A Way to Kill Chemo-Resistant Ovarian Cancer Cells: Cut Down Their Protector

A recent study provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

Protein Data Base 3-D rendering of the Gelsolin protein. (Photo: Wikipedia)

Protein Data Base 3-D rendering of the gelsolin protein. (Photo: Wikipedia)

Ovarian cancer is the most lethal gynecological cancer, claiming the lives of more than 60% of women who are diagnosed with the disease. A study involving Ottawa and Taiwan researchers, published in the influential Proceedings of the National Academy of Sciences (PNAS), provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

It is estimated that 2,700 Canadian women will be diagnosed with ovarian cancer in 2014 and that 1,750 Canadian women will die from the disease, according to Ovarian Cancer Canada. This cancer is often diagnosed late and develops a resistance to chemotherapy.

tsang_ben

Dr. Ben Tsang

“What we’ve discovered will help clinicians to better treat women with ovarian cancer,” says Dr. Ben Tsang, senior scientist at the Ottawa Hospital Research Institute and professor at the University of Ottawa. “The key is understanding the role of a protein called “gelsolin.” With our colleagues from National Cheng Kung University in Taiwan, we found that an increased level of this protein is associated with aggressive forms of ovarian cancer that are more likely to be resistant to chemotherapy and lead to death.”

The researchers showed how gelsolin works at the molecular level to protect cancer cells against a widely used chemotherapy drug called “cisplatin.”

The findings are important because they will help clinicians to determine the most effective treatment plan based on the level of gelsolin. Work still needs to be done to determine exactly how much gelsolin indicates a cancer that is chemo-resistant and would require different treatment options.

In addition, this same protein that makes ovarian cancer cells resistant to chemotherapy can be used to overcome this treatment obstacle. By cutting gelsolin down to a specific fragment and putting it into chemo-resistant cancer cells, the international team discovered they could make these cells susceptible to the cancer-killing effects of cisplatin.

Shieh

Dr. Dar-Bin Shieh

“We believe this discovery is a promising avenue for developing a new therapy to reduce chemo-resistance in women with this deadly disease,” said Dr. Dar-Bin Shieh, collaborative partner from National Cheng Kung University of Taiwan. Shieh is currently leading the International Institute of Macromolecular Analysis and Nanomedicine Innovation (IMANI), which is focused on translating molecular discoveries to the clinic.

Based on 2009 estimates, approximately one in 72 Canadian women will develop ovarian cancer in her lifetime and one in 93 will die from it.

This study was supported by the Canadian Institutes of Health Research and the National Science Council of Taiwan.

Ottawa Hospital Research Institute
The Ottawa Hospital Research Institute is the research arm of The Ottawa Hospital and is an affiliated institute of the University of Ottawa, closely associated with its faculties of Medicine and Health Sciences. The Ottawa Hospital Research Institute includes more than 1,700 scientists, clinical investigators, graduate students, postdoctoral fellows and staff conducting research to improve the understanding, prevention, diagnosis and treatment of human disease. Research at Ottawa Hospital Research Institute is supported by The Ottawa Hospital Foundation.

University of Ottawa: A crossroads of cultures and ideas
The University of Ottawa is home to almost 50,000 students, faculty and staff, who live, work and study in both French and English. The campus is a crossroads of cultures and disciplines, where bold minds come together to inspire game-changing ideas. The University of Ottawa is one of Canada’s top 10 research universities — our professors and researchers explore new approaches to today’s challenges. One of a handful of Canadian universities ranked among the top 200 in the world, we attract exceptional thinkers and welcome diverse perspectives from across the globe.

National Cheng Kung University
National Cheng Kung University (NCKU) is a research-led comprehensive university in Tainan City, Taiwan. Since its establishment in 1931, NCKU has nurtured countless social elites and leaders under the trailblazing efforts of its former faculties and staffs. NCKU is one of the most prestigious universities in Taiwan, with a high reputation in science, engineering, medicine, management, planning and design. The university is a role model for the transformation of Taiwan’s higher-educational institutes, and is also an important pillar of the country’s economic and industrial structure.

