TAU Research Links Childhood Obesity to Cancer Risk

 

New study reveals 50% higher risk of urothelial and colorectal cancers in adulthood

Parents are increasingly conscious of the dangers of childhood obesity. There is a growing recognition of health problems associated with extra pounds, including the risk of diabetes, heart disease, and joint and muscle pain.

New research from Tel Aviv University has revealed another significant reason for children to maintain a healthy weight. Dr. Ari Shamiss and Dr. Adi Leiba of TAU's Sackler Faculty of Medicine and the Sheba Medical Center and his fellow researchers found that obesity in adolescence, defined as a Body Mass Index (BMI) in the 85th percentile and above, has a direct link to the incidence of urothelial (bladder and urinary tract) and colorectal cancers in adulthood. According to the American Heart Association, one in three children and teenagers are now considered overweight or obese.

Children above the 84th percentile in BMI have a 1.42% greater chance, representing a 50% higher risk, of developing urothelial or colorectal cancers in adulthood compared to those beneath it, explains Dr. Shamiss, whose research has been published in the journalsCancer Epidemiology, Biomarkers and Prevention and Obesity.

Understanding the connection

To examine the relationship between obesity and cancers, the researchers conducted a longitudinal study of a cohort of 1.1 million males in the Israeli Defense Forces. Their health information was gathered by the army, with a follow-up period of 18 years. When they controlled for factors such as year of birth and education, the researchers discovered a clear link between childhood BMI and those who were diagnosed with urothelial or colorectal cancers later in life.

While the researchers have so far uncovered risk in two different types of cancer, Dr. Shamiss believes that further research will reveal connections between childhood obesity and a wide range of other cancers, including pancreatic cancer, which he is currently researching.

These findings show a distinct need for more research in this field, he notes. "We need to examine the questions of whether obesity is a direct risk factor for cancer or a confounding factor for a genetic variation, for example," he explains, pointing out that basic research could help researchers to understand the connection between obesity and cancer on a deeper level.

The role of weight loss

One of the crucial questions, says Dr. Shamiss, is whether or not a successful weight loss attempt can reduce a child's risk of developing urothelial or colorectal cancer in adulthood. Their current sample looks at children who were obese and those who were of normal weight, but does not reveal whether weight loss makes a significant difference.

New research should focus on researching the pathogenetic link between obesity and cancer, and whether losing weight in adulthood could lower the risk, Dr. Shamiss says. Although healthcare professionals are already stressing the importance of preventing childhood obesity, this finding certainly adds to the urgency.

Source: AFTAU

"Be Brave" - A Gynecologic Cancer Survivor's Story

This public service announcement from CDC's Inside Knowledge: Get the Facts About Gynecologic Cancer campaign, features gynecologic cancer survivor Jenny Allen. A mother, writer, and performer, she tells her story about noticing symptoms, being diagnosed with uterine and ovarian cancers, and getting treatment. She urges women to pay attention to their bodies and see a doctor if they have symptoms that last two weeks or longer.

Published by CDCStreamingHealth

NIH tools facilitate matching cancer drugs with gene targets

 

A new study details how a suite of web-based tools provides the research community with greatly improved capacity to compare data derived from large collections of genomic information against thousands of drugs. By comparing drugs and genetic targets, researchers can more easily identify pharmaceuticals that could be effective against different forms of cancer.

The newly updated software, called CellMiner, was built for use with the NCI-60, one of the most widely utilized collections of cancer cell samples employed in the testing of potential anti-cancer drugs. The tools, available free, provide rapid access to data from 22,379 genes catalogued in the NCI-60 and from 20,503 previously analyzed chemical compounds, including 102 U.S. Food and Drug Administration-approved drugs.

Cell plate with cell lines from the NCI-60.

The study, written by the scientists that developed the tools at the National Cancer Institute (NCI), part of the National Institutes of Health, appeared in the July 16, 2012, issue of Cancer Research.

"Previously you would have to hire a bioinformatics team to sort through all of the data, but these tools put the entire database at the fingertips of any researcher," explained Yves Pommier, M.D., Ph.D., of the NCI'sCenter for Cancer Research. "These tools allow researchers to analyze drug responses as well as make comparisons from drug to drug and gene to gene."

