Structure discovered of cancer drug candidate

Structure discovered of cancer drug candidate

Chemists at The Scripps Research Institute (TSRI) have determined the correct structure of a highly promising anticancer compound approved by the U.S. Food and Drug Administration (FDA) for clinical trials in cancer patients.

The new report, published this week by the international chemistry journal Angewandte Chemie, focuses on a compound called TIC10.

In the new study, the TSRI scientists show that TIC10's structure differs subtly from a version published by another group last year, and that the previous structure associated with TIC10 in fact describes a molecule that lacks TIC10's anticancer activity.

By contrast, the correct structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for their possible therapeutic uses.

"This new structure should generate much interest in the cancer research community," said Kim D. Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI.

A new report shows the structure of a promising anticancer compound, TIC10, differs subtly but importantly from a previously published version.
Credit: Figure courtesy of The Scripps Research Institute.

Antitumor Potential

TIC10 was first described in a paper in the journal Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells' production of a powerful natural antitumor protein, TRAIL. (TIC10 means TRAIL-Inducing Compound #10.)

As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper, which drew widespread media coverage, reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice, including notoriously treatment-resistant glioblastomas.

Tumors can develop resistance to TRAIL, but Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention. "I thought, 'They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor cell TRAIL resistance - the combination could be important,'" he said.

The original publication on TIC10 included a figure showing its predicted structure. "I saw the figure and asked one of my postdocs, Jonathan Lockner, to make some," Janda said.
A new report shows the structure of a promising anticancer compound, TIC10, differs subtly but importantly from a previously published version.
Credit: Image courtesy of The Scripps Research Institute.

Although the other team had seemingly confirmed the predicted structure with a basic technique called mass spectrometry, no one had yet published a thorough characterization of the TIC10 molecule. "There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis," Lockner said. "My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds."

Surprising Inactivity

There was just one problem with Lockner's newly synthesized "TIC10." When tested, it failed to induce TRAIL expression in cells, even at high doses.

"Of course I was nervous," remembered Lockner. "As a chemist, you never want to make a mistake and give biologists the wrong material."

To try to verify they had the right material, Janda's team obtained a sample of TIC10 directly from the NCI. "When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect," said Nicholas Jacob, a graduate student in the Janda Laboratory who, with Lockner, was a co-lead author of the new paper. "That prompted us to look more closely at the structures of these two compounds."

The two researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. With Assistant Professor Vladimir V. Kravchenko of the TSRI Department of Immunology and Microbial Science, Jacob also tested the two compounds' biological effects.

The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.

The Right Structure

The originally published structure has a core made of three carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle. In chemists' parlance, the two compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.

Ironically, Lockner found that the angular TRAIL-inducing structure was easier to synthesize than the one originally described.

Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.

The therapeutic implications of TIC10 may even go beyond cancer. The angular core of the TRAIL-inducing molecule discovered by Janda's team turns out to be a novel type of a biologically active structure - or "pharmacophore" - from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.

"One lesson from this has got to be: don't leave your chemists behind," said Janda.

Worse side effects from chemotherapy experienced when biological rhythms interrupted

Worse side effects from chemotherapy experienced when biological rhythms interrupted

Patients receiving chemical treatment for cancer often suffer fatigue and body weight loss, two of the most worrying effects of this therapy linked to the alteration of their circadian rhythms.

The circadian system, better known as our biological clock, is responsible for coordinating all the processes that take place in our organism.

If it does not function correctly, what is known as a circadian disruption or chronodisruption, has for years been linked to an increased incidence of cancer, obesity, diabetes, depression, cognitive problems or cardiovascular diseases.

"Also, circadian disruption in cancer patients aggravates the prognosis of the disease and the chance of survival for these patients diminishes," Elisabet Ortiz Tudela, a researcher at the University of Murcia, told SINC.

The expert is the author of a study published in the International Journal of Cancer, which reveals the importance of assessing how the circadian system works in order to prevent chronodisruption and to implement measures to strengthen the biological clock in people whose system is damaged.

However, measuring how the biological clock works is not easy in humans given that the "machinery" is located within the suprachiasmatic nucleus in the hypothalamus, deep within the brain.

"Therefore, it is impossible to directly assess how the clock works," adds Ortiz. "Today, biological rhythms are studied which are clock "interruptions" and which enable us to indirectly assess the status of the circadian system".

One of the most studied "interruptions", which can be measured with non-invasive techniques and during long periods of time, is the activity-rest rhythm.

Chronotherapy for cancer

Researchers characterised the evolution of the circadian system in cancer patients submitted to a standard chronotherapy protocol (synchronisation of medication with natural rhythms). The activity-rest rhythm was recorded in 49 patients with advanced cancer while being given a standard chronomodulated chemotherapy cycle, which resulted in circadian disruption.

All the parameters calculated according to the activity-rest rhythm worsened considerably with the chemotherapy. Also, the existence of circadian disruption during the treatment was linked to greater fatigue and body weight loss, two of the most worrying associated factors for doctors.

"After the treatment and at the end of the study, the mean values of all the parameters were recovered to near baseline values," stated the scientist from the institution in Murcia.

The results show four different patterns with regard to the evolution of the circadian system in response to the treatment: in 9.5% of the patients the activity-rest rhythm remained stable despite the chemotherapy, 14.3% of patients showed some improvement, 31% suffered alterations in response to the treatment and recovered completely at the end of the study and in 45% of these deterioration sustained, possibly through inadequate dosing or incorrect timing.

This effect shows the great differences between individuals, which could affect the effectiveness of the treatment.

"Minimising circadian disruption through the personalisation of chronotherapy delivery could help to improve clinical tolerability and potentially contribute towards the treatment being more effective," concludes Ortiz.

Understanding of how Taxol works could lead to better anticancer drugs

Understanding of how Taxol works could lead to better anticancer drugs

University of California, Berkeley, scientists have discovered the extremely subtle effect that the prescription drug Taxol has inside cells that makes it one of the most widely used anticancer agents in the world.

The details, involving the drug's interference with the normal function of microtubules, part of the cell's skeleton, could help in designing better anticancer drugs, or in improving Taxol and other drugs already known to disrupt the workings of microtubules.

The findings are reported in the journal Cell.

"Efforts towards understanding these chemotherapeutics better are very important, because there are some microtubule differences in cancer cells versus normal cells that maybe we can exploit," said principle author Eva Nogales, a biophysicist, UC Berkeley professor of molecular and cell biology and senior faculty scientist at Lawrence Berkeley National Laboratory (LBNL). "We are not there yet, but this is the kind of analysis we need to get there."

Taxol, originally extracted from the bark of the Pacific yew tree, is one of the mostly commonly used drugs against solid tumors, and is a front-line drug for treating ovarian and advanced breast cancer. The drug is known to bind to microtubules and essentially freeze them in place, which prevents them from separating the chromosomes when a cell divides. This kills dividing cells, in particular cancer cells, which are known for rapid proliferation.

Nogales, a Howard Hughes Medical Institute investigator, has worked on microtubules since she was a doctoral student in England in the early '90s, using techniques such as X-ray scattering and cryoelectron microscopy to study how Taxol and other anticancer agents affect microtubules. Later, during her postdoctoral work at LBNL with Ken Downing, she was the first to discover exactly where Taxol binds the basic building block, called tubulin, of the microtubule polymer.

Microtubules are the cell's skeleton

Work by many scientists around the world has shown the microtubule network inside cells, called the cytoskeleton, to be very different from rigid animal skeletons. Microtubules are polymer filaments that constantly grow and shrink, and in doing so push and pull things around the cell, including the chromosomes. Scientists call this dynamic instability. The microtubules also provide a highway for transporting the cell's organelles and other packages around the cell.

Tubulin, the basic structural unit of the microtubule, is a complex of two proteins - alpha and beta tubulin. Tubulin units stack one atop another to form strips that align with other strips and then zip up to form a hollow tube, the microtubule.

"Tubulin, the cytoskeletal protein that self-assembles into microtubules, is absolutely essential for the life of every eukaryotic cell, which is why it has become a major target of anticancer agents," Nogales said. "It's amazing how microtubules probe and try new things almost at random, but there is a level of control built into the cell that ultimately makes sense of this chaos, and the cell survives and prospers."

Microtubules grow from their free end at about 1 micron per minute by continually adding more tubulin (around 20 tubulin molecules per second). But if they stop growing, they rapidly peel apart like the skin of a banana, releasing tubulin for recycling into other microtubules. This peeling, or depolymerization, takes place at up to 15 microns per minute, or about 300 tubulin molecules falling off per second, Nogales said.

Microtubules are like compressed springs

Nogales has now discovered why microtubules peel apart so rapidly. When they assemble, the strips of tubulin are put under intense strain, but prevented from bending and pulling apart by the growing cap of tubulin on the end. Once growing stops and that cap disappears, the restrained tension rips the microtubule apart.

The tension is created when the tubulin complex, which has a small energy molecule called GTP (guanosine triphosphate) attached, becomes hydrolyzed and the GTP turns into GDP (guanosine diphosphate). This chemical reaction compacts the alpha and beta subunits, much like compacted vertebrae, keeping the tubulin stack under tension as long as the microtubule is growing at its end.

"It had been proposed that tubulin had to be constrained, but no one had proved it," Nogales said. "What we have seen is that as GTP hydrolysis happens, the tubulin structure gets stuck in a strained state, like a compressed spring. The end subunits are holding the whole thing together."

When growth stops, the tension is unleashed, and the strips peel apart rapidly.

"This work represents a major step forward on a problem with a long history," wrote Tim Mitchison in a commentary in the same issue of Cell. Mitchison, a Harvard University professor of systems biology, was the first to show the importance of GTP hydrolysis in destabilizing microtubules. The model proposed by Nogales and her team, he added, "provides our first glimpse into (the) destabilization mechanism."

