Outside-the-Body Filtration Device May Reduce Ovarian Cancer Cells In Abdominal Fluid

A paper published in the January issue of the journal Nanomedicine could provide the foundation for a new ovarian cancer treatment option — one that would use an outside-the-body filtration device to remove a large portion of the free-floating cancer cells that often create secondary tumors.

Schematic shows how fluids containing ovarian cancer cells could be removed from the body, treated with magnetic nanoparticles to remove the cells, then returned to the body. (Courtesy of Ken Scarberry)

Magnetic nanoparticles suspended in a liquid are attracted to a magnet. The nanoparticles could be attached to cancer cells and then removed from the body with magnetic filtration. (Credit: Gary Meek)

A paper published in the January issue of the journal Nanomedicine could provide the foundation for a new ovarian cancer treatment option — one that would use an outside-the-body filtration device to remove a large portion of the free-floating cancer cells that often create secondary tumors.

Researchers at the Georgia Institute of Technology have formed a startup company and are working with a medical device firm to design a prototype treatment system that would use magnetic nanoparticles engineered to capture cancer cells. Added to fluids removed from a patient’s abdomen, the magnetic nanoparticles would latch onto the free-floating cancer cells, allowing both the nanoparticles and cancer cells to be removed by magnetic filters before the fluids are returned to the patient’s body.

In mice with free-floating ovarian cancer cells, a single treatment with an early prototype of the nanoparticle-magnetic filtration system captured enough of the cancer cells that the treated mice lived nearly a third longer than untreated ones. The researchers expect multiple treatments to extend the longevity benefit, though additional research will be needed to document that — and determine the best treatment options.

“Almost no one dies from primary ovarian cancer,” said Dr. John McDonald, a professor in Georgia Tech’s School of Biology and chief research scientist of Atlanta’s Ovarian Cancer Institute. “You can remove the primary cancer, but the problem is metastasis. A good deal of the metastasis in ovarian cancer comes from cancer cells sloughing off into the abdominal cavity and spreading the disease that way.”

The removal system being developed by McDonald and postdoctoral fellow Ken Scarberry — who is also CEO of startup company Sub-Micro — should slow tumor progression in humans. It may reduce the number of free-floating cancer cells enough that other treatments, and the body’s own immune system, could keep the disease under control.

Professor John McDonald (standing) and postdoctoral fellow Ken Scarberry examine statistical data from their study of a potential new treatment option for ovarian cancer. (Credit: Gary Meek)

“If you can reduce metastasis, you can improve the lifespan of the person with the disease and get a better chance of treating it effectively,” said McDonald. “One goal is to make cancer a chronic disease that can be effectively treated over an extended period of time. If we can’t cure it, perhaps we can help people to live with it.”

Earlier in vitro studies published by the authors of the Nanomedicine paper showed that the magnetic nanoparticles could selectively remove human ovarian cancer cells from ascites fluid, which builds up in the peritoneal cavities of ovarian cancer patients. The nanoparticles are engineered with ligands that allow them to selectively attach to cancer cells.

The researchers believe that treating fluid removed from the body avoids potential toxicity problems that could result from introducing the nanoparticles into the body, though further studies are needed to confirm that the treatment would have no adverse effects.

The recently reported study in Nanomedicine used three sets of female mice to study the benefit of the nanoparticle-magnetic filtration system. Each mouse was injected with approximately 500,000 murine ovarian cancer cells, which multiply rapidly — each cell doubling within approximately 15 hours.

In the experimental group, the researchers — who included research scientist Roman Mezencev — removed fluid from the abdomens of the mice immediately after injection of the cancer cells. They then added the magnetic nanoparticles to the fluid, allowed them to mix, then magnetically removed the nanoparticles along with the attached cancer cells before returning the fluid. The steps were repeated six times for each mouse.

One control group received no treatment at all, while a second control group underwent the same treatment as the experimental group — but without the magnetic nanoparticles. Mice in the two control groups survived a median of 37 days, while the treated mice lived 12 days longer — a 32 percent increase in longevity.