Genomic sequencing and analysis have become increasingly important in biomedicine, but they are yielding data sets so vast that researchers may find it difficult to access and compare them. As new technologies emerge and more data are generated, tools to facilitate the comparative study of genes and potentially promising drugs will be of even greater importance. With the new tools, available at http://discover.nci.nih.gov/cellminer, researchers can compare patterns of drug activity and gene expression, not only to each other but also to other patterns of interest. CellMiner allows the input of large quantities of genomic and drug data, calculates correlations between genes and drug activity profiles, and identifies correlations that are statistically significant. Its data integration capacities are easier, faster, and more flexible than other available methods, and these tools can be adapted for use with other collections of data.

Screen shot from the CellMiner software.

Researchers looking at a particular drug can use the tools to access data from previous experiments done on that drug and analyze how the drug relates to other drugs and various gene profiles. As a case example for this study, the researchers compared drug activity levels and gene expression patterns from previous research to identify an investigational compound, called NSC732298, which is not currently being studied for colon cancer, but could be a potential therapy for the disease based on a CellMiner gene-drug match. In the same exercise, the researchers were able to identify that a second investigational drug that is being tested for colon cancer, called selumetinib, might also be effective against melanoma.

"We're looking forward to seeing how other people are going to use this tool to look at gene co-regulation, regulation of gene expression, and the relationship between gene expression and cancer," said Pommier.

This work was supported by NCI’s Center for Cancer Research and Division of Cancer Treatment and Diagnosis under intramural project number ZIA BC 006150.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Source: NIH

Coffee Consumption Inversely Associated With Risk of Most Common Form of Skin Cancer

Increasing the number of cups of caffeinated coffee you drink could lower your risk of developing the most common form of skin cancer, basal cell carcinoma, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.
“Our data indicate that the more caffeinated coffee you consume, the lower your risk of developing basal cell carcinoma,” said Jiali Han, Ph.D., associate professor at Brigham and Women’s Hospital, Harvard Medical School in Boston and Harvard School of Public Health.
“I would not recommend increasing your coffee intake based on these data alone,” said Han. “However, our results add basal cell carcinoma to a list of conditions for which risk is decreased with increasing coffee consumption. This list includes conditions with serious negative health consequences such as type 2 diabetes and Parkinson’s disease.”     
Basal cell carcinoma is the form of skin cancer most commonly diagnosed in the United States. Even though it is slow-growing, it causes considerable morbidity and places a burden on health care systems.
“Given the large number of newly diagnosed cases, daily dietary changes having any protective effect may have an impact on public health,” said Han.
Han and his colleagues generated their results by conducting a prospective analysis of data from the Nurses’ Health Study, a large and long-running study to aid in the investigation of factors influencing women’s health, and the Health Professionals Follow-up Study, an analogous study for men.
Of the 112,897 participants included in the analyses, 22,786 developed basal cell carcinoma during the more than 20 years of follow-up in the two studies. An inverse association was observed between all coffee consumption and risk of basal cell carcinoma. Similarly, an inverse association was seen between intake of caffeine from all dietary sources (coffee, tea, cola and chocolate) and risk of basal cell carcinoma. However, consumption of decaffeinated coffee was not associated with a decreased risk of basal cell carcinoma. 
“These results really suggest that it is the caffeine in coffee that is responsible for the decreased risk of basal cell carcinoma associated with increasing coffee consumption,” said Han. “This would be consistent with published mouse data, which indicate caffeine can block skin tumor formation. However, more studies in different population cohorts and additional mechanistic studies will be needed before we can say this definitively.”
In contrast to the findings for basal cell carcinoma, neither coffee consumption nor caffeine intake were inversely associated with the two other forms of skin cancer, squamous cell carcinoma and melanoma, the most deadly form of the disease.
Only 1,953 cases of squamous cell carcinoma and 741 cases of melanoma were recorded among the 112,897 participants included in Han’s analyses.
“It is possible that these numbers are insufficient for any association with coffee consumption to be seen,” said Han. “As the study participants are followed for a longer time, the number of cases of these conditions is likely to increase. We may be in a position in 10 years’ time to better address this issue.”    

