In the first phase of clinical testing of a new imaging device, researchers from Netherlands’ University of Twente and Medisch Spectrum Twente Hospital in Oldenzaal used photoacoustics — light-induced sound — rather than ionizing radiation to detect and visualize breast tumors. The team’s preliminary results, which were conducted on 12 patients with diagnosed malignancies and reported today in the Optical Society’s (OSA (http://www.osa.org)) open-access journal Optics Express(http://www.opticsinfobase.org/oe), provide proof-of-concept support that the technology can distinguish malignant tissue by providing high-contrast images of tumors.

“While we’re very early in the development of this new technology, it is promising. Our hope is that these early results will one day lead to the development of a safe, comfortable, and accurate alternative or adjunct to conventional techniques for detecting breast tumors,” explained researcher Michelle Heijblom, a Ph.D. student at the University of Twente.

Photoacoustics, a hybrid optical and acoustical imaging technique, builds on the established technology of using red and infrared light to image tissue and detect tumors. This technology, called optical mammography, reveals malignancies because blood hemoglobin readily absorbs the longer, redder wavelengths of light, which reveals a clear contrast between blood-vessel dense tumor areas and normal vessel environments. However, it is difficult to target the specific area to be imaged with this approach.

As a means of improving this, the researchers combined the light-based system’s ability to distinguish between benign and malignant tissue with ultrasound to achieve superior targeting ability. The result of their refinements is a specialized instrument, the Twente Photoacoustic Mammoscope (PAM), which was first tested in 2007.

The device is built into a hospital bed, where the patient lies prone and positions her breast for imaging. Laser light at a wavelength of 1,064 nanometers scans the breast. Because there is increased absorption of the light in malignant tissue the temperature slightly increases. With the rise in temperature, thermal expansion creates a pressure wave, which is detected by an ultrasound detector placed on one side of the breast. The resulting photoacoustic signals are then processed by the PAM system and reconstructed into images. These images reveal abnormal areas of high intensity (tumor tissue) as compared to areas of low intensity (benign tissue). This is one of the first times that the technique has been tested on breast cancer patients.

By comparing the photoacoustic data with conventional diagnostic X-rays, ultrasound imaging, MRI, and tissue exams, the researchers showed that malignancies produced a distinct photoacoustic signal that is potentially clinically useful for making a diagnosis of breast cancer. The team also observed that the photoacoustic contrast of the malignant tissue is higher than the contrast provided by the conventional X-ray mammographies.

In looking to the future, notes Heijblom, “PAM needs some technical improvements before it is a really valuable clinical tool for diagnosis or treatment of breast cancer. Our next step is to make those improvements and then evaluate less obvious potential tumors, benign lesions, and normal breasts with it.”

source from: sciencedaily

Lung cancer is the leading cause of cancer death throughout the world. Standard treatment methods do not usually result in long-term recovery. In addition to the proliferation of the tumour cells, the growth of blood vessels controls tumors development. The blood vessel growth is controlled by several signalling molecules. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Justus Liebig University Giessen have discovered a molecule that plays a key role in this process. They succeeded in reducing tumour growth in their experiments by blocking the phosphodiesterase PDE4.

Lung cancer mainly affects smokers; however the disease can also be caused by contact with carcinogenic substances like asbestos. Chemotherapy or radiotherapy often prove insufficient in treating the disease. Hence, scientists are engaged in an intensive search for ways of halting the growth of lung tumours. The blood vessels that supply the tumour with nutrients offer a potential point of attack.

New blood vessels form to ensure an adequate supply of nutrients to the growing tumour. The growing tissue is immediately penetrated by blood vessels. The growth of the blood vessels is regulated by the tumour cells using a complex signal cascade, which is triggered initially by a low oxygen content (hypoxia) in the tumour tissue. “This state, which is known as hypoxia prompts the activation of around 100 genes in the tumour cells,” explains Rajkumar Savai, research group leader at the Max Planck institute. “In addition to the growth of blood vessels, hypoxia also stimulates the proliferation of lung cancer cells.” Three molecules play a particularly important role in this process. The activation of the genes at the beginning of the cascade is triggered by the transcription factor HIF and a messenger molecule, cAMP, is involved again at the end of the cascade. The researchers examined the third molecule that acts as a link between these two molecules in detail.

The molecule in question is a phosphodiesterase, PDE4. The scientists from Bad Nauheim and Giessen were able to demonstrate in their study that various sections of PDE4 have binding sites for HIF.

The researchers then tested the influence of a PDE4 blockade on the cells from ten different cell lines, which are characteristic of around 80 percent of lung cancers, in the laboratory. The rate of cell division in the cells treated with a PDE4 inhibitor was significantly lower and the HIF level also declined as a result.