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Stanford Researchers Create “Evolved” Protein That May Stop Breast & Ovarian Cancers From Spreading

 Early but promising tests in lab mice suggest that a bioengineered protein therapy, administered intravenously, may halt the spread of breast and ovarian cancers from their original tumor sites. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein. This approach might one day provide an alternative to, or supplement, chemotherapy.

A team of Stanford researchers has developed a protein therapy that disrupts the process that causes cancer cells to break away from the original tumor site, travel through the bloodstream and start aggressive new growths elsewhere in the body.

stanford metastasis_news

Drs. Jennifer Cochran and Amato Giaccia led a team of researchers who have developed an experimental therapy to treat metastatic cancer. (Photo: Rod Searcey)

This process, known as “metastasis,” can cause cancer to spread with deadly effect.

“The majority of patients who succumb to cancer fall prey to metastatic forms of the disease,” said Dr. Jennifer Cochran, an associate professor of bioengineering, who describes a new therapeutic approach in Nature Chemical Biology.

Today, doctors try to slow or stop metastasis with chemotherapy, but these treatments are unfortunately not very effective and have severe side effects.

The Stanford team seeks to stop metastasis, without side effects, by preventing two proteins – Axl and Gas6 – from interacting to initiate the spread of cancer.

Axl proteins stand like bristles on the surface of cancer cells, poised to receive biochemical signals from Gas6 proteins.

When two Gas6 proteins link with two Axls, the signals that are generated enable cancer cells to leave the original tumor site, migrate to other parts of the body, and form new cancer nodules.

To stop this process Cochran used protein engineering to create a harmless version of Axl that acts like a decoy. This decoy Axl latches on to Gas6 proteins in the bloodstream and prevents them from linking with and activating the Axls present on cancer cells.

In collaboration with Dr. Amato Giaccia, who leads the Radiation & Cancer Biology Program in the Stanford Cancer Center, the researchers gave intravenous treatments of this bioengineered decoy protein to mice with aggressive breast and ovarian cancers.

The mice in the breast cancer treatment group had 78 percent fewer metastatic nodules than the untreated mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein.

“This is a very promising therapy that appears to be effective and nontoxic in preclinical experiments,” Giaccia said. “It could open up a new approach to cancer treatment.”

Drs. Giaccia and Cochran are scientific advisors to Ruga Corporation, a biotechnology startup located in Palo Alto that has licensed this technology from Stanford. Further preclinical and animal tests must be done before determining whether this therapy is safe and effective in humans.

Professor, Molecular Neurobiology Laboratory,  Françoise Gilot-Salk Chair

Professor, Molecular Neurobiology Laboratory,
Françoise Gilot-Salk Chair, Salk Institute

Greg Lemke, of the Molecular Neurobiology Laboratory at the Salk Institute, called this “a prime example of what bioengineering can do” to open new therapeutic approaches to treat metastatic cancer.

“One of the remarkable things about this work is the binding affinity of the decoy protein,” said Lemke, a noted authority on Axl and Gas6 who was not part of the Stanford experiments.

“The decoy attaches to Gas6 up to a hundredfold more effectively than the natural Axl,” Lemke said. “It really sops up Gas6 and takes it out of action.”

Directed Evolution

The Stanford approach is grounded on the fact that all biological processes are driven by the interaction of proteins, the molecules that fit together in lock-and-key fashion to perform all the tasks required for living things to function.

In nature, proteins evolve over millions of years. But bioengineers have developed ways to accelerate the process of improving these tiny parts using technology called “directed evolution.” This particular application was the subject of the doctoral thesis of Mihalis Kariolis, a bioengineering graduate student in Cochran’s lab.

Using genetic manipulation, the Stanford team created millions of slightly different DNA sequences. Each DNA sequence coded for a different variant of Axl.

The researchers then used high-throughput screening to evaluate more than 10 million Axl variants. Their goal was to find the variant that bound most tightly to Gas6.

 (Video: Tim Saguinsin, Ricecooker Studios)

Kariolis made other tweaks to enable the bioengineered decoy to remain in the bloodstream longer and also to tighten its grip on Gas6, rendering the decoy interaction virtually irreversible.

Yu Rebecca Miao, a postdoctoral scholar in Giaccia’s lab, designed the testing in animals and worked with Kariolis to administer the decoy Axl to the lab mice. They also did comparison tests to show that sopping up Gas6 resulted in far fewer secondary cancer nodules.