Source: AACR

Coffee Consumption Inversely Associated With Risk of Most Common Form of Skin Cancer

Increasing the number of cups of caffeinated coffee you drink could lower your risk of developing the most common form of skin cancer, basal cell carcinoma, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.
“Our data indicate that the more caffeinated coffee you consume, the lower your risk of developing basal cell carcinoma,” said Jiali Han, Ph.D., associate professor at Brigham and Women’s Hospital, Harvard Medical School in Boston and Harvard School of Public Health.
“I would not recommend increasing your coffee intake based on these data alone,” said Han. “However, our results add basal cell carcinoma to a list of conditions for which risk is decreased with increasing coffee consumption. This list includes conditions with serious negative health consequences such as type 2 diabetes and Parkinson’s disease.”     
Basal cell carcinoma is the form of skin cancer most commonly diagnosed in the United States. Even though it is slow-growing, it causes considerable morbidity and places a burden on health care systems.
“Given the large number of newly diagnosed cases, daily dietary changes having any protective effect may have an impact on public health,” said Han.
Han and his colleagues generated their results by conducting a prospective analysis of data from the Nurses’ Health Study, a large and long-running study to aid in the investigation of factors influencing women’s health, and the Health Professionals Follow-up Study, an analogous study for men.
Of the 112,897 participants included in the analyses, 22,786 developed basal cell carcinoma during the more than 20 years of follow-up in the two studies. An inverse association was observed between all coffee consumption and risk of basal cell carcinoma. Similarly, an inverse association was seen between intake of caffeine from all dietary sources (coffee, tea, cola and chocolate) and risk of basal cell carcinoma. However, consumption of decaffeinated coffee was not associated with a decreased risk of basal cell carcinoma. 
“These results really suggest that it is the caffeine in coffee that is responsible for the decreased risk of basal cell carcinoma associated with increasing coffee consumption,” said Han. “This would be consistent with published mouse data, which indicate caffeine can block skin tumor formation. However, more studies in different population cohorts and additional mechanistic studies will be needed before we can say this definitively.”
In contrast to the findings for basal cell carcinoma, neither coffee consumption nor caffeine intake were inversely associated with the two other forms of skin cancer, squamous cell carcinoma and melanoma, the most deadly form of the disease.
Only 1,953 cases of squamous cell carcinoma and 741 cases of melanoma were recorded among the 112,897 participants included in Han’s analyses.
“It is possible that these numbers are insufficient for any association with coffee consumption to be seen,” said Han. “As the study participants are followed for a longer time, the number of cases of these conditions is likely to increase. We may be in a position in 10 years’ time to better address this issue.”    

Source: AACR

Novel Chemotherapy Agent Appears to be a Promising Pancreatic Cancer Treatment

A novel chemotherapeutic agent, the highly selective MEK1/2 inhibitor BAY 86-9766, may be a promising future treatment for pancreatic ductal adenocarcinoma (PDAC), according to preclinical results presented at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference, held here June 18-21.

“We showed in our endogenous mouse model that our novel chemotherapeutic agent leads to dramatic tumor shrinkage after only one week of treatment,” said Nicole Teichmann, Ph.D., of the Klinikum rechts der Isar at the Technische Universität München in Munich, Germany. “Moreover, the therapy was as effective in animals with advanced tumors and ascites, which is often the case if patients come to the clinic.”

In this preclinical therapeutic study, BAY 86-9766 was evaluated in one of the most aggressive mouse models for PDAC, according to Teichmann. The researchers induced endogenous genetic alterations in these mice, and within eight weeks, the mice developed invasive, lethal PDAC. These genetic alterations closely mimic what is found in most human cases of the disease, she said.

“The mutations trigger the onset of a signaling cascade that is necessary for the survival and proliferation of the cancer cells,” Teichmann said. “Our novel chemotherapeutic drug inhibits one essential protein of this cascade and therefore leads to the cascade’s shutdown.”

A daily treatment of 25 mg/kg with BAY 86-9766 prolonged the survival of the mice in the study compared to their ‘placebo’-treated counterparts; median survival advantage was 20 days. The treatment caused dramatic tumor regression after only one week and was effective in animals with advanced tumors and ascites, which is often how patients present to the clinic.

“We were really surprised that the tumor load dramatically decreases after one week of therapy and also that the treatment conferred such a strong overall survival benefit,” Teichmann said. “Previous studies with gemcitabine, the standard-of-care agent for PDAC since 1997, or other novel inhibitors tested in our lab with the same mouse model showed no or only very modest effects. In our hands, this is the first targeted drug to have shown such strong tumor effects in an endogenous mouse model of PDAC.”