The effect in the tumour bearing mice was particularly obvious. To observe this, the Max Planck researchers implanted a human tumour cell line under the skin of nude mice and treated the animals with the phosphodiesterase 4 inhibitor. Tumour growth in these animals declined by around 50 percent. “Our microscopic analysis revealed that the blood vessel growth in the tumours of the mice that had been treated with the inhibitor was significantly reduced. We also observed indicators of decelerated cell division in the tumour cells. Overall, the tumour growth was strongly curbed.”

Werner Seeger, Director of the MPI and Medical Director of the JLU University Hospital Giessen, reports: “We were able to show that PDE4 plays an important regulation function in cell division in lung tumours and in the development of blood vessels in cancer. Therefore, we hope that we have found a starting point for the development of a treatment here.” In the view of tumour specialist Friedrich Grimminger, Chairman of the Department of Medical Oncology in Giessen, it may be possible in future to combine the inhibition of PDE4 with traditional radiotherapy or chemotherapy. In this way, the effect of the traditional treatment measures could be reinforced and patient prognoses may improve as a result. However, further laboratory studies are required before clinical tests can be carried out.

source from: sciencedaily

The oncology community has a recent history of using different microencapsulation techniques as an approach to cancer treatment. Microencapsulation is a single step process that forms tiny liquid-filled, biodegradable micro-balloons containing various drug solutions that can provide better drug delivery and new medical treatments for solid tumors and resistant infections. In other words, by using microcapsules containing antitumor treatments and visualization markers, the treatment can be directed right to the tumor, which has several benefits over systemic treatment such as chemotherapy. Testing in mouse models has shown that these unique microcapsules can be injected into human prostate tumors to actually inhibit tumor growth or can be injected following cryo-surgery (freezing) to improve the destruction of the tumors much better than freezing or local chemotherapy alone. The microcapsules also contain a contrast agent that enables C-T, X-ray or ultrasound imaging to monitor the distribution within the tissues to ensure that the entire tumor is treated when the microcapsules release their drug contents.

The Microencapsulation Electrostatic Processing System-II experiment, or MEPS-II, led by Dennis Morrison, Ph.D. (retired), at NASA Johnson Space Center, was performed on the station in 2002 and included innovative encapsulation of several different anti-cancer drugs, magnetic triggering particles, and encapsulation of genetically engineered DNA. The experiment system improved on existing microencapsulation technology by using microgravity to modify the fluid mechanics, interfacial behavior, and biological processing methods as compared to the way the microcapsules would be formed in gravity.

In effect, the MEPS-II system on the station combined two immiscible liquids in such a way that surface tension forces (rather than fluid shear) dominated at the interface of the fluids. The significant performance of the space-produced microcapsules as a cancer treatment delivery system motivated the development of the Pulse Flow Microencapsulation System, or PFMS, which is an Earth-based system that can replicate the quality of the microcapsules created in space.

As a result of this space station research, the results from the MEPS-II experiments have provided new insight into the best formulations and conditions required to produce microcapsules of different drugs, particularly special capsules containing diagnostic imaging materials and triggered release particles. Co-encapsulation of multiple drugs and Photodynamic Therapy, or PDT, drugs has enabled new engineering strategies for production of microcapsules on Earth designed for direct delivery into cancer tissues. Other microcapsules have now been made for treatment of deep tissue infections and clotting disorders and to provide delivery of genetically engineered materials for potential gene therapy strategies. Microcapsules that were made on the space station and are targeted at inhibiting the growth of human prostate tumors have been successfully demonstrated in laboratory settings. Although Morrison’s team had performed several similar microencapsulation experiments on space shuttle missions, because of the space station’s ability to support long-term experiments, more progress was made by the eight microencapsulation experiments conducted on the station in 2002 than from the 60+ prior experiments conducted on the four space shuttle missions — STS-77, STS-80, STS-95 and STS 107.

Benefits of Space Station Research

The microgravity environment on the station was an enabling environment that led the way to better methods of microcapsule development on Earth. The capability to perform sequential microencapsulation experiments on board the station has resulted in new, Earth-based technology for making these unique microballoons that provide sustained release of drugs over a 12-14 day period. The station research led directly to five U.S. patents that have been licensed by NASA and two more that are pending. NuVue Therapeutics, Inc., is one of several commercial companies that have licensed some of the MEPS technologies and methods to develop new applications, such as innovative ultrasound enhanced needles and catheters that will be used to deliver the microcapsules of anti-tumor drugs directly to tumor sites. More recent research uses a new device for freezing tumors (“cryo-ablation”) followed by ultrasound-guided deposition of the multi-layered microcapsules containing different chemotherapy drugs outside the freeze zone within a human prostate or lung tumor. In a 28-day study, combination therapy resulted in retarding tumor growth 78 percent and complete tumor regression of up to 30 percent after only three weekly injections of microencapsulated drug at tiny quantities that should not have slowed down tumor growth by more than 5-10 percent. NuVue Technologies, Inc., has now obtained two U.S. patents based on the combination therapy that includes the delivery of the NASA-type microcapsules. Upon securing funding, clinical trials to inject microcapsules of anti-tumor drugs directly into tumor sites will begin at MD Anderson Cancer Center in Houston and the Mayo Cancer Center in Scottsdale, Ariz.