Though much more research must be done before the technique can be tested in humans, McDonald and Scarberry envision a system very similar to what kidney dialysis patients now use, but with a buffer solution circulated through the peritoneal cavity to pick up the cancer cells.

“What we are developing is akin to hemofiltration or peritoneal dialysis in which the patient could come into a clinic and be hooked up to the device a couple of times a week,” said Scarberry. “The treatment is not heavily invasive, so it could be repeated often.”

The new treatment could be used in conjunction with existing chemotherapy and radiation. Reducing the number of free-floating cancer cells could allow a reduction in chemotherapy, which often has debilitating side effects, Scarberry said. The new treatment system could be used to capture spilled cancer cells immediately after surgery on a primary tumor.

The researchers hope to have a prototype circulation and filtration device ready for testing within three years. After that will come studies into the best treatment regimen, examining such issues as the number of magnetic nanoparticles to use, the number of treatments and treatment spacing. If those are successful, the company will work with the FDA to design human clinical trials.

The researchers also studying how their magnetic nanoparticles could be engineered to capture ovarian cancer stem cells, which are not affected by existing chemotherapy. Removing those cells could help eliminate a potent source of new cancer cells.

The research has been supported by the Georgia Research Alliance (GRA), the Ovarian Cancer Institute, the Robinson Family Foundation and the Deborah Nash Harris Endowment. A member of Georgia Tech’s Advanced Technology Development Center (ATDC) startup accelerator program and a GRA VentureLab company, Sub-Micro has also raised private funding to support its prototype development.

Challenges ahead include ensuring that nanoparticles cannot bypass the filtration system to enter the body, and controlling the risk of infection caused by opening the peritoneal cavity.

Beyond cancer, the researchers believe their approach could be useful for treating other diseases in which a reduction in circulating cancer cells or virus particles could be useful. Using magnetic nanoparticles engineered to capture HIV could help reduce viral content in the bloodstream, for instance.

“A technology like this has many different possibilities,” said Scarberry. “We are currently developing the technology to control the metastatic spread of ovarian cancer, but once we have a device that can efficiently and effectively isolate cancer cells from circulating fluids, including blood, we would have other opportunities.”

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Outside-the-Box: The Rogosin Institute Is Fighting Cancer With Cancer Cells In Clinical Trials

Researchers at the Rogosin Institute are using cancer “macrobeads” to fight cancer.  Cancer cells in the beads secrete proteins which researchers believe could signal a patient’s cancer to stop growing, shrink or even die. The treatment is currently being tested in human clinical trials.

Two groundbreaking preclinical studies demonstrate for the first time that encapsulated mouse kidney cancer cells inhibit the growth of freely-growing cancer cells of the same or different type in a laboratory dish and in tumor-bearing animals. These findings support the hypothesis that cancer cells entrapped in seaweed-based gel, called “macrobeads,” send biological feedback or signals to freely-growing tumors outside the macrobead to slow or stop their growth. Both studies (cited below) are published in the on-line January 24, 2011 issue of Cancer Research, a publication of the American Association For Cancer Research.

Barry H. Smith, M.D., Ph.D., Director, The Rogosin Institute; Professor, Clinical Surgery, Weill Cornell Medical College

The Rogosin Institute, an independent not-for-profit treatment and research center associated with New York-Presbyterian Hospital and Weill Cornell Medical College, developed the cell encapsulation technology that facilitated production of the macrobead and applied this technology in conducting preclinical studies. The research team was headed by Barry H. Smith, M.D., Ph.D.,  the Director of The Rogosin Institute, Professor of Clinical Surgery at the Weill Cornell Medical College, and lead author of the studies. Findings in the studies to date are consistent with the hypothesis that when macrobeads are implanted in a host, the encapsulated cells are isolated from the host’s immune system but continue to maintain their functionality.