In most animals, the tumor relapsed after three weeks of treatment, which modeled the situation in humans. “Often patients respond to a therapy and after a while, the tumor relapses,” she added. “We can exploit this same tumor relapse in the mouse to investigate the resistance mechanism to improve the therapeutic strategy.”

These findings encourage testing in mouse models rather than xenograft models. “Our results support testing novel agents for pancreatic cancer in endogenous mouse models, rather than conventional xenograft models because they take into account the genetic and morphological heterogeneity of the disease and may be more predictive with regard to efficacy,” Teichmann said.

Source: AACR

Abnormal Gene Product Associated With Prostate Cancer Generated by Unusual Mechanism

Researchers have identified a potential new pathway in prostate cancer cells by which cancer-driving gene products can be generated, according to a study published inCancer Discovery, a journal of the American Association for Cancer Research.

“Our work shows that cancers have many more tricks than we thought to generate potential cancer-driving genes or gene products,” said Hui Li, Ph.D., assistant professor of pathology at the University of Virginia in Charlottesville, and a recipient of an Innovative Research Grant from Stand Up To Cancer (SU2C). The AACR is the scientific partner of SU2C.

Gene fusion is a common characteristic of human cancers. In many cases, the protein products of these gene fusions, which are generated via an RNA intermediate, have a key role in the genesis of the cancer. A well-characterized example of this is the protein that drives chronic myeloid leukemia, BCR-ABL, which is generated via RNA intermediates from a fusion gene formed by chromosomal translocation — an event involving exchange of genomic DNA between two distinct chromosomes.   

“For many years, chromosomal translocation was considered the sole way in which single RNAs consisting of copies of parts of two genes, so-called fusion RNAs, could be generated,” said Li. “We have shown that fusion RNAs can be generated without changes to DNA by a new mechanism that we are calling cis-SAGe [cis-splicing of adjacent genes].” Recently, a fusion RNA formed from parts of the SLC45A3 and ELK4 genes was identified in prostate cancer cells in the absence of any DNA alterations. Li and his colleagues confirmed in two prostate cancer cells lines that the SLC45A3-ELK4 fusion RNA could be detected even though there was no evidence of genomic DNA rearrangement.

Detailed molecular analysis of the prostate cancer cell lines indicated that the SLC45A3-ELK4 fusion RNA was generated by cis-SAGe. SLC45A3 and ELK4 are neighboring genes, and cis-SAGe occurred when an RNA that crossed the boundary between the two genes was formed.

The protein CCCTC-binding factor normally acts to insulate SLC45A3 and ELK4 from each other. Li and his colleagues found that levels of this protein at the gene boundary inversely correlated with the amount of SLC45A3-ELK4 fusion RNA generated, providing molecular insight into how the quantity of this fusion RNA could be regulated.

A functional role for the SLC45A3-ELK4 fusion RNA in prostate cancer was suggested by two observations. First, it promoted the growth of the two prostate cancer cell lines in culture. Second, its levels in human prostate samples correlated with prostate cancer disease progression — normal prostate tissue expressed the lowest levels and prostate cancer specimens from men with metastatic disease expressed the highest levels.       

“These data are not sufficient to say that the SLC45A3-ELK4 fusion RNA has a causal role in prostate cancer,” said Li. “But they are highly suggestive, and I am very excited that this high-risk project, which I would not have been able to pursue without the grant from Stand Up To Cancer, has uncovered what seems to be a new way in which cancer can be driven.”   

Source: www.AACR.org.

Chemotherapy

More information on chemotherapy at http://www.cancerquest.org/chemotherapy-introduction.
Introduces chemotherapy and explains the purpose of chemotherapy. Explains how chemotherapy is administered to patients and the type of side effects that the chemotherapy can bring about.
For more information, visit CancerQuest at http://www.CancerQuest.org/.

Published by: CancerQuest

Arsenic turns stem cells cancerous, spurring tumor growth

 

Researchers at the National Institutes of Health have discovered how exposure to arsenic can turn normal stem cells into cancer stem cells and spur tumor growth. Inorganic arsenic, which affects the drinking water of millions of people worldwide, has been previously shown to be a human carcinogen. A growing body of evidence suggests that cancer is a stem-cell based disease. Normal stem cells are essential to normal tissue regeneration, and to the stability of organisms and processes. But cancer stem cells are thought to be the driving force for the formation, growth, and spread of tumors.