Other potential uses of this microencapsulation technology include microencapsulation of genetically engineered living cells for injection or transplantation into damaged tissues, enhancement of human tissue repair, and real-time microparticle analysis in flowing sample streams that would allow petrochemical companies to monitor pipeline volume flow.

source from: sciencedaily

Caffeic acid phenethyl ester, or CAPE, is a compound isolated from honeybee hive propolis, the resin used by bees to patch up holes in hives. Propolis has been used for centuries as a natural remedy for conditions ranging from sore throats and allergies to burns and cancer. But the compound has not gained acceptance in the clinic due to scientific questions about its effect on cells.

In a paper published in Cancer Prevention Research, researchers combined traditional cancer research methods with cutting-edge proteomics to find that CAPE arrests early-stage prostate cancer by shutting down the tumor cells’ system for detecting sources of nutrition.

“If you feed CAPE to mice daily, their tumors will stop growing. After several weeks, if you stop the treatment, the tumors will begin to grow again at their original pace,” said Richard B. Jones, PhD, assistant professor in the Ben May Department for Cancer Research and Institute for Genomics and Systems Biology and senior author of the study. “So it doesn’t kill the cancer, but it basically will indefinitely stop prostate cancer proliferation.”

Natural remedies isolated from plant and animal products are often marketed as cure-alls for a variety of maladies, usually based on vague antioxidant and anti-inflammatory claims. While substances such as ginseng or green tea have been occasionally tested in laboratories for their medicinal properties, scientific evidence is commonly lacking on the full biological effects of these over-the-counter compounds.

“It’s only recently that people have examined the mechanism by which some of these herbal remedies work,” Jones said. “Our knowledge about what these things are actually doing is a bit of a disconnected hodge-podge of tests and labs and conditions. In the end, you’re left with a broad, disconnected story about what exactly these things are doing and whether or not they would be useful for treating disease.”

To study the purported anti-cancer properties of CAPE, first author Chih-Pin Chuu (now at the National Health Research Institutes in Taiwan) tested the compound on a series of cancer cell lines. Even at the low concentrations expected after oral administration, CAPE successfully slowed the proliferation of cultured cells isolated from human prostate tumors.

CAPE was also effective at slowing the growth of human prostate tumors grafted into mice. Six weeks of treatment with the compound decreased tumor volume growth rate by half, but when CAPE treatment was stopped, tumor growth resumed its prior rate. The results suggested that CAPE stopped cell division rather than killing cancerous cells.

To determine the cellular changes that mediated this effect, the researchers then used an innovative proteomics technique invented by Jones and colleagues called the “micro-western array.” Western blots are a common laboratory tool used to measure the changes in protein levels and activity under different conditions. But whereas only one or a few proteins at a time can be monitored with Western blots, micro-western arrays allow researchers to survey hundreds of proteins at once from many samples.

Chuu, Jones and their colleagues ran micro-western arrays to assess the impact of CAPE treatment on the proteins of cellular pathways involved in cell growth — experiments that would have been prohibitively expensive without the new technique.

“What this allowed us to do is screen about a hundred different proteins across a broad spectrum of signaling pathways that are associated with all sorts of different outcomes. You can pick up all the pathways that are affected and get a global landscape view, and that’s never been possible before,” Jones said. “It would have taken hundreds of Westerns, hundreds of technicians, and a very large amount of money for antibodies.”

The micro-western array results allowed researchers to quickly build a new model of CAPE’s cellular effects, significantly expanding on previous work that studied the compound’s mechanisms. Treatment with CAPE at the concentrations that arrested cancer cell growth suppressed the activity of proteins in the p70S6 kinase and Akt pathways, which are important sensors of sufficient nutrition that can trigger cell proliferation.

“It appears that CAPE basically stops the ability of prostate cancer cells to sense that there’s nutrition available,” Jones said. “They stop all of the molecular signatures that would suggest that nutrition exists, and the cells no longer have that proliferative response to nutrition.”

The ability of CAPE to freeze cancer cell proliferation could make it a promising co-treatment alongside chemotherapies intended to kill tumor cells. Jones cautioned that clinical trials would be necessary before CAPE could be proven effective and safe for this purpose in humans. But the CAPE experiments offer a precedent to unlock the biological mechanisms of other natural remedies as well, perhaps allowing these compounds to cross over to the clinic.