In addition to the standard preclinical in vivo and in vitro experiments, a clinical veterinary study was conducted in cats and dogs suffering from various spontaneous (non-induced) cancers. More than 40 animals were treated with the macrobead technology. Consistent results, measured both in terms of tumor response and animal well-being, occurred with prostate, liver and breast cancer, as well as lymphoma. Additional research revealed that regardless of the animal specie or type of cancer cell that was encapsulated, the macrobead technology inhibited cancer growth across all species and cancer types tested.  The results have included slowed tumor growth or, in some cases, necrosis and elimination of tumors and the restoration of a normal animal lifespan.

Cancer macrobead therapy has proceeded to human clinical testing. A Phase 1 trial in more than 30 patients evaluated the safety of macrobeads implanted in the abdominal cavity as a biological treatment of end-stage, treatment-resistant, epithelial-derived cancer. Based on the safety profile data, Phase 2 efficacy trials are in progress in patients with colorectal cancer, pancreatic cancer and prostate cancer. The Phase 1 trial remains open to a range of epithelial-derived cancers, including ovarian.  To date, the Rogosin Institute research team has not found evidence to indicate that placing mouse tumors in humans or other animal species causes harm or side-effects.

Scientists are testing whether macrobeads containing cancer cells can be implanted into patients and communicate with the patient’s tumor to stop growing, shrink or die.

Step 1:  Small beads are made from a seaweed-derived sugar called agarose and mixed with 150,000 mouse kidney cancer cells, and a second layer of agarose is added, encapsulating the cancer cells.

Step 2:  Within 3-to-10 days, 99% of the kidney cancer cells die.  The remaining cells have traits similar to cancer stem cells.

Step 3:  The stem cells begin to recolonize the bead.  The colonies increase in sufficient numbers within a few weeks to reach a stable state.

Step 4:  The beads begin to release proteins —  chemical signals reflecting that the beads have sufficient numbers of cells for growth regulators to kick in.

Step 5: Several hundred beads (depending on patient’s weight) are implanted in the abdominal cavity in a laparoscopic surgical procedure.  The cancer cells are trapped in the beads; preventing their circulation elsewhere in the body and protecting them from attack by the body’s immune system.

Step 6: In animal studies, researchers believe some proteins released from the beads reached tumors elsewhere in the body and tricked them into sensing that other tumor cells are nearby.

Step 7:  As a result, researchers believe tumors in some animals stopped growing, shrank or died.  The hypothesis is being tested in people with cancer.

Howard Parnes, M.D., Chief, Prostate & Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute

“This is a completely novel way of thinking about cancer biology,” says Howard L. Parnes, a researcher in the Division of  Cancer Prevention at the National Cancer Institute who is familiar with the work but was not involved with it. “We talk about thinking outside the box. It’s hard to think of a better example.” “They demonstrate a remarkable proof of principle that tumor cells from one animal can be manipulated to produce factors that can inhibit the growth of cancers in other animals,” Dr. Parnes says. “This suggests that these cancer inhibitory factors have been conserved over millions of years of evolution.”

“Macrobead therapy holds promise as a new option in cancer treatment because it makes use of normal biological mechanisms and avoids the toxicities associated with traditional chemotherapy,” said Dr. Barry Smith. “The results of our research show that this approach is not specific to tumor type or species so that, for example, mouse cells can be used to treat several different human tumors and human cells can be used to treat several different animal tumors.”

“Because cancer and other diseases are their own biological systems, we believe that the future of effective disease treatment must likewise be biological and system-based,” said Stuart Subotnick, CEO of Metromedia Bio-Science LLC. “Many of the existing therapies are narrow, targeted approaches that fail to treat diseases comprehensively. In contrast, our unique macrobead technology delivers an integrated cell system that alters disease processes and utilizes the body’s natural defense mechanisms. The goal is to repair the body and not merely treat the symptoms.”