Michael Waalkes, Ph.D., and his team at the National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, part of NIH, had shown previously that normal cells become cancerous when they are treated with inorganic arsenic. This new study shows that when these cancer cells are placed near, but not in contact with normal stem cells, the normal stem cells very rapidly acquire the characteristics of cancer stem cells. It demonstrates that malignant cells are able to send molecular signals through a semi-permeable membrane, where cells can't normally pass, and turn the normal stem cells into cancer stem cells.

“This paper shows a different and unique way that cancers can expand by recruiting nearby normal stem cells and creating an overabundance of cancer stem cells,” said Waalkes. “The recruitment of normal stem cells into cancer stem cells could have broad implications for the carcinogenic process in general, including tumor growth and metastases.”

This reveals a potentially important aspect of arsenic carcinogenesis and may help explain observances by researchers working with arsenic that arsenic often causes multiple tumors of many types to form on the skin or inside the body. The paper is online in Environmental Health Perspectives.

Waalkes' lab started working with stem cells about five years ago. The researchers used a prostate stem cell line, not embryonic stem cells.

“Using stem cells to answer questions about disease is an important new growing area of research. Stem cells help to explain a lot about carcinogenesis, and it is highly likely that stem cells are contributing factors to other chronic diseases,” Waalkes said.

Stem cells are unique in the body. They stay around for a long time and are capable of dividing and renewing themselves. “Most cancers take 30 or 40 years to develop,” said Linda Birnbaum, Ph.D., director of NIEHS and NTP. “It makes sense that stem cells may play a role in the developmental basis of adult disease. We know that exposures to toxicants during development and growth can lead to diseases later in life.”

Next, the laboratory team will look to see if this finding is unique to arsenic or if it is applicable to other organic and inorganic carcinogens.

The NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

Source:NIH

NIH scientists find a potential new avenue for cancer therapies

Recent findings in mice suggest that blocking the production of small molecules produced in the body, known as epoxyeicosatrienoic acids (EETs), may represent a novel strategy for treating cancer by eliminating the blood vessels that feed cancer tumors. This research is the first to show that EETs work in concert with vascular endothelial growth factor (VEGF), a protein known to induce blood vessel growth. Together, EETs and VEGF promote metastasis, or the spread of cancer, by encouraging the growth of blood vessels that supply nutrients to cancer cells.

The research team comprised of scientists from the National Institute of Environmental Health Sciences (NIEHS), which is part of the National Institutes of Health, and several other institutions, published its data online in the Dec. 19 issue of The Journal of Clinical Investigation.

Preclinical research suggests that patients with a variety of vascular conditions, such as diabetes, hypertension, inflammation, stroke, and heart attack may benefit by increasing their EET levels, because the compounds cause blood vessels to dilate and reduce tissue inflammation and cell death. However, previous work has also demonstrated that EETs make tumor cells grow faster and cause them to migrate and become metastatic. Darryl Zeldin, M.D., NIEHS scientific director and author on the paper, said he believed that human metabolism has to achieve a certain harmony in regard to EETs.

"The body has to produce enough EETs to maintain a healthy cardiovascular system without promoting cancer. It has to balance the double-edged sword just right," Zeldin said.

To find out how EETs encourage the development of cancer, the team created two mice strains, one with high levels of EETs and one with low levels of EETs.

"The mice with higher EETs developed more metastatic tumors compared to the mice with lower EETs," Zeldin said. "Often, the tumor itself will produce more EETs, which can speed up tumor growth and its subsequent spread, but our analysis demonstrated that the EETs produced by the surrounding tissues encouraged tumor growth and migration."

Matthew Edin, Ph.D., a research fellow in Zeldin’s group, is one of the authors on the paper and helped develop the mice strains. He said EETs directly lead to the creation of new blood vessels, also known as angiogenesis, which the cancer cells need in order to receive oxygen and nutrients to grow. He equated the process to what happens when a builder begins constructing a new housing development.