“A typical problem in bringing some of these herbal remedies into the clinic is that nobody knows how they act, nobody knows the mechanism, and therefore researchers are typically very hesitant to add them to any pharmaceutical treatment strategy,” Jones said. “Now we’ll actually be able to systematically demonstrate the parts of cell physiology that are affected by these compounds.”

source from: sciencedaily

In a study published online April 15 in Nature Medicine, a team led by Sam Gambhir, MD, PhD, professor and chair of radiology, showed that the minuscule nanoparticles engineered in his lab homed in on and highlighted brain tumors, precisely delineating their boundaries and greatly easing their complete removal. The new technique could someday help improve the prognosis of patients with deadly brain cancers.

About 14,000 people are diagnosed annually with brain cancer in the United States. Of those cases, about 3,000 are glioblastomas, the most aggressive form of brain tumor. The prognosis for glioblastoma is bleak: the median survival time without treatment is three months. Surgical removal of such tumors — a virtual imperative whenever possible — prolongs the typical patient’s survival by less than a year. One big reason for this is that it is almost impossible for even the most skilled neurosurgeon to remove the entire tumor while sparing normal brain.

“With brain tumors, surgeons don’t have the luxury of removing large amounts of surrounding normal brain tissue to be sure no cancer cells are left,” said Gambhir, who is the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research and director of the Molecular Imaging Program at Stanford. “You clearly have to leave as much of the healthy brain intact as you possibly can.”

This is a real problem for glioblastomas, which are particularly rough-edged tumors. In these tumors, tiny fingerlike projections commonly infiltrate healthy tissues, following the paths of blood vessels and nerve tracts. An additional challenge is posed by micrometastases: minuscule tumor patches caused by the migration and replication of cells from the primary tumor. Micrometastases dotting otherwise healthy nearby tissue but invisible to the surgeon’s naked eye can burgeon into new tumors.

Although brain surgery today tends to be guided by the surgeon’s naked eye, new molecular imaging methods could change that, and this study demonstrates the potential of using high-technology nanoparticles to highlight tumor tissue before and during brain surgery.

The nanoparticles used in the study are essentially tiny gold balls coated with imaging reagents. Each nanoparticle measures less than five one-millionths of an inch in diameter — about one-sixtieth that of a human red blood cell.

“We hypothesized that these particles, injected intravenously, would preferentially home in on tumors but not healthy brain tissue,” said Gambhir, who is also a member of the Stanford Cancer Institute. “The tiny blood vessels that feed a brain tumor are leaky, so we hoped that the spheres would bleed out of these vessels and lodge in nearby tumor material.” The particles’ gold cores, enhanced as they are by specialized coatings, would then render the particles simultaneously visible to three distinct methods of imaging, each contributing uniquely to an improved surgical outcome.

One of those methods, magnetic resonance imaging, is already frequently used to give surgeons an idea of where in the brain the tumor resides before they operate. MRI is well-equipped to determine a tumor’s boundaries, but when used preoperatively it can’t perfectly describe an aggressively growing tumor’s position within a subtly dynamic brain at the time the operation itself takes place.

The Gambhir team’s nanoparticles are coated with gadolinium, an MRI contrast agent, in a way that keeps them stably attached to the relatively inert spheres in a blood-like environment. (In a 2011 study published in Science Translational Medicine, Gambhir and his colleagues showed in small animal models that nanoparticles similar to those used in this new study, but not containing gadolinium, were nontoxic.)

A second, newer method is photoacoustic imaging, in which pulses of light are absorbed by materials such as the nanoparticles’ gold cores. The particles heat up slightly, producing detectable ultrasound signals from which a three-dimensional image of the tumor can be computed. Because this mode of imaging has high depth penetration and is highly sensitive to the presence of the gold particles, it can be useful in guiding removal of the bulk of a tumor during surgery.

The third method, called Raman imaging, leverages the capacity of certain materials (included in a layer coating the gold spheres) to give off almost undetectable amounts of light in a signature pattern consisting of several distinct wavelengths. The gold cores’ surfaces amplify the feeble Raman signals so they can be captured by a special microscope.

To demonstrate the utility of their approach, the investigators first showed via various methods that the lab’s nanoparticles specifically targeted tumor tissue, and only tumor tissue.

Next, they implanted several different types of human glioblastoma cells deep into the brains of laboratory mice. After injecting the imaging-enhancing nanoparticles into the mice’s tail veins, they were able to visualize, with all three imaging modes, the tumors that the glioblastoma cells had spawned.

The MRI scans provided good preoperative images of tumors’ general shapes and locations. And during the operation itself, photoacoustic imaging permitted accurate, real-time visualization of tumors’ edges, enhancing surgical precision.