It is well-known that proof of anti-tumor activity in treating animals does not represent guaranteed effectiveness in humans. But, assuming the macrobead therapy proves ultimately effective in humans, it would represent a novel approach to treating cancer and challenge existing scientific dogmas.

The cancer macrobead therapy described above is backed by Metromedia Company, a privately held telecommunications company which was run by billionaire John Kluge until his recent death. The Metromedia Biosciences unit has invested $50 million into the research.  If the treatment proves successful in humans, a large part of the revenue generated will be contributed to Mr. Kluge’s charitable foundation.

About Metromedia Bio-Science LLC

Metromedia Bio-Science LLC, in conjunction with The Rogosin Institute, utilizes the novel cell encapsulation technology to conduct research into the treatment of various diseases, including cancer and diabetes, and the evaluation of disease therapies. Metromedia Bio-Science LLC is an affiliate of Metromedia Company, a diversified partnership founded by the late John W. Kluge and Stuart Subotnick.

About The Rogosin Institute

The Rogosin Institute is an independent not-for-profit treatment and research center associated with New York-Presbyterian Hospital (NYPH) and Weill Cornell Medical College. It is one of the nation’s leading research and treatment centers for kidney disease, providing services from early stage disease to those requiring dialysis and transplantation. It also has programs in diabetes, hypertension and lipid disorders. The Institute’s cancer research program, featuring the macrobeads, began in 1995. The Rogosin Institute is unique in its combination of the best in clinical care with research into new and better ways to prevent and treat disease.

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Disarming Specialized Stem Cells Might Combat Ovarian Cancer

Eliminating cancer stem cells (CSCs) within a tumor could hold the key to successful treatments for ovarian cancer, which has been notoriously difficult to detect and treat, according to new findings published this week in the journal Oncogene by Yale School of Medicine researchers.

Eliminating cancer stem cells (CSCs) within a tumor could hold the key to successful treatments for ovarian cancer, which has been notoriously difficult to detect and treat, according to new findings published this week in the journal Oncogene by Yale School of Medicine researchers.

“We found that stopping the expression of two genesLin28 and Oct4—reduces ovarian cancer cell growth and survival,” said Yingqun Huang, M.D., Ph.D., assistant professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Ovarian cancer is challenging to treat because it tends to recur frequently and develop resistance to treatment. The poor outcome for women with ovarian cancer is associated with subtle and nonspecific symptoms—earning it the moniker the “disease that whispers.”

“This recurrence and drug resistance may be due to the presence of CSCs within the tumors that have the capacity to reproduce and to differentiate into non-CSC tumor cells that repopulate the tumor mass,” said Huang, who is a member of Yale Stem Cell Center and Yale Cancer Center. “Eliminating these CSCs may be key to successful treatments.”

While in the process of studying the functions of stem cell proteins in human embryonic stem cells, Huang and her colleagues unexpectedly discovered that a sub-population of ovarian cancer cells express stem cell proteins Lin28 and Oct4. They also found that the two proteins appear to act together in ovarian cancer tissue cells to produce more advanced tumors. Inhibiting their combined expression led to a significant decrease in the growth and survival of cancer cells. A larger-scale ovarian cancer study is currently underway to confirm the significance of the findings.

Genetic researchers prevent genes from functioning — a process commonly referred to as “knocking down” the gene — by inserting small interfering RNA (siRNA) molecules into the cells. Next, the research team will examine the effect of siRNA in ovarian cancer cells in the lab, and test the technique on mice. If successful, human clinical trials would follow. Treatment on cancer patients could occur within 10 years, Huang said.

“We hope we will soon be able to apply this new information to improve outcomes, perhaps by developing better diagnostic markers and treatment strategies that may be useful in customizing treatment for ovarian cancer patients,” said Huang.

The study was supported by Connecticut Innovations, the Fannie E. Rippel Foundation and the National Cancer Institute.

Other Yale authors on the study included Nita Maihle, Ph.D., and Shuping Peng.

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