"One of the first things construction crews have to do is build the roads, so that materials and workers can be transported to the site," Edin said. "In cancer, EETs accelerate the road building, allowing the housing development to expand quickly."

According to Dipak Panigrahy, M.D., an author on the paper and a research associate at the Dana-Farber/Children’s Hospital Cancer Center, Boston, EETs have a potent stimulatory effect promoting cancer growth and metastasis, a process that could be effectively inhibited using novel antagonists, such as EEZE, which are compounds that interfere with this pathway in mice. EEZE has not been approved for human use, and is only used for research.

"EEZE is structurally similar to EETs, but it blocks the effect of EETs and dramatically slows tumorigenesis," Panigrahy explained.

Mark Kieran, M.D., Ph.D., another author of this collaborative study and also from Dana-Farber, commented on the importance of the research.

"The identification of an old pathway studied for many years in cardiovascular disease has found a new role in regulating cancer growth and metastasis, the primary causes of cancer related deaths," he said. "With these findings, opportunities to better understand the underlying mechanisms that drive cancer, and thus the development of effective therapies for their treatment, moves one step closer to a reality."

Ovarian Cancer Treatment: Where We Are Now

 

 

AUGUST 2, 2011, 3:46PM

By Aleea Farrakh Khan

Ovarian cancer has proven to be a very difficult cancer to diagnose at a curable stage and thus treat successfully.  Even though it has one of the highest mortality rates of all gynecological cancers in the United States, there are no validated or proven screening tests, making it a challenge to diagnose at an early stage. To date, there is no evidence that any of the various screening tests that are performed, including pelvic examinations,                                                                                                                transvaginal ultrasounds and a CA-125 assay (a test that measures the level of CA-125 in the blood to see if it is elevated), leads to a decrease in ovarian cancer deaths.  These tests have not been shown to diagnose ovarian cancer early, and the risk of falsely calling a benign mass a cancer when it is not present is unacceptably high.  This can lead to unnecessary surgery, treatments, and stress for patients.

Ovarian cancer symptoms are  fairly non-specific, therefore only about 19 percent of all cases are detected at an early, localized stage. In the U.S. alone, an estimated 22,000 women will be diagnosed with, and 15,000 women will die from this disease in 2011.  Even with all these challenges, researchers have made important clinical advances over the years in chemotherapy regimens, surgery techniques and biologic therapies to find better treatment options for ovarian cancer patients.

Three-panel drawing of stage IA, IB, and IC ovarian cancer. Credit: Terese Winslow

The image above depicts stage IA, IB, and IC ovarian cancer. The first panel shows a stage IA tumor inside one ovary. The second panel shows two stage IB tumors, one inside each ovary. The third panel shows two stage IC tumors, one inside each ovary, and one tumor has a ruptured capsule. An inset shows cancer cells floating in the peritoneal fluid surrounding abdominal organs.

The primary surgical objective in ovarian cancer treatment is removal of the tumor. It has been shown consistently that the more complete the resection, or removal of the tumor, the better the clinical outcome since the current surgical aim is removal of disease to the point that there is no visible disease present.  However, not every woman can undergo such surgery.  This fact led to a trial, recently reported by the European Organization for Research and Treatment of Cancer–Gynecologic Cancer Group (EORTC–GCG) and the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) examining the question of whether surgery should precede chemotherapy or if chemotherapy should come first, a method called neoadjuvant chemotherapy.  Results demonstrated that there was no difference between the approaches and that neoadjuvant chemotherapy could be considered, given the similar survival outcomes and the increased side-effects of primary surgery.  Newer GOG trials will allow physicians and their patients to elect neoadjuvant therapy or traditional chemotherapy after primary surgical debulking, or removal of the malignancies.

Cisplatin crystals, a platinum compound used as a chemotherapy drug.

In 1978, the U.S. FDA approved cisplatin, a chemotherapy drug containing platinum, for treatment of metastatic ovarian cancer.  Shortly after that approval, the delivery of anticancer drugs intraperitoneally (IP) was established—a technique where chemotherapy drugs are administered through a surgically implanted catheter, allowing passage of fluids into the abdominal cavity. This method allows direct administration of drugs to the intra-abdominal cancer, creating higher local drug exposure.  Some of the drugs used intraperitoneally, such as cisplatin and its close relative carboplatin, are also absorbed into the general circulation and assist with attacking ovarian cancer that has spread to other parts of the body.