Nogales also found that Taxol inserts itself into the tubulin protein and prevents compaction of the alpha and beta subunits, so that no tension builds up. As a result, even if the microtubule stops growing, it remains intact, basically frozen in place, unable to peel apart, or depolymerize, and carry out its normal function.

"Taxol reverses the effects of GTP hydrolysis," she said.

Nogales and her team discovered these structural changes by pushing the limits of cryoelectron microscopy, a technique in which samples are frozen and probed with a high-powered electron beam. They have now achieved a resolution sufficient to see details smaller than 5 angstroms (one-tenth of a nanometer) across, which is about the size of five hydrogen atoms. While most information to date about the structure of tubulin inside the microtubule has come from the study of artificial, flat sheets of aligned strips of tubulin, Nogales was able to probe three-dimensional microtubules frozen into their natural state, with and without Taxol bound to tubulin. This comparison clearly showed the effect Taxol has on microtubule structure.

For dysplastic Barrett's esophagus, radiofreqeuncy ablation and complete endoscopic resection equally effective

For dysplastic Barrett's esophagus, radiofreqeuncy ablation and complete endoscopic resection equally effective

According to a new systematic review article, radiofrequency ablation and complete endoscopic resection are equally effective in the short-term treatment of dysplastic Barrett's esophagus, but adverse event rates are higher with complete endoscopic resection. The article comparing the two treatments appears in the May issue of GIE: Gastrointestinal Endoscopy, the monthly peer-reviewed scientific journal of the American Society for Gastrointestinal Endoscopy (ASGE).

Barrett's esophagus is a condition in which the lining of the esophagus changes and becomes more like the lining of the small intestine. It is believed that Barrett's esophagus (BE) occurs because of chronic inflammation resulting from long-standing Gastroesophageal Reflux Disease (GERD). Barrett's esophagus is more common in Caucasian males older than the age of 50 who have had GERD for greater than five years. Most patients with Barrett's esophagus will not develop cancer. However, in some patients further precancerous change in the tissue, called dysplasia, will develop. Those patients that develop dysplasia, especially high grade dysplasia, are significantly more likely to develop esophageal cancer.

Esophagectomy (surgery to remove part or all of the esophagus) has previously been the recommended treatment for BE with high grade dysplasia (HGD) or intramucosal cancer (cancer limited to the most superficial layer of the esophagus), but this surgery is associated with significant morbidity and mortality. As a result, endoscopic therapies for treatment of HGD or superficial cancers have been developed which minimize treatment-related morbidity. Ideally, endoscopic treatments need to target the entire segment of Barrett's mucosa (lining of the esophagus) in order to maximally reduce the risk of developing esophageal cancer.

To date, two distinct endoscopic approaches have been widely used for this purpose. The first is complete endoscopic mucosal resection (EMR) where the BE mucosa is resected or removed endoscopically. This has the advantage of providing a large histologic specimen, which can then be evaluated for unrecognized, more advanced pathology, and may be curative. The other approach is ablation of the BE mucosa by using a variety of techniques such as photodynamic therapy, argon plasma coagulation (APC), and more recently, radiofrequency ablation (RFA). RFA uses a focal heat process to destroy the Barrett's tissue. In recent years, RFA has become the ablative treatment of choice in the management of dysplastic BE, with early studies suggesting excellent efficacy and low rates of adverse events.

"Only one trial to date has directly compared complete EMR and RFA in treating dysplastic BE. The aim of this systematic review was to compare the efficacy and safety of these two techniques. This is important because RFA is substantially more expensive than complete EMR and may require multiple procedures over six months or more, making it less acceptable to patients. Therefore, in order to justify the use of RFA in the future it must be convincingly proven to be superior to complete EMR, in terms of both efficacy and risk of adverse events," said study lead author Georgina Chadwick, MRCP, The Royal College of Surgeons of England. "We found that RFA and complete EMR are equally effective in the short-term treatment of dysplastic BE, but adverse event rates are higher with complete EMR."

Methods

This article was a systematic review of literature to compare the efficacy and safety of complete EMR and radiofrequency ablation in the treatment of dysplastic BE. Patients had a diagnosis of BE with HGD or intramucosal cancer treated with either complete EMR or RFA. Main outcome measurements included complete eradication of dysplasia and intestinal metaplasia at the end of treatment and after more than 12 months' follow-up, as well as short and long-term adverse event rates associated with either treatment.

Results

A total of 22 studies met the inclusion criteria. Only one trial directly compared the two techniques; most studies were observational case series. Dysplasia was effectively eradicated at the end of treatment in 95 percent of patients after complete EMR and 92 percent after RFA. After a median follow-up of 23 months for complete EMR and 21 months for RFA, eradication of dysplasia was maintained in 95 percent of patients treated with complete EMR and 94 percent of patients treated with RFA. Short-term adverse events were seen in 12 percent of patients treated with complete EMR, but in only 2.5 percent of those treated with RFA. Esophageal strictures were long-term adverse events in 38 percent of patients treated with complete EMR, compared with 4 percent of those treated with RFA. Progression to cancer appeared to be rare after either treatment, although follow-up was short.

The authors concluded that both complete EMR and RFA have proven efficacy in eradication of BE with HGD or intramucosal cancer, but both short and long-term adverse events are significantly greater after complete EMR. The results of this review suggest that RFA, with prior resection of any nodules, is the endoscopic treatment of choice for dysplastic BE. But further research needs to be done to prove the long-term durability of both treatments in order to confirm their superiority over surgery in the management of dysplastic BE. Though low, the risk of recurrence of dysplasia and intestinal metaplasia after treatment reiterates the need for continuing endoscopic surveillance. Further research needs to determine the optimal surveillance regimen after successful eradication.

Ultra-sensitive nano-chip capable of detecting cancer at early stages

Ultra-sensitive nano-chip capable of detecting cancer at early stages

Today, the majority of cancers are detected on the macroscopic level, when the tumor is already composed of millions of cancer cells and the disease is starting to advance into a more mature phase. But what if we could diagnose cancer before it took hold - while it was still only affecting a few localized cells? It would be like putting a fire out while it was still just a few sparks versus after having already caught on and spread to many areas of the house.

An international team of researchers, led by ICFO- Institute of Photonic Sciences in Castelldefels, announce the successful development of a "lab-on-a-chip" platform capable of detecting protein cancer markers in the blood using the very latest advances in plasmonics, nano-fabrication, microfluids and surface chemistry. The device is able to detect very low concentrations of protein cancer markers in blood, enabling diagnoses of the disease in its earliest stages. The detection of cancer in its very early stages is seen as key to the successful diagnosis and treatment of this disease.

This cancer-tracking nano-device shows great promise as a tool for future cancer treatments, not only because of its reliability, sensitivity and potential low cost, but also because of its easy carry-on portable properties, which is foreseen to facilitate effective diagnosis and suitable treatment procedures in remote places with difficult access to hospitals or medical clinics.
This shows the lab-on-a-chip.
Credit: ICFO - the Institute of Photonic Sciences

How it works: Although very compact (only a few square centimeters), the lab-on-a-chip hosts various sensing sites distributed across a network of fluidic micro-channels that enables it to conduct multiple analyses. Gold nano-particles lie on the surface of the chip and are chemically programed with an antibody receptor in such a way that they are capable of specifically attracting the protein markers circulating in blood. When a drop of blood is injected into the chip, it circulates through the micro-channels and if cancer markers are present in the blood, they will stick to the nano-particles located on the micro-channels as they pass by, setting off changes in what is known as the "plasmonic resonance". The device monitors these changes, the magnitude of which are directly related to the concentration/number of markers in the patient blood thus providing a direct assessment of the risk for the patient to develop a cancer.
This shows the lab-on-a-chip.
Credit: ICFO - The Institute of Photonic Sciences

ICREA Professor at ICFO Romain Quidant, coordinator of the project comments, "the most fascinating finding is that we are capable of detecting extremely low concentrations of this protein in a matter of minutes, making this device an ultra-high sensitivity, state-of-the-art, powerful instrument that will benefit early detection and treatment monitoring of cancer". In 2009, Prof. Quidant's research group at ICFO, in collaboration with several groups of oncologists, joined the worldwide effort devoted to the ultra-sensitive detection of protein markers located on the surface of cancer cells and in peripheral blood, which had been determined to be a clear indicator of the development of cancer. In 2010, they successfully obtained funding for the project called SPEDOC (Surface Plasmon Early Detection of Circulating Heat Shock Proteins and Tumor Cells) under the 7th Framework Program (FP7) of the European Commission. The effort was also boosted by generous philanthropic support from Cellex Foundation Barcelona. Today's announcement is an important outcome of this project.

About this study:

This work has been supported by Cellex Foundation Barcelona and by the SPEDOC project, funded by the Seventh Framework Program (FP7) of the European Commission.

Reference: Srdjan S Acimovic , Maria Alejandra Ortega , Vanesa Sanz , Johann Berthelot , Jose Luis Garcia-Cordero , Jan Renger , Sebastian J. Maerkl , Mark Patrick Kreuzer , and Romain Quidant, LSPR Chip for Parallel, Rapid, and Sensitive Detection of Cancer Markers in Serum, Nano Letters, DOI: 10.1021/nl500574n

ICFO-The Institute of Photonic Sciences

New anticancer compound discovered using accelerated drug screening process

New anticancer compound discovered using accelerated drug screening process

A team of research scientists from VTT Technical Research Centre of Finland, the University of Turku and the University of Eastern Finland has discovered a previously unknown Cent-1 molecule that kills cancer cells. Their research also shows that new cancer drug candidates can be identified faster and at lower cost by using computer-assisted and cell-based screening of compounds.

