillos-Ruiz  (Photo Source:  Dartmouth Medical School News Release,

Dr. Jose Conejo-Garcia (right) with graduate student Juan Cubillos-Ruiz (Photo Source: Dartmouth Medical School News Release, 13 Jul. 09)

“We have modulated elements of the tumor microenvironment that are not cancer cells, reversing their role as accomplices in tumor growth to attackers that boost responses against the tumor,” said Dr. Jose Conejo-Garcia, assistant professor of microbiology and immunology and of medicine, who led the research. “The cooperating cells hit by the particles return to fighters that immediately kill tumor cells.”

The study, in mice with established ovarian tumors, involves a polymer now in clinical trials for other tumors. The polymer interacts with a receptor that senses danger to activate cells that trigger an inflammatory immune response.

The Dartmouth work focuses on dendritic cells–an immune cell particularly abundant in the ovarian cancer environment. It does take direct aim at tumor cells, so it could be an amenable adjunct to other current therapies.

“The cooperating cells hit by the particles return to fighters that immediately kill tumor cells.” —Dr. Jose Conejo-Garcia

“That’s the beautiful part of story–people usually inject these nanoparticles to target tumor cells. But we found that these dendritic cells that are commonly present in ovarian cancer were preferentially and avidly engulfing the nanoparticles. We couldn’t find any tumor cells taking up the nanoparticles, only the dendritic cells residing in the tumor,” explained Juan R. Cubillos-Ruiz, graduate student and first author.

Dendritic cells are phagocytes–the soldiers of the immune system that gobble up bacteria and other pathogens, but ovarian cancer has co-opted them for its own use, he continued. “So we were trying to restore the attributes of these dendritic cells–the good guys; they become Trojan horses.”

Cancer is more than tumor cells; many other circulating cells including the dendritic phagocytes converge to occupy nearby space. The dendritic cells around ovarian cancer scoop up the nanocomplexes, composed of a polymer and small interfering RNA (siRNA) molecules to silence their immunosuppressive activity.

Nanoparticle incorporation transforms them from an immunosuppressive to an immunostimulatory cell type at tumor locations, provoking anti-tumor responses and also directly killing tumor cells. The effect is particularly striking with an siRNA designed to silence the gene responsible for making an immune protein called PD-L.

The new findings also raise a warning flag about the use of gene silencing complexes in cancer treatment. Inflammation is a helpful immune response, but the researchers urge caution when using compounds that can enhance inflammation in a patient already weakened by cancer.

Ovarian cancer, which claims an estimated 15,000 US lives a year, is an accessible disease for nanoparticle delivery, according to the investigators. Instead of systemic administration, complexes can be put directly into the peritoneal cavity where the phagocytes take them up.

Samples of human ovarian cancer cells show similar responses to nanoparticle stimulation, the researchers observed, suggesting feasibility in the clinical setting. It could be part of a “multimodal approach,” against ovarian cancer, said Conejo-Garcia also a member of the Dartmouth’s Norris Cotton Cancer Center. “The prevailing treatment is surgical debulking, followed by chemotherapy. Our findings could complement those because they target not the tumor cells themselves, but different cells present around the tumor.”

Co-authors are Xavier Engle, Uciane K. Scarlett, Diana Martinez, Amorette Barber, Raul Elgueta, Li Wang, Yolanda Nesbeth and Charles Sentman of Dartmouth; Yvon Durant of University of New Hampshire, Andrew T Gewirtz of Emory, and Ross Kedl of University of Colorado.

The work was supported by grants from the National Institutes of Health, including the National Cancer Institute and National Center for Research Resources, a Liz Tilberis Award from the Ovarian Cancer Research Fund, and the Norris Cotton Cancer Center Nanotechnology Group Award.

Read an interview of Jose Conejo – Garcia with the Ovarian Cancer Research Fund.

Source: Trojan Horse for Ovarian Cancer–Nanoparticles Turn Immune System Soldiers against Tumor Cells, News Release, Dartmouth Medical School, July 13, 2009 (summarizing Cubillos-Ruiz JR, Engle X, Scarlett UK, et. al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest. 2009 Aug 3;119(8):2231-2244. doi: 10.1172/JCI37716. Epub 2009 Jul 13).

__________________

* The Trojan Horse was a tale from the Trojan War, as told in Virgil’s Latin epic poem The Aeneid. The events in this story from the Bronze Age took place after Homer’s Iliad, and before Homer’s Odyssey. It was the strategy that allowed the Greeks finally to enter the city of Troy and end the conflict. In the best-known version, after a fruitless 10-year siege of Troy, the Greeks built a huge horse figure and hid a select force of men within it. The Greeks left the Horse at the city gates of Troy and pretended to sail away.  Thereafter, the Trojans pulled the Horse into their city as a victory trophy. That night the Greek force crept out of the Horse and opened the gates for the returning Greek army, which had sailed back to Troy under cover of night. The Greek army entered and destroyed the city, decisively ending the war. A “Trojan Horse” has come to mean any trick that causes a target to invite a foe into a securely protected bastion or place.

M.D. Anderson’s EphA2-Targeted Therapy Delivers Chemo Directly to Ovarian Cancer Cells

With a novel therapeutic delivery system, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center has successfully targeted a protein that is over-expressed in ovarian cancer cells. Using the EphA2 protein as a molecular homing mechanism, chemotherapy was delivered in a highly selective manner in preclinical models of ovarian cancer, the researchers report in the July 29 issue of the Journal of the National Cancer Institute. … In the models, the therapy inhibited tumor growth in treated mice by 85 percent – 98 percent compared to control mice. … [Anil] Sood said, “We are gearing up to bring it to phase I clinical trials. A lot of the safety studies are well under way or nearing completion and we anticipate that this drug will enter clinical trials within the next few months.”