Irimpan Mathews, a protein crystallography expert at SLAC National Accelerator Laboratory, joined the research effort to help the team better understand the binding mechanism between the Axl decoy and Gas6.

Protein crystallography captures the interaction of two proteins in a solid form, allowing researchers to take X-ray-like images of how the atoms in each protein bind together. These images showed molecular changes that allowed the bioengineered Axl decoy to bind Gas6 far more tightly than the natural Axl protein.

Next Steps

Years of work lie ahead to determine whether this protein therapy can be approved to treat cancer in humans. Bioprocess engineers must first scale up production of the Axl decoy to generate pure material for clinical tests. Clinical researchers must then perform additional animal tests in order to win approval for and to conduct human trials. These are expensive and time-consuming steps.

But these early, promising results suggest that the Stanford approach could become a nontoxic way to fight metastatic cancer.

Glenn Dranoff, M.D., a professor of medicine at Harvard Medical School and a leading researcher at the Dana-Farber Cancer Institute, reviewed an advance copy of the Stanford paper but was otherwise unconnected with the research. “It is a beautiful piece of biochemistry and has some nuances that make it particularly exciting,” Dranoff said, noting that tumors often have more than one way to ensure their survival and propagation.

Axl has two protein cousins, Mer and Tyro3, that can also promote metastasis. Mer and Tyro3 are also activated by Gas6.

“So one therapeutic decoy might potentially affect all three related proteins that are critical in cancer development and progression,” Dranoff said.

Erinn Rankin, a postdoctoral fellow in the Giaccia lab, carried out proof of principle experiments that paved the way for this study.

Other co-authors on the Nature Chemical Biology paper include Douglas Jones, a former doctoral student, and Shiven Kapur, a postdoctoral scholar, both of Cochran’s lab, who contributed to the protein engineering and structural characterization, respectively.

Cochran said Stanford’s support for interdisciplinary research made this work possible.

Stanford ChEM-H (Chemistry, Engineering & Medicine for Human Health) provided seed funds that allowed Cochran and Mathews to collaborate on protein structural studies.

The Stanford Wallace H. Coulter Translational Research Grant Program, which supports collaborations between engineers and medical researchers, supported the efforts of Cochran and Giaccia to apply cutting-edge bioengineering techniques to this critical medical need.

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

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

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

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

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

Richard G. Moore, M.D.

Richard G. Moore, M.D.

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

The study resulted in multiple findings:

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

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

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

About Women & Infants Hospital

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

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

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

Sources:

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

Related Posts:

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

Glutamine Ratio is Key Ovarian Cancer Indicator

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

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

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

Deepak Nagrath

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

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

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

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

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

Rice University Researchers

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

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

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

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

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

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

Lifeng

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

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

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

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

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

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

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

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

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

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Ovarian Cancer Cells Are More Aggressive On Soft Tissues

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

Model Release-YES

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

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

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

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

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

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

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

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

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

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

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

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

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

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

TGen-led Study Discovers Genetic Cause of a Rare Type of Ovarian Cancer

TGen-led study discovers genetic cause of a rare type of ovarian cancer. Scientific breakthrough could lead to new cancer treatments; study inspired by the memory of Taryn Ritchey, a 22-year-old patient who lost her battle to the disease.

The cause of a rare type of ovarian cancer that most often strikes girls and young women has been uncovered by an international research team led by the Translational Genomics Research Institute (TGen), according to a study published online recently by the renowned scientific journal, Nature Genetics. [1] In a scientific rarity, two additional studies with similar results were also published online on the same day in Nature Genetics, producing immediate validation and reflecting a scientific consensus that usually takes months or even years to accomplish. [2-3]

By applying its groundbreaking work in genomics, TGen led a study that included: Scottsdale Healthcare, Mayo Clinic, Johns Hopkins University, St. Joseph’s Hospital and Medical Center; Evergreen Hematology and Oncology, Children’s Hospital of Alabama, the Autonomous University of Barcelona, British Columbia Cancer Agency, University of British Columbia, and the University Health Network-Toronto.