The objective of the research project led by Marko Kallio, Principal Scientist at VTT, was to accelerate the drug development process by identifying new compounds that would possess similar binding properties and cellular phenotype , but a different chemical structure, as the selected drugs in clinical use or investigational compounds in development.

The scientists combined computer-based screening and cell-based assays to create a method that can significantly accelerate drug discovery and thereby lower development costs. It is highly likely that the new compounds identified using this method have not yet been patented.

The research team conducted a computer-assisted screening of 65,000 compounds and cell-based assays on the 150 highest scoring hit compounds, before identifying the Cent-1 molecule. The Cent-1 molecule kills cancer cells through a mechanism similar to that of the template drug Rigosertib that is currently under commercial development. However, since the chemical structure of the Cent-1 compound differs from Rigosertib, there are no major obstacles to further development.

What makes the study also significant is evidence that Rigosertib did not inhibit its reported target genes; there is reason to believe that the drug has a different mechanism of action at molecular level than anticipated. This drug discovery related study was published recently in Molecular Cancer Therapeutics.

Development of new drugs is an expensive and time-consuming process. It usually takes around 10-15 years to complete and costs several hundreds of millions of euros. In addition, risks associated with the usability, therapeutic efficacy and market share of medicinal substances are usually realised only in the final stages of drug development.

Early steps of totipotency in sperm precursors uncovered

Early steps of totipotency in sperm precursors uncovered

In the body, a skin cell will always be skin, and a heart cell will always be heart. But in the first hours of life, cells in the nascent embryo become totipotent: they have the incredible flexibility to mature into skin, heart, gut, or any type of cell.

It was long assumed that the joining of egg and sperm launched a dramatic change in how and which genes were expressed. Instead, new research shows that totipotency is a step-wise process, manifesting as early as in precursors to sperm, called adult germline stem cells (AGSCs), which reside in the testes.

The study was co-led by Bradley Cairns, Ph.D., University of Utah professor of oncological sciences, and Huntsman Cancer Institute investigator, and Ernesto Guccione, Ph.D., of the Agency for Science Technology and Research in Singapore. They worked closely with first author and Huntsman Cancer Institute postdoctoral fellow, Saher Sue Hammond, Ph.D. The research was published online in the journal Cell Stem Cell.

Typically, sperm precursors live a mundane life. They divide, making more cells like themselves, until they receive the signal instructing them to mature into sperm.

There is evidence, however, that these cells have the potential to do more. Under the unusual conditions that promote the cells to form dense cancerous masses called testicular teratomas, the young sperm transform into precursors of skin, muscle, and gut.

This realization prompted the investigators to examine the gene program within sperm precursors. They wondered, would it be like that of a cell that is destined to become a single cell type, or like that of a cell with the potential to become anything?

The answer, they found, is that the sperm precursors are somewhere in between. The most telling evidence is the status of a quartet of genes: Lefty, Sox2, Nanog, and Prdm14. When activated, the genes can trigger a cascade of events that give cells stem cell properties. In cells limited to becoming one cell type, the genes are silent.

Yet in sperm precursors, the genes bear a code of chemical tags, called methylation groups, indicating that the four genes are silenced, but poised to become active. In other words, embedded within these cells, is the potential to become totipotent.

Cairns compares the tags on the poised genes to bookmarks. "Sperm cells and their precursors put 'bookmarks' at all the important genes they need to access quickly." Once fertilization occurs, he explains, cells have to become fully totipotent in a short amount of time. "Then, when the sperm and egg come together, all you have to do is complete the job that you had already started."

The engineering principal, as he calls it, ensures the transition occurs rapidly and accurately.

The result is just one of many that together comprise a detailed playbook documenting genetic and epigenetic changes that take place along the journey to becoming totipotent. The rich resource will guide future studies toward a deeper understanding of totipotency, cancer, and fertilization.

Destroying brain tumors using herpes-loaded stem cells

Destroying brain tumors using herpes-loaded stem cells

Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital have a potential solution for how to more effectively kill tumor cells using cancer-killing viruses. The investigators report that trapping virus-loaded stem cells in a gel and applying them to tumors significantly improved survival in mice with glioblastoma multiforme, the most common brain tumor in human adults and also the most difficult to treat.

The work, led by Khalid Shah, MS, PhD, an HSCI Principal Faculty member, is published in the Journal of the National Cancer Institute. Shah heads the Molecular Neurotherapy and Imaging Laboratory at Massachusetts General Hospital.

Cancer-killing or oncolytic viruses have been used in numerous phase 1 and 2 clinical trials for brain tumors but with limited success. In preclinical studies, oncolytic herpes simplex viruses seemed especially promising, as they naturally infect dividing brain cells. However, the therapy hasn't translated as well for human patients. The problem previous researchers couldn't overcome was how to keep the herpes viruses at the tumor site long enough to work.

Shah and his team turned to mesenchymal stem cells (MSCs) - a type of stem cell that gives rise to bone marrow tissue - which have been very attractive drug delivery vehicles because they trigger a minimal immune response and can be utilized to carry oncolytic viruses. Shah and his team loaded the herpes virus into human MSCs and injected the cells into glioblastoma tumors developed in mice. Using multiple imaging markers, it was possible to watch the virus as it passed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.

"So, how do you translate this into the clinic?" asked Shah, who also is an Associate Professor at Harvard Medical School.

"We know that 70-75 percent of glioblastoma patients undergo surgery for tumor debulking, and we have previously shown that MSCs encapsulated in biocompatible gels can be used as therapeutic agents in a mouse model that mimics this debulking," he continued. "So, we loaded MSCs with oncolytic herpes virus and encapsulated these cells in biocompatible gels and applied the gels directly onto the adjacent tissue after debulking. We then compared the efficacy of virus-loaded, encapsulated MSCs versus direct injection of the virus into the cavity of the debulked tumors."

Using imaging proteins to watch in real time how the virus combated the cancer, Shah's team noticed that the gel kept the stem cells alive longer, which allowed the virus to replicate and kill any residual cancer cells that were not cut out during the debulking surgery. This translated into a higher survival rate for mice that received the gel-encapsulated stem cells.

"They survived because the virus doesn't get washed out by the cerebrospinal fluid that fills the cavity," Shah said. "Previous studies that have injected the virus directly into the resection cavity did not follow the fate of the virus in the cavity. However, our imaging and side-by-side comparison studies showed that the naked virus rarely infects the residual tumor cells. This could give us insight into why the results from clinical trials with oncolytic viruses alone were modest."

The study also addressed another weakness of cancer-killing viruses, which is that not all brain tumors are susceptible to the therapy. The researchers' solution was to engineer oncolytic herpes viruses to express an additional tumor-killing agent, called TRAIL. Again, using mouse models of glioblastoma - this time created from brain tumor cells that were resistant to the herpes virus - the therapy led to increased animal survival.

"Our approach can overcome problems associated with current clinical procedures," Shah said. "The work will have direct implications for designing clinical trials using oncolytic viruses, not only for brain tumors, but for other solid tumors."

Further preclinical work will be needed to use the herpes-loaded stem cells for breast, lung and skin cancer tumors that metastasize to the brain. Shah predicts the approach will enter clinical trials within the next two to three years.

New approach for sampling gut bacteria to illuminate bacteria's role in disease

New approach for sampling gut bacteria to illuminate bacteria's role in disease

Scientists at Forsyth, Massachusetts General Hospital and the Harvard School of Public Health have developed a new protocol for collecting saliva and stool samples for genomic and transcriptomic analyses. This method eliminates the need for specialized personnel and facilities while keeping the sample intact. It also provides critical insight into the genetic makeup of the microbiome of the digestive tract and the bacteria associated with celiac disease, oral cancer, perodontitis and obesity.

This study, "Relating the metatranscriptome and metagenome of the human gut," is published in the Proceedings of the National Academy of Sciences and available online the week of May 19th. By removing some of the burden for the study subjects, this technique will enable both longitudinal studies and large collection studies that are not limited by geography.

In recent years, the Human Microbiome Project has helped define the normal bacterial makeup of the human body. Scientists have conducted large-scale studies to analyze the microbial (bacterial) organisms living in and on the human body. Studying human-bacteria interactions could lead to new ways to monitor human health status and to new methods for preventing or treating oral and systemic human diseases. However, such studies typically require subjects to report to clinics for sample collection - a complicated practice that is impractical for large studies. To address these issues, the team of scientists developed a protocol that allows subjects to collect microbiome samples at home and ship them to laboratories for multiple types of molecular analysis. The microbial species, gene, and gene transcript composition were consistent in all samples despite the diverse sampling methods. Subsequent analysis of these samples revealed interesting similarities and differences between the measured functional potential and activity of the human microbiome.

Dr. Jacques Izard, Associate Member of Staff at The Forsyth Institute designed the choice of the fixatives and the sampling protocol in collaboration with Dr. Curtis Huttenhower, Harvard School of Public Health; and Dr. Andrew Chan, Massachusetts General Hospital.

"It was rewarding to confirm the findings of the human microbiome project by showing that genetic diversity is lower than the bacterial diversity present in a sample," said Dr. Izard. "Furthermore, we are excited about the opportunities this protocol presents for future large-scale studies. As the sensitivity of the sequencing technologies and the computing tools are improving, minute change can be detected. Our collaborative group demonstrated that we can analyze samples self-collected and shipped, in confidence for future biological marker discovery".

"Several longitudinal Harvard cohort studies - including the Nurses' Health Study and the Health Professionals Follow-up Study - follow over 200,000 individuals that reside across the U.S. Participants have provided us a wealth of prospective information on diet, lifestyle and diagnoses of several diseases over the last 30 years. In this work, we demonstrate the feasibility of having individuals within these cohorts self-collect their samples at home. Scaling up this collection to the larger cohort represents a great opportunity to study the microbiome as a risk factor for multiple chronic diseases," said Dr. Chan.