But neither MRI nor photoacoustic imaging by themselves can distinguish healthy from cancerous tissue at a sufficiently minute level to identify every last bit of a tumor. Here, the third method, Raman imaging, proved crucial. In the study, Raman signals emanated only from tumor-ensconced nanoparticles, never from nanoparticle-free healthy tissue. So, after the bulk of an animal’s tumor had been cleared, the highly sensitive Raman-imaging technique was extremely accurate in flagging residual micrometastases and tiny fingerlike tumor projections still holed up in adjacent normal tissue that had been missed on visual inspection. This, in turn, enabled these dangerous remnants’ removal.

“Now we can learn the tumor’s extent before we go into the operating room, be guided with molecular precision during the excision procedure itself and then immediately afterward be able to ‘see’ once-invisible residual tumor material and take that out, too,” said Gambhir, who suggested that the nanoparticles’ propensity to heat up on photoacoustic stimulation, combined with their tumor specificity, might also make it possible for them to be used to selectively destroy tumors. He also expressed optimism that this kind of precision could eventually be brought to bear on other tumor types.

The study was funded by the National Institutes of Health, the National Cancer Institute’s Center for Cancer Nanotechnology Excellence, the Ben and Catherine Ivy Foundation, the Canary Foundation and the Leon Levy Foundation.

source from: sciencedaily

Patients with glioblastoma multiforme (GBM), the most common and aggressive malignant primary brain tumor, typically have a prognosis of 14-month median survival time despite medical interventions, which currently include surgery, chemotherapy and radiation.

The Rice-Methodist group developed the hydrophilic carbon cluster (HCC) antibody drug enhancement system (HADES), named after the Greek god of the underworld. Through a 20-nanometer syringe, which is 2 million times smaller than a coffee mug, this nanovector successfully delivered a combination of three chemotherapy drugs into GBM cells in vivo, resulting in a high kill rate.

“Without our nano-delivery system, we know that current drug delivery would be highly toxic to patients if we tried to deliver all three of these drugs at once,” said David Baskin, M.D., neurosurgeon at the Methodist Neurological Institute, who began his nanomedicine research in 2004 with the late Nobel laureate and Rice chemist Richard Smalley. “But delivered in combination using these nano-syringes, our research demonstrated extreme lethality, with at least a three-fold increase in the number of dead cancer cells following treatment. The nano-syringes selectively deliver these drugs only to cancer cells, and appear not to be toxic to normal neurons and other non-cancerous brain cells.”

HCCs are nanovectors with protective antioxidant properties, capable of transporting and delivering drugs and bioactive molecules. In order to bring the drug carriers close enough to the cancer cells and successfully deliver the chemotherapy combination, three different antibodies were combined with the HCC to allow the nanoparticle to stick to the cell membrane. The drugs stayed inside the HCC until it attached to the cell membrane. Once binding occurred, the drugs were released into the fatty (lipid) environment in the membrane. The chemical properties of the chemotherapy drugs inside the HCC are such that they prefer to accumulate in areas with high concentrations of lipids and avoid areas with high water content, such as the extracellular space.

“A new and exciting advance is that now we have a carrier with protective properties, unlike previous nanotubes which were shown to be toxic,” said Martyn Sharpe, the paper’s lead author and a scientist with the Methodist NI’s department of neurosurgery. “Some of the chemotherapy agents used in this research traditionally perform poorly with GBMs. Now that we’ve shown a successful kill rate of these cells in vivo, we’re looking at treating human tumors that will be grown in immune-compromised mice models.”

As personalized medicine continues to evolve, Baskin says this research could also be significant for other forms of cancer, including breast and head and neck cancers.

The paper represents an important collaboration between the laboratories of Baskin at Methodist, and James Tour, Ph.D. with Rice University’s Smalley Institute for Nanoscale Science. Further work developing this system and expanding its utility is under way with continued collaboration between these two research groups.

The research was supported by The Henry J. N. Taub Fund for Neurological Research, The Pauline Sterne Wolff Memorial Foundation, Golfers Against Cancer, The Taub Foundation, The Verdant Foundation Limited and The Methodist Hospital Foundation.

source from: sciencedaily

Created by a team from the University of Exeter, the fish makes it easier than ever before to see where in the body environmental chemicals act and how they affect health.

The fluorescent fish has shown that estrogenic chemicals, which are already linked to reproductive problems, impact on more parts of the body than previously thought.

The research by the University of Exeter and UCL (University College London) is published in the journalEnvironmental Health Perspectives.

Numerous studies have linked ‘endocrine-disrupting’ chemicals, used in a wide range of industrial products and contraceptive pharmaceuticals, to reproductive problems in wildlife and humans. Previous University of Exeter research identified the potential for a major group of ‘these chemicals to cause male fish to change gender. Human exposure to these chemicals, which can alter hormone signalling in the body, has been associated with decreases in sperm count and other health problems, including breast and testicular cancer.

Scientists worldwide are now working to find better ways of screening and testing for these chemicals in the body, to target the health risks to humans and wildlife. This new development, led by Dr Tetsuhiro Kudoh and Professor Charles Tyler at the University of Exeter, gives the first comprehensive insight into the effects of these chemicals on the whole body. It shows that more organs and parts of the body react to environmental estrogens than previously thought.