The next significant pharmaceutical advancement was the approval of paclitaxel in the mid-90’s; the first of a class of drugs known as taxanes. Paclitaxel interferes with cell growth and division in rapidly dividing cells, such as cancer cells.  Unlike the platinums, the taxanes do not get absorbed when administered into the abdominal cavity and thus provide high local drug exposure.

Researchers studied both cisplatin and paclitaxel extensively and found that chemotherapy regimens that contain both types of drugs are most effective in preventing recurrence of ovarian cancer and improving a woman’s survival period. The combination of cisplatin and paclitaxel has become the standard recommended therapy for treatment for women with ovarian cancer who may benefit from chemotherapy.  Further improving this method in 2006, a study by the Gynecologic Oncology Group (GOG) showed that women with advanced ovarian cancer who receive a combination of intravenous (IV) and IP chemotherapy post-surgery extended their overall survival by about a year.  The combined method of delivering drugs into the vein and directly into the abdomen simultaneously allows for improved progression-free survival.  It is possible that this was due to the intra-abdominal administration of the drugs; however, more total chemotherapy was administered on the combination IV and IP therapy arm, suggesting that quantity of drug, known as dose density, may be the factor.

Biologic therapy is another area of interest that is being explored for ovarian cancer treatments. Researchers continue to study the benefits of targeted agents in the form ofmonoclonal antibodies and small molecules to treat a number of other cancers, including ovarian cancer. Anti-angiogenic agents, a form of targeted therapy that uses small molecule drugs or antibodies to stop tumors from making new blood vessels, have also shown promise in clinical settings. Trials are currently underway to investigate whether the addition of bevacizumab, a type of anti-angiogenic drug, to first-line treatment will improve clinical outcomes. In 2010, a study by the Gynecologic Oncology Group (GOG) found that women who received bevacizumab (Avastin) during their initial chemotherapy for ovarian cancer and continued up to 16 months after completion of initial chemotherapy had a reduced risk of progression of 28 percent compared to those who received chemotherapy alone.  The benefit was short-lived leaving the community in a quandary regarding application of this therapy as a new standard of care.  A newer study, reported this spring, the OCEANS trial, added bevacizumab to carboplatin and gemcitabine for women with first recurrence of ovarian cancer.  There was a greater reduction in risk of progression in this study and an improvement in overall survival.  How these studies will change practice patterns for the future is not yet known.

One of the most exciting recent advances in ovarian cancer has been the discovery and use of a new class of targeted agents, the PARP inhibitors.  Olaparib, one type of PARP inhibitor, blocks the activity of PARP1 and PARP2 proteins that are necessary for cells to repair damaged DNA.  This agent was found to be clinically active in breast and ovarian cancer patients who carry germ line mutations in the BRCA1 or 2 genes, and olaparib has also been active in high grade serous ovarian cancer, a type of epithelial ovarian cancer. Researchers hope that combining a PARP inhibitor, like olaparib, with traditional chemotherapy drugs, such as the platinums, will produce greater anticancer effects than either chemotherapy or a PARP inhibitor alone.  This approach is based on the observation that cells are unable to survive if they accumulate high levels of DNA damage. Additional PARP-inhibitors are now under development and their roles are being investigated in women who are both BRCA1 and 2 mutation carriers and other women with ovarian cancer.

Acknowledging the poor prognosis of ovarian cancer, The Cancer Genome Atlas (TCGA) sponsored by the NCI, selected serous ovarian cancer, the most prevalent form of the disease, as one of the first to have its genomic changes charted in depth.  The goal of the TCGA profiling was to look for gene expression patterns that are linked to differences in patient survival and to establish whether certain gene changes can be linked to response to therapy.  To date, TCGA has achieved comprehensive sequencing, characterization, and analysis of the genomic changes in ovarian cancer.  Their initial findings, just reported in the journal Nature, were of interest to many investigators.  It showed that there are no frequent driving genetic mutations in ovarian cancer as has been shown in many other solid tumors.  Serous ovarian cancer distinguished itself by its genetic complexity and variability.  Investigators are now combing this remarkable data collection to identify leads for typing ovarian cancer in ways that will focus therapy for greater clinical benefit, survival advantages, and to reduce toxicity and patient injury.