Overview of Study

Although the composition of the human microbiome is now well-studied, there is little known about the more than the eight million genes in the microbiota, and their regulation remain largely uncharacterized. This knowledge gap is in part because of the difficulty of acquiring large numbers of samples amenable to functional studies of the microbiota. This project demonstrates the representativeness of self-collected, self-shipped, saliva and stool samples in metagenomic and metatranscriptomic assays of the microbiome.

This is one of the first human microbiome studies in a well-phenotyped prospective cohort incorporating taxonomic, metagenomic, and metatranscriptomic profiling at multiple body sites using self-collected samples. Stool and saliva were provided by eight healthy subjects, with the former preserved by three different methods (freezing, ethanol, and RNAlater) to validate self-collection. Within-subject microbial species, gene, and transcript abundances were highly concordant across sampling methods, with only a small fraction of transcripts (<5%) displaying between-method variation. Next, the team investigated relationships between the oral and gut microbial communities, identifying a subset of abundant oral microbes that routinely survive transit to the gut but have minimal transcriptional activity there. Finally, systematic comparison of the gut metagenome and metatranscriptome revealed that a substantial fraction (41%) of microbial transcripts were not differentially regulated relative to their genomic abundances. Of the remainder, consistently underexpressed pathways included sporulation and amino acid biosynthesis, whereas up-regulated pathways included ribosome biogenesis and methanogenesis. Across subjects, metatranscriptional profiles were significantly more individualized than DNA-level functional profiles, but less variable than microbial composition, indicative of subject-specific whole-community regulation.

Height hormone offers target for fighting cancer and diabetes

Height hormone offers target for fighting cancer and diabetes

An international team - including scientists from the University of Queensland in Australia - has discovered that a hormone that controls how tall we grow could be used to treat diseases like cancer and diabetes.

Led by Mike Waters, a professor in the Institute for Molecular Bioscience at the University of Queensland, the researchers report their findings in the journal Science.

"People without growth hormone receptor don't die from cancer or diabetes, making it an ideal drug target," says Prof. Waters.

However, he goes on to explain that we do not know enough about how growth hormone works to be able to design drugs to fight these diseases.

The hormone acts through its receptor - a unique protein on the surface of cells that binds uniquely to a hormone and allows it to send signals into cells.

The team thought if they could discover more about how the hormone interacts with its receptor - for instance which part of the molecule switches the receptor on and off - then they might uncover a useful target for designing drugs to fight diseases like cancer and diabetes.

This hunch did not arise suddenly. Prof. Waters has been studying growth hormone for 45 years. He originally cloned the receptor with leading global biotech Genentech.

"We've now figured out how growth hormone turns on its receptor at the molecular level," he explains, "and so have a clear idea of which part of the molecule to target to design drugs to combat these diseases."

Lead author Dr. Andrew Brooks says the impact of their study goes further than cancer and diabetes:

"Growth hormone receptor is one of a group of proteins known as cytokine receptors, which are important targets for therapeutics for a range of disorders, including inflammatory bowel disease, blood disorders, osteoporosis and obesity."

He says that a better understanding of how the growth hormone receptor works will also give clues about how receptors for other cytokines work, which should help drug developers make treatments for many diseases.
Researchers say growth hormones could provide a target for fighting many diseases, including cancer.

For the study, the team used a combination of crystal structures, cell biology experiments, biophysical measurements, and dynamic models of how the receptor actually transmits the information bound in the hormone molecule.

The results suggest that the receptor remains in a dormant state that relies on two component molecules inhibiting each other. But when growth hormone comes along and binds to the receptor, it causes a structural change that "wakes up" the two components so they activate each other and trigger the cellular response to the hormone.

This mutual inhibition and activation model may also be how other similar cytokine receptors work, conclude the researchers.

Funds from the Australian Cancer Research Foundation, the National Health and Medical Research Council and the Australian Research Council helped finance the study.

In January 2011, Medical News Today learned how a compound that acts like an "un-growth" hormone can reverse some of the signs of aging.

The research team, which included a Saint Louis University physician, found that the compound, known as MZ-5-156, which acts in the opposite way to growth hormone, inhibited several human cancers, including prostate, breast, brain and lung cancers. The said the discovery may be counter-intuitive to some older adults who take growth hormone, thinking it will revitalize them.

Advance could offer a fast and cost-effective way to identify safe replacements for BPA

Advance could offer a fast and cost-effective way to identify safe replacements for BPA

Numerous studies have linked exposure to bisphenol A (BPA) in plastic, receipt paper, toys, and other products with various health problems from poor growth to cancer, and the FDA has been supporting efforts to find and use alternatives. But are these alternatives safer? Researchers reporting in the Cell Press journal Chemistry & Biology have developed new tests that can classify such compounds' activity with great detail and speed. The advance could offer a fast and cost-effective way to identify safe replacements for BPA.

Millions of tons of BPA and related compounds are produced each year. "I think it is fair to say that many of these BPA analogs have not been thoroughly tested, yet they are used in everyday plastics such as water bottles, baby bottles, and the lining of canned goods." says lead author Dr. Fabio Stossi of Baylor College of Medicine.

BPA and BPA analogs belong to a class of compounds called endocrine disruptors, so named because they can interfere with the body's endocrine, or hormonal, system. Using their newly developed assays on living cells, Dr. Stossi and his colleagues characterized how 18 different BPA analogs affect alpha and beta estrogen receptors, which are the primary targets of this class of chemicals. Their studies were conducted using high throughput microscopy and automated image analysis in different cell line models, with varying exposures to BPA analogs.

The investigators were able to record and analyze massive data sets related to BPA analogs. "The high throughput approach that we've refined during the past several years can simultaneously quantify what these compounds are doing to a wide range of processes such as protein levels, nuclear trafficking, DNA binding, protein interactions, transcription, cell cycle, and proliferation," says senior author Dr. Michael A. Mancini, of Baylor and the Texas A&M Health Science Center Institute of Biosciences and Technology (IBT). "The results showed us that various BPA analogs increased or decreased certain receptor activities, while others were receptor specific; clearly, the various BPA analogs can have unique properties."

The investigators found that many BPA analogs have inhibitory effects on the beta form of the estrogen receptor, a less well-studied steroid receptor that has tumor fighting properties. Many analogs also acted to stimulate the alpha form of the estrogen receptor or they had mixed inhibitory and stimulatory effects. Determining precisely how these effects influence human health will require additional research. "These studies represent a breakthrough in our ability to focus precious resources on those BPA analogs and other endocrine disrupting chemicals of greatest concern," says coauthor Dr. Cheryl Walker of the IBT.

The scientists note that there are likely many more BPA-like compounds that can be found in products and in the environment. The widely applicable technologies used in the study will enable investigators to rapidly test such compounds for any unexpected or undesirable properties.

Defining Estrogenic Mechanisms of Bisphenol A Analogs through High Throughput Microscopy-Based Contextual Assays, Fabio Stossi, Michael J. Bolt, Felicity J. Ashcroft, Jane E. Lamerdin, Jonathan S. Melnick, Reid T. Powell, Radhika D. Dandekar, Maureen G. Mancini, Cheryl L. Walker, John K. Westwick, Michael A. Mancini, Chemistry & Biology, DOI: 10.1016/j.chembiol.2014.03.013, published online May 2014.

Cell Press

Scripps Research Institute chemists discover structure of cancer drug candidate

Scripps Research Institute chemists discover structure of cancer drug candidate

Chemists at The Scripps Research Institute (TSRI) have determined the correct structure of a highly promising anticancer compound approved by the U.S. Food and Drug Administration (FDA) for clinical trials in cancer patients.

The new report, published this week by the international chemistry journal Angewandte Chemie, focuses on a compound called TIC10.

In the new study, the TSRI scientists show that TIC10's structure differs subtly from a version published by another group last year, and that the previous structure associated with TIC10 in fact describes a molecule that lacks TIC10's anticancer activity.

By contrast, the correct structure describes a molecule with potent anticancer effects in animals, representing a new family of biologically active structures that can now be explored for their possible therapeutic uses.

"This new structure should generate much interest in the cancer research community," said Kim D. Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI.

Antitumor Potential

TIC10 was first described in a paper in the journal Science Translational Medicine in early 2013. The authors identified the compound, within a library of thousands of molecules maintained by the National Cancer Institute (NCI), for its ability to boost cells' production of a powerful natural antitumor protein, TRAIL. (TIC10 means TRAIL-Inducing Compound #10.)

As a small molecule, TIC10 would be easier to deliver in a therapy than the TRAIL protein itself. The paper, which drew widespread media coverage, reported that TIC10 was orally active and dramatically shrank a variety of tumors in mice, including notoriously treatment-resistant glioblastomas.

Tumors can develop resistance to TRAIL, but Janda had been studying compounds that defeat this resistance. The news about TIC10 therefore got his attention. "I thought, 'They have this molecule for upregulating TRAIL, and we have these molecules that can overcome tumor cell TRAIL resistance - the combination could be important,'" he said.

The original publication on TIC10 included a figure showing its predicted structure. "I saw the figure and asked one of my postdocs, Jonathan Lockner, to make some," Janda said.

Although the other team had seemingly confirmed the predicted structure with a basic technique called mass spectrometry, no one had yet published a thorough characterization of the TIC10 molecule. "There were no nuclear magnetic resonance data or X-ray crystallography data, and there was definitely no procedure for the synthesis," Lockner said. "My background was chemistry, though, so I was able to find a way to synthesize it starting from simple compounds."