The findings revealed a “genetic superhighway” mutation in a gene found in the overwhelming majority of patients with small cell carcinoma of the ovary, hypercalcemic type, also known as “SCCOHT.” This rare type of ovarian cancer is usually not diagnosed until it is in its advanced stages. It does not respond to standard chemotherapy, and 65 percent of patients with the disease die within 2 years. SCCOHT can affect girls as young as 14 months, and women as old as 58 years – with a mean age of only 24 years old. In this study, the youngest patient was 9 years old.

The three separate groups of international researchers reported strikingly similar scientific findings related to SCCOHT, as provided below.

  • Identification of germline (i.e., inherited) and somatic (lifetime acquired) inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases, in addition to SMARCA4 protein loss in 82% (14/17) of the SCCOHT tumors. Notably, only 0.4% (2/485) of the other primary ovarian tumors tested possessed similar genomic characteristics. [Ref. 1]
  • Identification of recurrent inactivating mutations in the SMARCA4 gene in 12 of 12 SCCOHT tumor samples. [Ref. 2]
  • Indentification of germline inactivating mutations in familial cases of SCCOHT. Through additional analysis of non-familial tumors, the researchers determined that nearly 100% of tumors carry SMARCA4 mutations, and 38 of 40 lack protein expression.[Ref. 3]

Collectively, these findings implicate inactivating mutations in the SMARCA4 gene as a major cause of SCCOHT, and may lead researchers to improvements in genetic counseling, as well as the development of new targeted therapy treatment approaches.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study's senior author.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study’s senior author.

“This is a thoroughly remarkable study. Many genetic anomalies can be like a one-lane road to cancer; difficult to negotiate. But these findings indicate a genetic superhighway that leads right to this highly aggressive disease,” said Dr. Jeffrey Trent, President and Research Director of TGen, and the study’s senior author. “The correlation between mutations in SMARCA4 and the development of SCCOHT is simply unmistakable.”

Dr. Trent added that while the breakthrough is for a relatively rare cancer, discovering the origins of this type of ovarian cancer could have implications for more common diseases.

Much of the work in this study was inspired by the memory of Taryn Ritchey, a 22-year-old TGen patient who in 2007 lost her battle with ovarian cancer, the 5th leading cause of cancer death among American women.

“Taryn would be incredibly excited about this amazing new study, and she would be glad and thankful that other young women like her might now be helped because of TGen’s ongoing research,” said Taryn’s mother Judy Jost of Cave Creek, Arizona. “My daughter never gave up, and neither has TGen.”

The SMARCA4 gene – previously associated with lung, brain and pancreatic cancer – was the only recurrently mutated gene in the study’s samples. The implications of this discovery, therefore, may be widespread.

“The findings in this study represent a landmark in the field. The work identifies SMARCA4 mutations as the culprit, and most future research on this disease will be based on this remarkable discovery,” said Dr. Bert Vogelstein, Director of the Ludwig Center at Johns Hopkins University, Investigator at the Howard Hughes Medical Institute, and pioneer in the field of cancer genomics. He did not participate in the study but is familiar with its findings.

“The past decade of research has taught us that cancer is a vastly complex disease. Profound patient-to-patient variability has made treatment and diagnosis for many tumor types at times very difficult. In this case, however, we have found a single genetic event driving SCCOHT in nearly every patient,” said Dr. William Hendricks, a TGen Staff Scientist and another author of the study.

“We have shown that loss of SMARCA4 protein expression is extremely specific to SCCOHT and can facilitate the diagnosis of SCCOHT,” said Dr. Anthony N. Karnezis, a fellow at the British Columbia Cancer Agency located in Vancouver, Canada, and one of the study’s authors.

Pilar Ramos, a TGen Research Associate, is the study's lead author.

Pilar Ramos, a TGen Research Associate, is the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“We set out to uncover any small sliver of hope for women afflicted with this rare cancer. What we found instead are the nearly universal underpinnings of SCCOHT,” said Pilar Ramos, a TGen Research Associate, and the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

The TGen-led study was supported by grants from: the Marsha Rivkin Center for Ovarian Cancer Research, the Anne Rita Monahan Foundation, the Ovarian Cancer Alliance of Arizona, the Small Cell Ovarian Cancer Foundation, and philanthropic support to the TGen Foundation. Further support was provided by the Terry Fox Research Initiative’s New Frontiers Program in Cancer, and the Canadian Institutes of Health Research.