The team created a new transgenic zebrafish, which when exposed to environmental estrogens shows where these chemicals work in the body through the production of green fluorescent signals. The research team tested the fish’s sensitivity to different chemicals known to affect estrogen hormone signalling, including ethinyloestradiol, used in the contraceptive pill and hormone replacement therapy treatments, nonylphenol, used in paints and industrial detergents, and Bisphenol A, which is found in many plastics.

Eventually, they produced a fish that was sufficiently sensitive to the chemicals to give fluorescent green signals to show which parts of its body were responding. This was done by placing a genetic system into the fish that amplifies the response to estrogens producing the fluorescent green signal.

In the laboratory, PhD student Okhyun Lee exposed the fish to chemicals at levels found in wastewaters that are discharged into our rivers. She was then able to observe the effects of the exposure on the fish, in real time, watching specific organs or areas of tissue glow green, in response to the chemicals.

The team identified responses in parts of the body already associated with these chemicals: for example, the liver and, in the case of Bisphenol A, the heart. They also witnessed responses in tissues that were not previously known to be targeted by these chemicals, including the skeletal muscle and eyes.

Corresponding author Professor Charles Tyler of Biosciences at the University of Exeter said: “This is a very exciting development in the international effort to understand the impact of estrogenic chemicals on the environment and human health. This zebrafish gives us a more comprehensive view than ever before of the potential effects of these hormone-disrupting chemicals on the body.

“By being able to localise precisely where different environmental estrogens act in the body, we will be able to more effectively target health effects analyses for these chemicals of concern. While it is still early days, we are confident that our zebrafish model can help us better understand the way the human body responds to these pollutants.”

source from: sciencedaily

The study appears April 16 in the online edition of Cancer Cell.

“Clearly, we have a drug that is extremely effective against this type of cancer in mice,” said study leader Thomas Diacovo, MD, associate professor of pediatrics and pathology and cell biology at CUMC. “If this treatment strategy can safely and selectively target the activity of these enzymes in T-ALL tumors, we might be able to reduce the need for conventional chemotherapies that more broadly affect proliferating cells, including those in healthy tissues. This would be a major advancement in helping to reduce drug toxicities in young patients.”

The dual inhibitor was developed by Gilead Sciences.

T-ALL is a cancer that arises during the development of T-cells, a type of white blood cell. The abnormal T cells multiply rapidly, invading and impairing the function of organs critical for sustaining life. T-ALL typically begins in childhood but can also appear later in life. The disease is caused by mutations in DNA, which permit the cancer cell to continue growing and dividing, when a healthy cell would normally die. Left untreated, T-ALL is invariably fatal. It is highly resistant to chemotherapy, compared with other forms of leukemia. The relapse rate is about 25 percent in children and 50 percent in adults.

In studies of autoimmune disease done some years ago, Dr. Diacovo and his team found that inhibition of both PI3K gamma and delta not only reduced inflammation but also caused developing T cells to die at an accelerated rate. “This led us to ask in what disease states it would be advantageous to kill off aberrant T-cells,” he said. “One of the first diseases that came to mind was T-ALL.

The current study was designed to take a closer look at the role of these enzymes in T-ALL and to see whether an experimental PI3K inhibitor called CAL-130 might affect disease progression.

In the first part of the study, using a mouse model of the disease, Dr. Diacovo and his team, led by Dr. Subramaniam, confirmed that both PI3K gamma and delta are essential for the development of T-ALL and the survival of leukemic (abnormal) cells. The researchers also demonstrated that administration of CAL-130 significantly lowered the number of leukemic T-cells in animals’ general circulation. “The level of circulating leukemia cells dropped very rapidly, from an average of 100 million per ml to less than 1 million per ml within 24 to 48 hours,” Dr. Diacovo said. “The counts remained low after just 7 days of therapy.” The median survival time for mice treated with CAL-130 was 45 days, compared with 7.5 days for untreated controls.

The researchers also evaluated the effects of CAL-130 on blood samples taken from patients with T-ALL. The drug prevented proliferation of leukemic cells and promoted a self-destruct mechanism called apoptosis.

“We’ve made great strides in treating childhood acute lymphoblastic leukemias over the years, with an overall cure rate approaching 90 percent,” said Dr. Diacovo. “Unfortunately, conventional treatment — chemotherapy — is quite toxic. This is a particular problem for children, who have an entire lifetime ahead of them and are likely to develop secondary cancers and other complications as a result of their treatment. So anything we can do to lessen associated toxicities would be a welcome advancement in the field.”

Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, said, “Even in cancers where cure rates are high — such as this form of childhood leukemia — our researchers are continually searching for less toxic ways to treat our patients, in an effort to improve their quality of life and to enable them to lead long, healthy lives. This is one of the key approaches to the future of cancer care.”