Surprising Inactivity

There was just one problem with Lockner's newly synthesized "TIC10." When tested, it failed to induce TRAIL expression in cells, even at high doses.

"Of course I was nervous," remembered Lockner. "As a chemist, you never want to make a mistake and give biologists the wrong material."

To try to verify they had the right material, Janda's team obtained a sample of TIC10 directly from the NCI. "When we got that sample and tested it, we saw that it had the expected TRAIL-upregulating effect," said Nicholas Jacob, a graduate student in the Janda Laboratory who, with Lockner, was a co-lead author of the new paper. "That prompted us to look more closely at the structures of these two compounds."

The two researchers spent months characterizing their own synthesized material and the NCI material, using an array of sophisticated structural analysis tools. With Assistant Professor Vladimir V. Kravchenko of the TSRI Department of Immunology and Microbial Science, Jacob also tested the two compounds' biological effects.

The team eventually concluded that the TIC10 compound from the NCI library does boost TRAIL production in cells and remains promising as the basis for anticancer therapies, but it does not have the structure that was originally published.

The Right Structure

The originally published structure has a core made of three carbon-nitrogen rings in a straight line and does not induce TRAIL activity. The correct, TRAIL-inducing structure differs subtly, with an end ring that sticks out at an angle. In chemists' parlance, the two compounds are constitutional isomers: a linear imidazolinopyrimidinone and an angular imidazolinopyrimidinone.

Ironically, Lockner found that the angular TRAIL-inducing structure was easier to synthesize than the one originally described.

Now, with the correct molecule in hand and a solid understanding of its structure and synthesis, Janda and his team are moving forward with their original plan to study TIC10 in combination with TRAIL-resistance-thwarting molecules as an anticancer therapy.

The therapeutic implications of TIC10 may even go beyond cancer. The angular core of the TRAIL-inducing molecule discovered by Janda's team turns out to be a novel type of a biologically active structure - or "pharmacophore" - from which chemists may now be able to build a new class of candidate drugs, possibly for a variety of ailments.

"One lesson from this has got to be: don't leave your chemists behind," said Janda.

PKD patients who receive kidney transplants may have a reduced risk of cancer

PKD patients who receive kidney transplants may have a reduced risk of cancer

Patients with a certain form of kidney disease may have a reduced risk of cancer compared with patients with other kidney diseases, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN).

Polycystic kidney disease (PKD) is a kidney disorder passed down through families in which many cysts form in the kidneys, causing them to become enlarged. It's thought to have cancer-like features, but cancer risk has never been compared between PKD patients and others with kidney disease. Cancer risk is also elevated in people who have received a kidney transplant, due to the immunosuppressive drugs they must take.

James B. Wetmore, MD, MS (University of Kansas Medical Center) and his colleagues conducted the first study to examine cancer risk in kidney transplant recipients with PKD and to compare their risk to that of other kidney transplant recipients.

The team analyzed data from the National Cancer Institute's Transplant Cancer Match Study, which contains information on all solid organ transplant recipients in the United States, as well as data from 15 population-based US cancer registries. For PKD recipients, the investigators compared overall cancer risk to that in the general population. They also compared cancer incidence in PKD vs non-PKD kidney transplant recipients. The analysis included 10,166 kidney transplant recipients with PKD and 107,339 without.

After adjusting for demographic differences between kidney recipients with PKD and other recipients, PKD patients were 16% less likely to develop cancer than others who received a kidney transplant. Compared with the general population, overall cancer risk was increased 48% in PKD recipients, while the overall cancer risk in non-PKD recipients was increased 86%.

The findings indicate that PKD patients who received transplants do not have a higher risk of cancer than other kidney recipients. In fact, their cancer risk may be lower. "The reason for the decreased risk is uncertain, but some factor or factors in PKD patients - either inherent in the disease process itself or related to the care PKD patients receive - is associated with lower risks of cancers," said Dr. Wetmore. "Further study is required to determine how PKD might influence the development of cancer."

Dr. Wetmore speculated that PKD may induce certain anti-neoplastic defense mechanisms that guard against the subsequent development of cancer. Alternatively, it may be that PKD patients, who are frequently aware that they have a progressive medical condition and who therefore typically receive close medical care for many years or decades, engage in other healthy behaviors that prevent cancer.

Study co-authors include James Calvet, PhD, Alan Yu, Charles Lynch, MD, PhD Connie Wang, MD, Bertram Kasiske, MD, and Eric Engels, MD, MPH.

Disclosures: The authors reported no financial disclosures.

The article, entitled "Polycystic Kidney Disease and Cancer after Renal Transplantation," appears online at http://jasn.asnjournals.org/.

American Society of Nephrology

Are intuitions about the causes of rising obesity wrong?

Are intuitions about the causes of rising obesity wrong?

Everything you think you know about the causes of rising obesity in the U.S. might be wrong, researchers say in a new report.

Contrary to popular belief, people are exercising more today, have more leisure time and better access to fresh, affordable food - including fruits and vegetables - than they did in past decades. And while troubling disparities exist among various groups, most economic, educational, and racial or ethnic groups have seen their obesity levels rise at similar rates since the mid-1980s, the researchers report.

The new analysis appears in CA: Cancer Journal for Clinicians.

Obesity rates in the U.S. have been going up for decades, said University of Illinois kinesiology and community health professor Ruopeng An, who conducted the new analysis with Roland Sturm, of the RAND Corp. in Santa Monica, California.

"Many factors have been suggested as causes," the researchers wrote. Snack food, fast food, automobile use, time spent viewing television or looking at computer screens, the ubiquity of vending machines, suburban sprawl, increasing portion sizes, female labor force participation, poverty, affluence, supermarket availability and even the absence of supermarkets are blamed, the researchers said.

"As it turns out, some widely held beliefs about societal trends are unambiguously false; others require some qualifications," they wrote.

Geography and the existence of so-called "food deserts" (neighborhoods or regions with limited access to affordable, healthy food) appear to have little bearing on the obesity trend in general, although they may be linked to differences between groups at any given point in time, An said.

"A common misconception is that the obesity epidemic reflects increasing social disparities and that the largest weight gains are concentrated in groups identifiable by race, ethnicity, income, education or geography," he said. "And it's true that if you look at the national data for any one point in time, it's not hard to figure out, for example, that the people with the lowest education tend to have the highest obesity rate. Everyone buys this argument. But what is less obvious is how surprisingly similar the obesity trend is for all groups."

A look at graphs of obesity over time (see The Obesity Trend) offers a more universal view of what is going on, An said. Obesity is higher for blacks than for whites, but both groups are getting heavier at almost the same rate over time. The same disparity is seen in people who never finished high school versus those with a college degree, or those with lower versus higher incomes. The trend lines vary somewhat - the gap between white men and black men has recently narrowed, for example, while the gap for black and white women has widened - but obesity is going up in all these groups at about the same rate, An said.

"The gap between groups is secondary to the increase that all groups experience over time," he said. "So a reversal of the obesity epidemic would need universal intuitions rather than a focus on certain groups."

Some common explanations for the upward surge in obesity are simply wrong, An said. For example, the idea that longer workdays or less leisure time are to blame is not supported by the data. Americans are working fewer hours and have more leisure time than they did in the 1960s, he said. People are spending less time on household chores and caring for dependents than they did decades ago, and they have more free time than ever, he said.

The notion that people are getting fatter because they have less access to affordable, healthy foods also contradicts the data, An said.

"The percent of disposable income spent on food fell quite a bit from 1970 to 2010," he said. "And in fact in the 1930s American people spent one-third of their disposable income on food, while today people spend less than one-tenth. So it's hard to argue that food has become more expensive in general."

The cost of fruits and vegetables has not increased over time, as some have argued, but has gone down more than 20 percent since 1970, the researchers report.

"The price of fruits and vegetables is decreasing - but not as rapidly as the cost of junk food," An said.

Overall, food is more accessible and affordable than ever in the United States, and this may be an important factor in the dramatic rise in obesity, he said.

The data on exercise and physical activity also are muddier than some people like to admit, An said. American participants in the Behavioral Risk Factor Survey reported in 2012 that they were exercising on average four minutes more a day than reported in 2003. But they also reported sleeping 10 minutes longer and watching 15 more minutes of TV.

"Self-reported exercise increases over time, and the total sedentary time also increases over time," An said. "So we are kind of in a dilemma trying to figure out what really contributes to the obesity epidemic. We have a lot of hypotheses but we really don't have much data to support them at this stage."

UN officials warn refugees are struggling to access cancer treatment

UN officials warn refugees are struggling to access cancer treatment

A study published in The Lancet Oncology journal reveals a high demand for costly cancer treatment among refugees from the recent conflicts in Iraq and Syria, with host countries struggling to find the money and the medicine to treat their new patients. The findings have prompted calls from lead author Dr Paul Spiegel, the United Nations High Commissioner for Refugees (UNHCR) Chief Medical Expert, for innovative financing schemes to improve access to affordable high-quality cancer care for refugees.

In the first study of its kind, Spiegel and colleagues examined data from funding applications made to the UNHCR Exceptional Care Committee (ECC) from refugees in Jordan and Syria whose cancer treatment costs were likely to exceed US$2000 a year.

The findings show that cancer is an important public health problem in refugee settings and highlight the huge challenges and immense costs that national health systems and humanitarian organisations face when overwhelmed by massive influxes of refugees.

For example, in Jordan the ECC assessed 1989 applications for treatment between 2010 and 2012, of which roughly a quarter (511) were for cancer - breast cancer and colorectal cancer being the most common. Around half (48%) of these cases were approved and funded. The main reasons for denied funding were a poor prognosis (43% of cases in 2011 and 31% in 2012) or that the treatment was too costly (25% in 2011). The average amount requested from the ECC for cancer treatment was US$11 540 in 2011 and US$5151 in 2012; however, the amounts approved were substantially lower - US$4626 in 2011 and US$3501 in 2012.