For more information about TGen’s research into small cell carcinoma of the ovary (SCCO), or to participate in a future study, visit: www.tgen.org/scco.

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting cutting-edge genomic research to accelerate breakthroughs in healthcare. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

References:

1./ Ramos P, et al.  Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2928.

2./ Jelinic P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovaryNature Genetics (published online 23 March 2014) doi:10.1038/ng.2922.

3./ Witkowski L, et al.  Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.  Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2931

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Tel Aviv University Researchers Target Drug-Resistant Ovarian Tumors with Nanotechnology

Tel Aviv University researchers devise a fast and effective nanotechnology — called “gagomers” — to combat drug-resistant ovarian cancer.

Professor Dan Peer of Tel Aviv University’s Department of Cell Research and Immunology has proposed a new strategy to tackle drug-resistant ovarian cancer using a new nanoscale drug-delivery system designed to target specific cancer cells. The study was published in February in the journal ACS Nano.

Nanotechnology usually refers to an object that is 1-to–100 nanometers in size. A nanometer is a billionth of a meter. By comparison, the width of a strand of hair is approximately 100,000 times larger than a nanometer.

Prof. Peer and his team — Keren Cohen and Rafi Emmanuel from Peer’s Laboratory of Nanomedicine and Einat Kisin-Finfer and Doron Shabbat, from TAU’s Department of Chemistry — devised a cluster of nanoparticles called “gagomers,” which are made from fats and coated with a kind of polysugar. When filled with chemotherapy drugs (in this case doxorubicin), these clusters accumulate in tumors, producing dramatic therapeutic benefits.

The objective of Peer’s research is two-fold: to provide a specific target for anti-cancer drugs to increase their therapeutic benefits, and to reduce the toxic side effects of anti-cancer therapies.

Why Chemotherapy Fails

According to Prof. Peer, traditional courses of chemotherapy are not an effective line of attack. Chemotherapy’s failing lies in the inability of the medicine to be absorbed and maintained within the tumor cell long enough to destroy it. In most cases, the chemotherapy drug is almost immediately ejected by the cancer cell, severely damaging the healthy organs that surround it, leaving the tumor cell intact.

Gagomers (labeled in color) accumulating on ovarian cancer cells. (Credit: Image courtesy of American Friends of Tel Aviv University)

Gagomers (labeled in color) accumulating on ovarian cancer cells.
(Credit: Image courtesy of American Friends of Tel Aviv University)

But with this new nanotechnology therapy, Peer and his colleagues saw a 25-fold increase in tumor-accumulated medication and a dramatic dip in toxic accumulation in healthy organs. Tested on laboratory mice, the gagomer affects a change in drug-resistant ovarian cancer tumor cells. Receptors on tumor cells recognize the sugar that encases the gagomer, allowing the binding gagomer to slowly release tiny particles of chemotherapy into the cancerous cell. As more and more of the drug accumulates within the tumor cell, the cancer cells begin to die off within 24-48 hours. In this preclinical setting, the doxorubicin encased gagomers even outperformed pegylated liposomal doxorubicin (Doxil) — a standard of care drug used to treat recurrent ovarian cancer.

“Tumors become resistant very quickly. Following the first, second, and third courses of chemotherapy, the tumors start pumping drugs out of the cells as a survival mechanism,” said Prof. Peer. “Most patients with tumor cells beyond the ovaries relapse and ultimately die due to the development of drug resistance. We wanted to create a safe drug-delivery system, which wouldn’t harm the body’s immune system or organs.”

A Personal Perspective

Prof. Peer chose to tackle ovarian cancer in his research because his mother-in-law passed away at the age of 54 from the disease. “She received all the courses of chemotherapy and survived only a year and a half,” Peer said. “She died from the drug-resistant aggressive tumors.”

“At the end of the day, you want to do something natural, simple, and smart. We are committed to try to combine both laboratory and therapeutic arms to create a less toxic, focused drug that combats aggressive drug-resistant cancerous cells,” said Prof. Peer. “We hope the concept will be harnessed in the next few years in clinical trials on aggressive tumors,” said Prof. Peer.

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