Clinical trials of a dual PI3K gamma/delta inhibitor in patients with leukemia are in the planning stages, said Dr. Diacovo.

The paper is entitled, “Targeting non‐classical oncogenes for therapy in T-ALL.” In addition to Dr. Diacovo, the study authors are Prem S. Subramaniam, PhD (CUMC); Dosh W. Whye, BSc (CUMC); Evgeni Efimenko, PhD (CUMC); Jianchung Chen, PhD (CUMC); Valeria Tosello, PhD (CUMC); Kim De Keersmaecker, PhD (CUMC); Adam Kashishian, BSc (Calistoga Pharmaceuticals and Gilead Sciences, Seattle, WA); Mary Ann Thompson, MD, PhD (Vanderbilt University Medical Center, Nashville, TN); Mireia Castillo, PhD (Mount Sinai School of Medicine, New York); Carlos Cordon-Cardo, MD (Mount Sinai); Upal Davé, MD (Vanderbilt); Adolfo Ferrando, MD, PhD (CUMC); and Brian J. Lamnutti, PhD (Calistoga Pharmaceuticals and Gilead Sciences).

Brian Lannutti and Adam Kashishian are employees of the company (Gilead Sciences) that manufactured CAL-130. None of the other authors report any financial or other conflict of interest.

This research was supported by the Department of Defense (grant # PR093714), the Leukemia & Lymphoma Society Translational Research Program, and Gilead Sciences.

source from: sciencedaily

Angiogenesis, the growth of new blood vessels, is a complex process during which different signalling proteins interact with each other in a highly coordinated fashion. The growth factor VEGF and the Notch signalling pathway both play important roles in this process. VEGF promotes vessel growth by binding to its receptor, VEGFR2, while the Notch signalling pathway acts like a switch capable of suppressing angiogenesis. Until recently, scientists had assumed that Notch cancels the effects of VEGF through the downregulation of VEGFR2. Now, researchers at the Max Planck Institute for Molecular Biomedicine and the Westphalian Wilhelms-University in Münster, Germany, were able to demonstrate that defective Notch signalling enables strong and deregulated vessel growth even when VEGF or VEGFR2 are inhibited.

In this case, a different VEGF family receptor, VEGFR3, is strongly upregulated, promoting angiogenesis. “This finding might help explain drug resistance issues in certain types of cancer therapy and could become the basis for novel treatment strategies,” suggests Ralf Adams, MPI’s Executive Director and Chair of the Department of Tissue Biology and Morphogenesis.

An extensively branched network of blood vessels provides every organ of the body with nutrients and removes harmful metabolic waste products from tissues. Growth of this vascular system is essential for development and wound healing processes. Uncontrolled angiogenesis contributes to diseases like hemangiomas, the sponge-like overgrowth of blood vessels in the skin, or retinopathies impairing the eyesight of diabetic and elderly individuals. In cancer therapy, inhibition of angiogenesis is used to starve tumours and prevent the metastatic spread of cancer cells via the circulation. At present, this is most frequently done by targeting VEGF or its receptor VEGFR2. When their oxygen supply becomes inadequate, tissues begin to release VEGF, which binds to VEGFR2, activating the receptor and thereby triggering vessel growth. Thus, the formation of new blood vessels can be blocked by inhibiting VEGF or VEGFR2. Unfortunately, existing treatments are inadequate and, for reasons that are not yet known, some patients respond poorly or not at all to VEGF/VEGFR2 inhibition.

Now, Rui Benedito, a postdoctoral research fellow in Adams’ Department, has demonstrated that inhibition of the Notch pathway in blood vessels of the mouse eye permits strong and deregulated vessel growth even when VEGF or VEGFR2 are inhibited. “It turns out that another VEGF family receptor, VEGFR3, takes over, promoting the formation of new blood vessels,” explains Benedito. VEGFR3 is strongly upregulated in blood vessels in the absence of Notch and is active even without growth signals from the surrounding tissues.

“What we need to do now is confirm whether VEGFR3 and other Notch-regulated signals are in fact capable of promoting VEGF-independent vessel growth in eye disease or cancer not only in mice but also in humans,” explains Adams. “It might become possible to predict whether patients, depending on their vascular Notch activation status, are going to respond to VEGF or VEGFR2 inhibition. This would allow physicians to choose alternative therapies if necessary. Here, too, collaboration between MPI, the medical faculty, and the University of Münster is essential: “Our work is strongly benefitting from the excellent support provided by the University.”

source from: sciencedaily

To address this challenge, researchers from the Georgia Institute of Technology and Emory University have designed a new treatment approach that appears to halt the spread of cancer cells into normal brain tissue in animal models. The researchers treated animals possessing an invasive tumor with a vesicle carrying a molecule called imipramine blue, followed by conventional doxorubicin chemotherapy. The tumors ceased their invasion of healthy tissue and the animals survived longer than animals treated with chemotherapy alone.