"The countries in the Middle East have welcomed millions of refugees, first from Iraq and then Syria. This massive influx has strained health systems at all levels. Despite help from international organisations and donors to expand health facilities and pay for additional personnel and drugs, it has been insufficient. The burden has fallen disproportionately on the host countries to absorb the costs. For example, the Jordanian Ministry of Health footed an estimated $53 million bill for medical care for refugees in the first four months of 2013", says Dr Spiegel.*

The authors call for improved cancer prevention and treatment in refugee settings through the use of innovative financing schemes, better primary care including screening for common cancers (eg, colonoscopies and mammograms), and the development of electronic web-based cancer registries to prevent interruption of treatment.

According to Dr Spiegel, "Until now, the response to humanitarian crises have been primarily based on experiences from refugee camps in sub-Saharan Africa where infectious diseases and malnutrition have been the priority. In the 21st century, refugee situations are substantially longer and increasingly occur in middle-income countries where the levels of chronic diseases, including cancer, are higher. Cancer diagnosis and care in humanitarian emergencies typifies a growing trend towards more costly chronic disease care, something that seems to have been overlooked, but is of increasing importance because the number of refugees is growing."*

When it comes to making tough life-or-death calls, molecule acts as umpire

When it comes to making tough life-or-death calls, molecule acts as umpire

St. Jude Children's Research Hospital solves mystery of enzyme's role in cell survival, offering clues of how immune system fights infection and possible strategies to treat problems ranging from heart attack to cancer

Researchers have demonstrated that an enzyme required for animal survival after birth functions like an umpire, making the tough calls required for a balanced response to signals that determine if cells live or die. St. Jude Children's Research Hospital scientists led the study, which was published online and appears in the scientific journal Cell.

The work involved the enzyme receptor-interacting protein kinase 1 (RIPK1). While RIPK1 is known to be involved in many vital cell processes, this study shows that its pivotal role in survival after birth is as an inhibitor of two different pathways that lead to the death of cells. Functioning properly, the pathways provide a way to get rid of dangerous, damaged or unneeded cells.

By removing different components of each pathway in different combinations, researchers demonstrated that after birth RIPK1 helps cells maintain a balanced response to signals that promote either pathway. "We are learning that in disease this balancing act can be perturbed to produce damage and cell death," said the study's corresponding author Douglas Green, Ph.D., chair of the St. Jude Department of Immunology.

The results resolve long-standing questions about RIPK1's role in cell survival and provide clues about how the disease-fighting immune system might use these pathways to contain infections. The findings have also prompted researchers to launch an investigation into whether RIPK1 could be harnessed to kill cancer cells or provide insight into tumor development. RIPK1 is already the focus of drug development efforts designed to limit cell damage following heart attack, stroke or kidney injury.

"This study fundamentally changes the way we think about RIPK1, a molecule that we care about because it is required for life," Green said. "The results helped us identify new pathways involved in regulating programmed cell death and suggest that we might be able to develop cancer therapies that target these the pathways or engage them in other ways to advance treatment of a range of diseases."

The study is one of two involving RIPK1 being published in the same edition of Cell.

The St. Jude report builds on previous research from Green's laboratory regarding regulation of the pathways that control two types of programmed cell death. One, called apoptosis, is driven by an enzyme named caspase-8. It forms a complex with a protein named FADD as well as other proteins that prompt cells to bundle themselves into neat packages for disposal. The other, called necroptosis, involves a different pathway that is orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Researchers knew that before birth, RIPK1 worked through RIPK3 to trigger cell death by necroptosis, but until now the enzyme's primary role after birth was uncertain.

For this study, researchers bred mice lacking different combinations of genes for ripk1, ripk3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.

Mice lacking ripk1 died. Mice missing two genes - ripk1 plus ripk3 or ripk1 plus caspase-8 or FADD - also died soon after birth. Mice survived and developed normally, however, when researchers removed three genes - ripk1, ripk3 and either caspase-8 or FADD. "The fact that the mice survived was totally unexpected and made us rethink how these pathways worked," Green said.

Added Christopher Dillon, Ph.D., a postdoctoral fellow in Green's laboratory: "Knocking out two genes to restore balance following the loss of another gene, in this case RIPK1, is exceedingly rare." Dillon and St. Jude postdoctoral fellows Ricardo Weinlich, Ph.D., and Diego Rodriguez, Ph.D., are the paper's first authors.

The finding established RIPK1's premier role in cell survival as inhibition of apoptosis and necroptosis.

The results also demonstrated that other pathways must exist in cells to maintain a balanced response to signals pushing for cell death via apoptosis or necroptosis. Evidence in this study, for example, suggested one possible new pathway that triggered necroptosis using interferon and other elements of the immune response to infections.

The study’s other authors are James Cripps, Giovanni Quarato, Prajwal Gurung, Katherine Verbist, Taylor Brewer, Fabien Llambi, Yi-Nan Gong, Laura Janke and Thirumala-Devi Kanneganti, all of St. Jude, and Michelle Kelliher, of the University of Massachusetts Medical School, Worcester, Mass.

The research was funded in part by grants (AI44828 and CA169291) from the National Institutes of Health and ALSAC.

St. Jude Children's Research Hospital

Cardiac screening guidelines for survivors of childhood cancer may need revision

Cardiac screening guidelines for survivors of childhood cancer may need revision

One of the first studies to analyze the effectiveness of screening survivors of childhood cancer for early signs of impending congestive heart failure (CHF) finds improved health outcomes but suggests that less frequent screening than currently recommended may yield similar clinical benefit. The researchers, in a study published in the Annals of Internal Medicine, utilized a simulation-based model to estimate the long-term benefits associated with routine screening.

The study's findings suggest that the current CHF screening guidelines for survivors of pediatric cancer should be re-examined. The current guidelines recommend that survivors treated with chemotherapy agents known to affect long-term heart health be screened as often as every year, with a schedule dependent on their level of CHF risk. The new study suggests that screening survivors less often may be nearly as effective in detecting heart disease early. Some survivors might be better served by a different method of screening than the one currently used.

"It is important to monitor survivors so we can reduce the late effects of treatment whenever possible, but we may be asking them to be tested too often, which burdens both individuals and the health care system," says senior author Lisa Diller, MD, chief medical officer of Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "We think it is worthwhile to review the current CHF screening guidelines."

"Our findings suggest that there is a long-term benefit in screening survivors at elevated risk for CHF," says lead author Jennifer Yeh, PhD, of the Center for Health Decision Science at Harvard School of Public Health. "Yet less frequent screening than currently recommended may be reasonable when other factors are considered. We hope these results can help inform the ongoing discussion about screening childhood cancer survivors."

As cure rates of pediatric cancers have risen, increasing numbers of survivors are at a substantially higher risk of heart disease, including congestive heart failure, compared to the general population. The increase in risk varies depending on several factors, including whether a patient was treated with anthracyclines, a class of drugs known to cause heart disease, and/or radiation to the heart. For instance, those who received no or low (<250 mg/m2) cumulative doses of anthracyclines have a relatively low lifetime risk of developing CHF, while those who received large (=250 mg/m2) cumulative doses are at higher risk.

The Children's Oncology Group (COG) currently recommends that survivors undergo screening by echocardiography for asymptomatic left ventricular dysfunction (ALVD). If left untreated, this clinically silent condition can progress to CHF, so clinicians typically prescribe beta blockers and ACE inhibitors to patients with signs of ALVD. COG recommends that patients at high risk of developing CHF be screened every year or two and those at low risk be screened every two or five years.

"Survivors are screened for decades and face risks for other late effects, as well," Diller says. "We need to consider carefully how often we ask survivors to be screened over the course of their lives, given the substantial cumulative economic impact and anxiety that screening may cause."

To estimate the clinical benefits and cost-effectiveness of the current heart screening guidelines, Diller, Yeh and their co-author, cardiologist Anju Nohria, MD, of Brigham and Women's Hospital, constructed a computer model of a virtual cohort of 15-year-olds who had survived cancer at least five years. Using data from the Childhood Cancer Survivors Study and the Framingham Heart Study, the researchers modeled the cohort's CHF risk and clinical progression over the course of survivors' lifetimes. Their analysis suggests that routine screening may prevent as many as one in 12 cases of CHF.

The authors then used Medicare data to estimate the costs and value (expressed in cost per quality-adjusted life year [QALY]) of different screening schedules (i.e., every 1, 2, 5 or 10 years) and methods (echocardiography versus cardiac magnetic resonance imaging [cMRI]) for the different CHF risk groups (i.e., low, high).

At a cost-effectiveness threshold of $100,000/QALY, the model's results indicate that echocardiographic screening might not be the best value for resources invested to reduce lifetime CHF risk among survivors at low risk of developing the disease. On the other hand, the data suggest that biennial echocardiography screening may be a high-value strategy for high-risk survivors.

The simulation's data also suggested that cMRI may be preferable to echocardiography as a screening method, with cMRI's greater cost per test balanced by its greater sensitivity. According to the model, cMRI-based screening of low-risk survivors every 10 years and high-risk survivors every five years was more cost effective than any echocardiography-based schedule.

Lastly, the data suggest that it may be most beneficial to treat high-risk survivors before signs of ALVD even appear. For instance, proactively treating all high-risk patients in the virtual cohort with ACE inhibitors and beta blockers reduced their lifetime CHF risk more than if they received an echocardiograph every two years, although additional clinical studies on the benefit of the treatments are needed to support this strategy in practice.