M. D. Anderson-led team finds potent antitumor activity with a monoclonal antibody-chemotherapy combination

With a novel therapeutic delivery system, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center has successfully targeted a protein that is over-expressed in ovarian cancer cells. Using the EphA2 protein as a molecular homing mechanism, chemotherapy was delivered in a highly selective manner in preclinical models of ovarian cancer, the researchers report in the July 29 issue of the Journal of the National Cancer Institute.

EphA2 is attractive for such molecularly targeted therapy because it has increased expression in ovarian and other cancers, including breast, colon, prostate and non-small cell lung cancers and in aggressive melanomas, and its expression has been associated with a poor prognosis.

Anil K. Sood, M.D., professor and in the Departments of Gynecologic Oncology and Cancer Biology at the Univ. of Texas M. D. Anderson Cancer Center

Anil K. Sood, M.D., professor in the Departments of Gynecologic Oncology and Cancer Biology at the Univ. of Texas M. D. Anderson Cancer Center

“One of our goals has been to develop more specific ways to deliver chemotherapeutic drugs,” said senior author Anil K. Sood, M.D., professor and in the Departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson. “Over the last several years we have shown that EphA2 is a target that is present quite frequently in ovarian and other cancers, but is either present in low levels or is virtually absent from most normal adult tissues. EphA2’s preferential presence on tumor cells makes it an attractive therapeutic target.”

The researchers used a carrier system to deliver chemotherapy directly to ovarian cancer cells. The immunoconjugate contains an anti-EphA2 monoclonal antibody linked to the chemotherapy drug monomethyl auristatin phenylalanine (MMAF) through the non-cleavable linker maleimidocaproyl. Research has shown that auristatins induce cell cycle arrest at the G – M border, disrupt microtubules and induce apoptosis (programmed cell death) in cancer cells.

The investigators evaluated the delivery system’s specificity in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells through antibody-binding and internalization assays. They also assessed viability and apoptosis in ovarian cancer cell lines and tumor models and examined anti-tumor activity in orthotopic mouse models with mice bearing HeyA8-luc and SKOV3ip1 ovarian tumors.

According to Sood, who is also co-director of both the Center for RNA Interference and Non-Coding RNA and the Blanton-Davis Ovarian Cancer Research Program at M. D. Anderson, the immunoconjugate was highly specific in delivering MMAF to the tumor cells that expressed EphA2 while showing minimal uptake in cells that did not express the protein. In the models, the therapy inhibited tumor growth in treated mice by 85 percent – 98 percent compared to control mice.

“Once we optimized the dosing regimen, the drug was highly effective in reducing tumor growth and in prolonging survival in preclinical animal models,” Sood said. “We actually studied bulkier masses because that is what one would see in a clinical setting where there are pre-existent tumors, and even in this setting the drug was able to reduce or shrink the tumors.”

As for future research with the EphA2-silencing therapy, Sood said, “We are gearing up to bring it to phase I clinical trials. A lot of the safety studies are well under way or nearing completion and we anticipate that this drug will enter clinical trials within the next few months.”

He added that his group is simultaneously conducting preclinical testing on other chemotherapy drugs to determine which agents might combine well with the immunoconjugate used in the current study.

“There is growing interest in molecularly targeted therapy so that we are not indiscriminately killing normal cells,” Sood noted. “The goal is to make the delivery of chemotherapy more specific. The immunoconjugate we used is in a class of drugs that is certainly quite attractive from that perspective.”

Research was funded by NCI-DHHS-NIH T32 Training Grant (T32 CA101642 to A.M.N.). This research was funded in part by support from M. D. Anderson’s ovarian cancer SPORE grant (P50 CA083639), the Marcus Foundation, the Gynecologic Cancer Foundation, the Entertainment Industry Foundation, the Blanton-Davis Ovarian Cancer Research Program, and Sood’s Betty Ann Asche Murray Distinguished Professorship.

Co-authors with Sood are Jeong-Won Lee, Hee Dong Han, Mian M. K. Shahzad, Seung Wook Kim, Lingegowda S. Mangala, Alpa M. Nick, Chunhua Lu, Rosemarie Schmandt, Hye-Sun Kim, Charles N. Landen, Robert L. Coleman, all of M. D. Anderson’s Department of Gynecologic Oncology; Robert R. Langley, of M. D. Anderson’s Department of Cancer Biology; Jeong-Won Lee, also of the Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Mian M. K. Shahzad, also of the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; Hye-Sun Kim, also of the Department of Pathology, Cheil General Hospital and Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, Korea; and Shenlan Mao, John Gooya, Christine Fazenbaker, Dowdy Jackson, and David Tice , all of MedImmune, Inc., Gaithersburg, Maryland.

Source: EphA2-Targeted Therapy Delivers Chemo Directly to Ovarian Cancer Cells – M. D. Anderson-led team finds potent antitumor activity with a monoclonal antibody-chemotherapy combination, M.D. Anderson News Release, 29 Jul. 09 [summarizing the findings of Lee JW, Han HD, Shahzad MM et. al. EphA2 Immunoconjugate as Molecularly Targeted Chemotherapy for Ovarian Carcinoma. J Natl Cancer Inst. 2009 Jul 29. [Epub ahead of print]].