“Our results show that imipramine blue stops tumor invasion into healthy tissue and enhances the efficacy of chemotherapy, which suggests that chemotherapy may be more effective when the target is stationary,” said Ravi Bellamkonda, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “These results reveal a new strategy for treating brain cancer that could improve clinical outcomes.”

The results of this work were published on March 28, 2012 in the journal Science Translational Medicine. The research was supported primarily by the Ian’s Friends Foundation and partially by the Georgia Cancer Coalition, the Wallace H. Coulter Foundation and a National Science Foundation graduate research fellowship.

In addition to Bellamkonda, collaborators on the project include Jack Arbiser, a professor in the Emory University Department of Dermatology; Daniel Brat, a professor in the Emory University Department of Pathology and Laboratory Medicine; and the paper’s lead author, Jennifer Munson, a former Fulbright Scholar who was a bioengineering graduate student in the Georgia Tech School of Chemical & Biomolecular Engineering when the research was conducted.

Arbiser designed the novel imipramine blue compound, which is an organic triphenylmethane dye. After in vitro experiments showed that imipramine blue effectively inhibited movement of several cancer cell lines, the researchers tested the compound in an animal model of aggressive cancer that exhibited attributes similar to a human brain tumor called glioblastoma.

“There were many reasons why we chose to use the RT2 astrocytoma rat model for these experiments,” said Brat. “The tumor exhibited properties of aggressive growth, invasiveness, angiogenesis and necrosis that are similar to human glioblastoma; the model utilized an intact immune system, which is seen in the human disease; and the model enabled increased visualization by MRI because it was a rat model, rather than a mouse.”

Because imipramine blue is hydrophobic and doxorubicin is cytotoxic, the researchers encapsulated each compound in an artificially-prepared vesicle called a liposome so that the drugs would reach the brain. The liposomal drug delivery vehicle also ensured that the drugs would not be released into tissue until they passed through leaky blood vessel walls, which are only present where a tumor is growing.

Animals received one of the following four treatments: liposomes filled with saline, liposomes filled with imipramine blue, liposomes filled with doxorubicin chemotherapy, or liposomes filled with imipramine blue followed by liposomes filled with doxorubicin chemotherapy.

All of the animals that received the sequential treatment of imipramine blue followed by doxorubicin chemotherapy survived for 200 days — more than 6 months — with no observable tumor mass. Of the animals treated with doxorubicin chemotherapy alone, 33 percent were alive after 200 days with a median survival time of 44 days. Animals that received capsules filled with saline or imipramine blue — but no chemotherapy — did not survive more than 19 days.

“Our results show that the increased effectiveness of the chemotherapy treatment is not because of a synergistic toxicity between imipramine blue and doxorubicin. Imipramine blue is not making the doxorubicin more toxic, it’s simply stopping the movement of the cancer cells and containing the cancer so that the chemotherapy can do a better job,” explained Bellamkonda, who is also the Carol Ann and David D. Flanagan Chair in Biomedical Engineering and a Georgia Cancer Coalition Distinguished Cancer Scholar.

MRI results showed a reduction and compaction of the tumor in animals treated with imipramine blue followed by doxorubicin chemotherapy, while animals treated with chemotherapy alone presented with abnormal tissue and glioma cells. MRI also indicated that the blood-brain barrier breach often seen during tumor growth was present in the animals treated with chemotherapy alone, but not the group treated with chemotherapy and imipramine blue.

According to the researchers, imipramine blue appears to improve the outcome of brain cancer treatment by altering the regulation of actin, a protein found in all eukaryotic cells. Actin mediates a variety of essential biological functions, including the production of reactive oxygen species. Most cancer cells exhibit overproduction of reactive oxygen species, which are thought to stimulate cancer cells to invade healthy tissue. The dye’s reorganization of the actin cytoskeleton is thought to inhibit production of enzymes that produce reactive oxygen species.

“I formulated the imipramine blue compound as a triphenylmethane dye because I knew that another triphenylmethane dye, gentian violet, exhibited anti-cancer properties, and I decided to use imipramine — a drug used to treat depression — as the starting material because I knew it could get into the brain,” said Arbiser.

For future studies, the researchers are planning to test imipramine blue’s effect on animal models with invasive brain tumors, metastatic tumors, and other types of cancer such as prostate and breast.

“While we need to conduct future studies to determine if the effect of imipramine blue is the same for different types of cancer diagnosed at different stages, this initial study shows the possibility that imipramine blue may be useful as soon as any tumor is diagnosed, before anti-cancer treatment begins, to create a more treatable tumor and enhance clinical outcome,” noted Bellamkonda.

source from: sciencedaily