The researchers relied on simulation modeling using the best available clinical and epidemiologic data because of the immense logistical obstacles to conducting prospective randomized clinical studies of survivors' long-term cardiovascular outcomes. The number of survivors that clinical studies would need to enroll and follow for years is challenging given how rare childhood cancers are. Yet guidance on the health benefits associated with current recommendations is needed.

"Our findings suggest that current recommendations for cardiac assessment may reduce systolic CHF incidence, but less frequent screening than currently recommended may be preferred," the study concludes. "Possible revision of current recommendations is warranted."

How antibodies cluster in solution revealed by neutron beams

How antibodies cluster in solution revealed by neutron beams

Results from neutron spin-echo analysis at the Institut Laue-Langevin (ILL) and the National Center of Neutron Research (NCNR) in the United States are an important advance towards enabling subcutaneous injections of concentrated biopharmaceuticals used to treat cancer and autoimmune disorders (e.g. arthritis, multiple sclerosis). The insights obtained could help drug companies reduce the viscosity and mitigate phase separation in injectable biopharmaceuticals, making them easier to manufacture and fluid enough to be self-administered in the home.

Scientists have used small-angle neutron scattering (SANS) and neutron spin-echo (NSE) techniques for the first time to understand how monoclonal antibodies (mAbs), a class of targeted biopharmaceuticals used to treat autoimmune disorders and cancer, dynamically cluster and move in high concentration solutions. Certain mAb cluster arrangements can thicken pharmaceutical solutions; they could thus limit the feasible concentration of injectables administered to patients around the world. The insights provided by a team of neutron scientists from the National Center of Neutron Research (NCNR) and the Institut Laue-Langevin (ILL), in collaboration with colloid and proteins scientists at the University of Delaware and biopharmaceutical company Genentech (a member of the Roche group), are an important step towards the development and manufacture of high-concentration biopharmaceuticals needed for high-dose indications and potential self-administration at home.

Monoclonal antibodies (mAbs) are proving to be a vital tool in modern pharmacology, providing the basis for a growing number of successful drugs for cancer and autoimmune disorders such as arthritis and multiple sclerosis. As agents for targeted therapy with a good safety profile, they are an alternative to harsher chemotherapy treatment.

The mAbs work by attaching themselves to specific protein targets on cancerous cells, or blocking target proteins in a known biochemical pathway responsible for a disease. These treatments usually require high doses, and lately in some indications there has been considerable interest in moving from intravenous (IV) delivery to a more convenient subcutaneous (SC) delivery - a shallow injection into the cutis just below the skin (such as the home treatments offered to sufferers of type 1 diabetes). However, progress has been hampered by the high viscosity of solutions containing high amounts of mAbs, and this provides challenges to efficient and economical large-scale production, purification, and delivery of these drugs.

"For some proteins at concentrations higher than 100 mg/ml, you can't deliver them fast enough through thin, SC injection needles, so repeat visits to the hospital with intravenous drips are needed," explains Prof. Yun Liu from the National Center of Neutron Research (NCNR) in the US, who is also affiliated with the University of Delaware. "The thickening may also cause problems in processing, when filtration pressures are too high, for example, or during freeze and thaw in large tanks where potential gelation or phase separation of the freeze concentrate can occur."

As a result, efforts to find ways to raise the concentration of monoclonal antibody pharmaceuticals are focused on understanding the root cause of this thickening. Previous studies using static light scattering (Lilyestrom et al, 2013) on concentrated mAb solutions had suggested a strong link between the development of protein clustering formations and increases in viscosity.

In this latest study (Yearley et al. 2014) led by Prof. Yun Liu (NCNR) and Dr. Dan Zarraga from Genentech, in collaboration with the Institut Laue-Langevin (ILL) in Grenoble, small-angle neutron scattering (SANS) and neutron spin-echo (NSE) techniques were used to study the structure and dynamics of mAb clustering responsible for the bulk solution properties. Two types of antibody were placed in solution - one known to increase solution viscosity and one which did not - so any differences in behaviour could be observed. Neutron spin-echo (NSE) measures cluster dynamics by determining their self diffusivity (as opposed to collective diffusivity measured in dynamic light scattering). Neutrons are able to probe very high concentrations since they are scattered only by nuclei (these occupy very little space and thus appear dilute in the neutron beam's perspective). Also the unrivalled high resolution and very high neutron intensity provided by the ILL neutron spin-echo instrument IN15 allowed a systematic exploration of many different mAb samples.

Using this technique for the high viscosity mAb solution the team confirmed the presence of small extended clusters of mAbs with lifetimes sufficiently long to have an impact on bulk solution properties. On the other hand, the diffusivity measured for the low viscosity mAb solution indicated no such clustering at timescales greater than 50 nanoseconds. The two mAbs only differed in the sequence of their complementarity determining region (CDR); this shows that seemingly small changes in the sequence can have profound consequences on mAb solution behaviour.

Taking into account these insights on mAb clustering, recent studies (Zarraga et al 2013; Allmendinger et al 2014) have shown that there is a window of expulsion rates through a thin needle that reversibly disrupts these mAb clusters, helping mitigate the viscosity issue without irreversibly damaging the individual mAbs. This provides a basis for designing an optimal device system for delivering biopharmaceutical injectable solutions at very high concentrations.

The progress made in these studies is due in part to bringing research institutions and industry together to address practical problems. Research institutions in academe and national labs are often in search of applications for their technological solutions, whilst industry encounters practical problems when looking for solutions. In addition, such collaboration can spur research in adjacent, often very important, fields.

Dr Peter Falus, instrument scientist at ILL said: "Whilst the potential impact of these studies on drug design is very exciting, the subject of protein clustering is an extremely interesting area in its own right. A lot of well-known phenomena, such as the cataracts in our eyes, or Alzheimer's disease, are the results of proteins clustering in our bodies. As a physicist, I am interested in clustering in general, and neutron techniques here at the ILL provide a unique, high-resolution tool to investigate these complex interactions in natural organic systems."

Observation of Small Cluster Formation in Concentrated Monoclonal Antibody Solutions and Its Implications to Solution Viscosity. DOI: http://dx.doi.org/10.1016/j.bpj.2014.02.036 Small Angle Neutron Scattering of mAb Conformations and Interactions at High Concentration, Yearley E et al, Biophys J 105:720-731 (2013).

Monoclonal antibody self-association, cluster formation, and rheology at high concentrations, Lilyestrom et al, J Phys Chem B 117:6373-84 (2013).

High shear rheology and anisotropy in concentrated solutions of monoclonal antibodies, Zarraga IE, Taing R, et al , J Pharm Sci 102: 2538–2549 (2013).

Rheological characterization and injection forces of concentrated protein formulations: An alternative predictive model for non-Newtonian solutions, Allmendinger A, et al Eur J Pharm Biopharm pii: S0939-6411 (Feb 18 2014)

Institut Laue-Langevin

Recruiting more Hispanics to cancer clinical trials crucial to reducing health disparities

Recruiting more Hispanics to cancer clinical trials crucial to reducing health disparities

Hispanics are the fastest-growing demographic group in the United States, and they suffer from major health disparities, including higher rates of cancers of the cervix, stomach and liver.

However, their enrollment levels in cancer clinical trials seeking to cure these problems is abysmally low: 3.9 percent.

In a paper published in the Journal of Clinical Oncology, three physicians from The University of Texas Health Science Center at San Antonio analyzed Hispanic accrual rates to randomized clinical trials, and in response to the results, are issuing a call to arms to other cancer researchers to improve their recruitment of Hispanic patients.

"Fundamentally, in the most recent published cancer clinical trials, either the number and proportion of Hispanics are not reported or are far below their actual representation in the national population," said Ian M. Thompson Jr., M.D., director of the Health Science Center's Cancer Therapy & Research Center.

"We have a major responsibility to ensure adequate representation," Dr. Thompson said. "How else will we know how best to treat our patients, and how else are we going to reduce the health disparities in this population?"

Dr. Thompson, Anand Karnad, M.D., CTRC chief of the division of hematology/oncology at the CTRC, and Alberto Parra, M.D., internal medicine resident at the UT Health Science Center, examined clinical trial participation.

Fifty-eight percent of San Antonio residents are Hispanic, with 68 percent in the South Texas region as a whole. As the National Cancer Institute-designated cancer center serving South Texas, the CTRC has a strategic focus on improving health care in the region by working to increase Hispanic participation in cancer clinical trials.

In 2012, 45 percent of the 822 patients enrolled onto the clinical trials offered at CTRC were Hispanic. The CTRC achieved this by studying ways to reduce barriers that might be unique to Hispanic patients, developing a minority recruitment toolbox with bilingual forms, and creating a coordinator of minority programs who is bilingual.

"For institutions like ours that serve a 'minority-majority' population, it's a major responsibility for us to ensure adequate representation so that we can tell our patients how they can best be treated and how we can reduce the disparities of this rapidly-growing population," Dr. Thompson said.

Cholesterol plays a key role in cell migration

Cholesterol plays a key role in cell migration

University of Barcelona's researchers led by Professor Carles Enrich, from the Department of Cell Biology, Immunology and Neurosciences of the Faculty of Medicine at the University of Barcelona (UB) and CELLEX Biomedical Research Centre of IDIBAPS, have found that cholesterol plays a key role in cell mobility and tissue invasion. The results of the study prove that the accumulation of LDL cholesterol cells - the one carried by low-density lipoproteins - may play a crucial role in promoting cell mobility. On the contrary, high levels of HDL cholesterol - the one carried by high-density lipoproteins - may avoid cell propagation. This is a key study to better understand cancer metastasis, the process in which cancer cells invade healthy tissues, and foster the discussion on the relationship between cholesterol levels and cancer incidence.

Daniel Grinberg and Lluïsa Vilageliu, from the Department of Genetics of the Faculty of Biology, and Joan Blasi, from the Department of Pathology and Experimental Therapy of the Faculty of Medicine, participated in the paper, published on the journal Cell Reports. Researchers from the Garvan Institute of Medical Research, the University of Sidney (Australia), Queensland University of Technology (Brisbane, Australia) and the University of Hamburg (Germany) also collaborated in the study.

The study was developed by means of experiments carried out with cell cultures of patients with Niemann-Pick disease. These people present a genetic anomaly that causes cholesterol accumulation in the cell; that produces different motor and neurological disorders. "It is generally thought that cholesterol, one of the most important lipids in our body, is in the blood; but few people ask themselves what cholesterol does in the cell", points out Carles Enrich. "Cholesterol -adds the researcher - plays different functions in the cell. Besides being crucial to produce membranes, it also regulates vesicular trafficking. Now, it has been proved that cholesterol plays a key role in the regulation of other mechanisms, for instance cell mobility and propagation and, therefore, it is a crucial factor in metastasis".

Most cells in our body bind other cells by means of integrins, molecules that act as bridges located at the cell surface. UB researchers explored how integrins move in the cells and discovered cholesterol's key role. Enrich points out that "in the cell, cholesterol controls the trafficking of vesicles, which are responsible for transporting integrins to cell surface. Cholesterol depletion in the trans-Golgi network interferes integrin trafficking which has direct repercussions on cell migration".

New knowledge about the mechanisms of cancer metastasis

The study provides new therapeutic options to control metastasis and points out a strategy to be applied to cancer patients who also have cholesterol disorders. "It must be considered that the drugs prescribed to regulate cholesterol may modify cell migration ability. Therefore, progress in personalized therapy is absolutely important", highlights Enrich.

Now, researchers' challenge is to understand why cholesterol stays in the cell. "We want to study what endosome membrane mechanisms block intracellular traffic and hold cholesterol and their negative consequences for our health", concludes Carles Enrich.

Cholesterol Regulates Syntaxin 6 Trafficking at trans-Golgi Network Endosomal Boundaries. Reverter M, Rentero C, Garcia-Melero A, Hoque M, Vilà de Muga S, Alvarez-Guaita A, Conway JR, Wood P, Cairns R, Lykopoulou L, Grinberg D, Vilageliu L, Bosch M, Heeren J, Blasi J, Timpson P, Pol A, Tebar F, Murray RZ, Grewal T, Enrich C., Cell Rep. doi: 10.1016/j.celrep.2014.03.043, published online 17 April 2014.

University of Barcelona

Misguided DNA-repair proteins caught in the act

Misguided DNA-repair proteins caught in the act

Accumulation of DNA damage can cause aggressive forms of cancer and accelerated aging, so the body's DNA repair mechanisms are normally key to good health. However, in some diseases the DNA repair machinery can become harmful. Scientists led by a group of researchers at The Scripps Research Institute (TSRI) in La Jolla, CA, have discovered some of the key proteins involved in one type of DNA repair gone awry.

The focus of the new study, published in the journal Cell Reports, is a protein called Ring1b. The TSRI researchers found that Ring1b promotes fusion between telomeres - repetitive sequences of DNA that act as bumpers on the ends of chromosomes and protect important genetic information. The scientists also showed inhibiting this protein can significantly reduce the burden on cells affected by such telomere dysfunction.

"We are very far from therapy, but I think a lot of the factors we've identified could play key roles in processing dysfunctional telomeres, a key event in tumorigenesis [cancer initiation]," said Eros Lazzerini Denchi, assistant professor at TSRI who led the study.

The Trouble with Telomeres

Humans are born with long telomeres, but these become shorter every time a cell in the body divides. With age, telomeres become very short, especially in tissues that have high proliferation rate.

That's when the problems start. When telomeres become too short, they lose their telomere protective cap and become recognized by the DNA repair machinery proteins. This can lead to the fusion of chromosomes "end-to-end" into a string-like formation.

Joined chromosomes represent an abnormal genomic arrangement that is extremely unstable in dividing cells. Upon cell division, joined chromosomes can rupture, creating new break points that can further re-engage aberrant DNA repair. These cycles of fusion and breakage cause a rampant level of mutations that are fertile ground for cancer.

"You basically scramble the genome, and then you have lots of chances to select very nasty mutations," said Lazzerini Denchi.

Setting a DNA Trap

To understand how to prevent these deleterious fusions, Lazzerini Denchi and his colleagues wanted to identify all the repair factors involved.

The researchers decided to set a trap. Using genetically engineered cells, the researchers were able to remove a telomere binding protein called TRF2. Without TRF2, telomeres are unprotected and DNA repair proteins are recruited to chromosome ends, where they promote chromosome fusions.

The researchers then trapped and isolated all the proteins they found bound to the telomeres. "It was like a fishing expedition, and the bait in our case was the telomeric DNA sequence," said Lazzerini Denchi.

Cristina Bartocci, a postdoctoral fellow in Lazzerini Denchi's lab at the time and first author of the new study, spent more than two years perfecting a technique to identify proteins that flocked to the telomeres. "It was a pretty challenging experiment to perform," she said.

The researchers then separated the proteins from the DNA sequences and sent the proteins to TSRI Professor John Yates's laboratory for mass spectrometry analysis. This analysis revealed 24 known repair proteins and 100 additional proteins whose role in dysfunctional telomeres had not been previously described.

The team then refined their search and took a closer look at the role of the repair factor protein called Ring1b. For the first time, the scientists were able to link Ring1b to the chromosome fusion process. Bartocci said the role of Ring1b in dysfunctional telomere repair was "pretty striking."

"If you don't have Ring1b, the process of fusing the chromosomes is not very efficient," said Lazzerini Denchi.

In addition to Ring1b, the team has found nearly 100 factors that might be related to errors in DNA damage repair. The next step in this research is to further refine the long list of DNA repair factors and study other proteins that could affect human health.

In addition to Lazzerini Denchi, Bartocci and Yates, other contributors to the paper, "Isolation of Chromatin from Dysfunctional Telomeres Reveals an Important Role for Ring1b in NHEJ-Mediated Chromosome Fusions," were Jolene K. Diedrich, Iliana Ouzounov and Julia Li of TSRI, and Andrea Piunti and Diego Pasini of the European Institute of Oncology. DOI: 10.1016/j.celrep.2014.04.002

The research was supported by a Pew Scholars Award, the Novartis Advanced Discovery Institute, National Institutes of Health Grants AG038677 and P41 GM103533, the Italian Association for Cancer Research, the Italian Ministry of Health and a fellowship from FIRC.

Scripps Research Institute

Tumor modeling predicts most effective drugs targeting brain cancer

Tumor modeling predicts most effective drugs targeting brain cancer

Researchers at University of California, San Diego School of Medicine and Moores Cancer Center have used computer simulations of cancer cells - cancer avatars - to identify drugs most likely to kill cancer cells isolated from patients' brain tumors.

The findings, published in the online issue of the Journal of Translational Medicine, may help researchers stratify cancer patients for clinical trials according to their cancers' genomic signatures and predicted sensitivities to different cancer drugs.

Such an approach would allow scientists to selectively test cancer drugs on those who would be most likely to respond to them, while simultaneously reducing patients' exposures to toxic drugs that would likely be ineffective.

"Genomics tells us that cancers are a lot like snowflakes. No two cancers are alike so it does not make sense to give all patients the same drugs. This is the idea behind personalizing therapies for cancer," said lead author Sandeep Pingle, MD, PhD, a project scientist in the laboratory of Santosh Kesari, MD, PhD, chief of the division of Neuro-Oncology, professor in the department of neurosciences, director of Neuro-Oncology at UC San Diego Moores Cancer Center and the study's senior author.

"With the virtual cell model, we can take into account all the complexity of cellular processes to predict which drugs will be the most effective against a particular tumor based on its genomic profile," Pingle said. "This is a first step toward personalized medicine."

Researchers developed a virtual cell that represents the internal workings of a normal, healthy cell, depicting them as a complex collection of signaling pathways and metabolic networks. The virtual healthy cell can be made cancerous. Indeed, it can be turned into any kind of cancer cell by distorting specific points and pathways in the system. These cellular distortions represent a person's so-called cancer avatar. Once the avatar is generated, a computer model predicts which drugs, based upon their known functions, are most likely to kill a real cancer cell.

For the study, researchers generated cancer avatars for cells obtained from patients with glioblastoma, a highly aggressive cancer of the brain's glial cells. The condition has a five-year survival rate of about 10 percent. The computer generated predictions were then "truth-checked" against standard, cultured cells in drug-sensitivity experiments.

"The advantage of computational modeling is the ability to incorporate the wealth of genomic and proteomic information on cancer cells and to screen drugs and combinations of drugs much faster and cost effectively," said Kesari. "Our ultimate goal is to take this technology to the clinic to identify the best drugs for treating each individual cancer patient."

Co-authors include Zeba Sultana, Shweta Kapoor, Ansu Kumar, Shahabuddin Usmani and Ashish Agrawal, Cellworks Research India Ltd.; Sandra Pastorino, Pengfei Jiang, Rajesh Mukthavaram,Ying Chao, Ila Sri Bharati, Natsuko Nomura and Milan Makale, UC San Diego Moores Cancer Center; Taher Abbasi, Cellworks Group Inc.; and Shireen Vali, Cellworks Research India Ltd. and Cellworks Group Inc.

The study was funded, in part, by the National Brain Tumor Society, Barbara and Joseph Ajello Trust Fund, Tuttleman Family Foundation, MCJ Amelior Foundation and Boston Fire Department/Kenney Foundation.

University of California - San Diego