A Northwestern University research team has developed a promising nanomaterial-based biomedical device that could be used to deliver chemotherapy drugs locally to sites where cancerous tumors have been surgically removed.

The flexible microfilm device, which resembles a piece of plastic wrap and can be customized easily into different shapes, has the potential to transform conventional treatment strategies and reduce patients’ unnecessary exposure to toxic drugs.  The device takes advantage of nanodiamonds, an emergent technology, for sustained drug release.

The researchers demonstrated that the device releases the chemotherapy agent Doxorubicin in a sustained and consistent manner -a requirement of any implanted device for localized chemotherapy.  The results of the study are published online today (Oct.  2) by the journal ACS Nano.

“The thin device -a sort of blanket or patch -could be used to treat a localized region where residual cancer cells might remain after a tumor is removed,” said Dean Ho, assistant professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science, who led the research.

If a surgical oncologist, for example, was removing a tumor from the breast or brain, the device could be implanted in the affected area as part of the same surgery.  This approach, which confines drug release to a specific location, could mitigate side effects and complications from other chemotherapy treatments.

“Several surgeons at Northwestern’s Feinberg School of Medicine, as well as other medical schools and hospitals, are very interested in the device because it is biocompatible and provides such stable and consistent drug release,” said Ho, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In their study, Ho and his colleagues embedded millions of tiny drug-carrying nanodiamonds in the FDA-approved polymer parylene.  Currently used as a coating for implants, the biostable parylene is a flexible and versatile material resembling plastic wrap.  A substantial amount of drug can be loaded onto clusters of nanodiamonds, which have a high surface area.  The nanodiamonds then are put between extremely thin films of parylene, resulting in a device that is minimally invasive.

To test the device’s drug release performance, the researchers used Doxorubicin, a chemotherapeutic used to treat many types of cancer.  They found the drug slowly and consistently released from the embedded nanodiamond clusters for one month, with more Doxorubicin in reserve, indicating a more prolonged release (several months and longer) was possible.  The device also avoided the “burst” or massive initial release of the drug, a common disadvantage with conventional therapy.

In control experiments, where the drug was present but without the nanodiamonds, virtually all of the drug was released within one day.  By adding the drug-laden nanodiamonds to the device, drug release was instantly lengthened to the months-long timescale.

In addition to their large surface area, nanodiamonds have many other advantages that can be utilized in drug delivery.  They can be functionalized with nearly any type of therapeutic.  They can be suspended easily in water, which is important for biomedical applications.  The nanodiamonds, each being four to six nanometers in diameter, are minimally invasive to cells, biocompatible and do not cause inflammation, a serious complication.  And they are very scalable and can be produced in large quantities.

The architecture of the device is amenable to housing small molecule, protein, antibody or RNAor DNA-based therapeutics.  This gives the technology the potential to impact a range of treatment strategies where implanted, long-term drug release is needed.

Ho and his research group previously pioneered the application of nanodiamonds for systemic drug-carrying applications.  This new work successfully transitions the nanodiamonds from basic materials to serving as a foundation for device manufacturing.

To build the biomedical device, the researchers developed a streamlined approach where a double layer of parylene was fabricated, with the nanodiamond-drug complexes sandwiched in between.  The bottom layer, approximately 20 to 30 microns thick, serves as the backbone of the device, allowing it to be easily handled.  For the top layer, the research team created a thinner semi-porous film that allows the drug to slowly release from the device.

“One of the most significant aspects of this work is that the fabrication procedures are highly scalable, meaning hundreds, or even thousands, of devices potentially could be manufactured in parallel and at low cost,” said Ho.

“The nanodiamonds are quite economical and have already been mass-produced as lubrication components for automobiles and for use in electronics,” added Robert Lam, a graduate student in Ho’s research group and the article’s lead author.

In the area of localized chemotherapy, the team hopes that this technology will bring new levels of treatment efficacy that can complement injected chemotherapy to reduce dosages and decrease devastating side effects.

Because of the proven biocompatibility and massively parallel deposition capabilities of parylene, the researchers are engaged with pre-clinical trials of the nanodiamond-embedded parylene.

A novel anti-tumor vaccine for neuroblastoma and melanoma developed by scientists and clinicians at Children’s National Medical Center in collaboration with investigators from the University of Iowa is showing significant impact on tumor growth in mice, according to new research published in the October edition of the research journal Cancer Immunology, Immunotherapy.  The vaccine uses the tumor’s own protein to induce an immune system response, allowing for a personalized approach to treatment.

The vaccine and delivery system, developed in the laboratory of Children’s National Chief of General and Thoracic Surgery Anthony Sandler, MD, involves the creation of synthetic microparticles known as “immune stimulatory antigen loaded particles” (ISAPs), that consist of tumor antigens (proteins) from the specific tumor to be targeted, as well as immune stimulatory agents.  The ISAPs are detected and engulfed by specialized immune cells and sensed to be immune-stimulating “foreign bodies.”

The study shows that ISAPs are effective at blocking the growth of tumors in mice by inducing activation of immune cells that then stimulate the immune system to specifically target the tumor whose antigens match those that are loaded in the particles – known as tumor specific immunity.

The research team also discovered, however, that the impact of ISAPs on tumor growth was partially mitigated by an increased presence of regulatory t-cells (T-reg) when ISAPs are introduced into the body.  The researchers believe that T-regs play a key role in how the vaccine impacts tumor growth by suppressing the development of the specific immune cells needed to combat the tumor.  By adding a T-reg suppressor such as cyclosphosphamide or anti-CD25 antibody, the scientists were able to have a greater impact on preventing tumor growth using the ISAP approach.

“For tumors like neuroblastoma, reduction to minimal residual disease with standard therapies like chemotherapy and/or surgical resection and subsequent treatment with this vaccine could quite possibly cure the patient of the disease in the not too distant future,” said Dr. Sandler, lead author of the study.  “Creation of ISAPs allows us to target our treatments to the specific tumor of interest, a capability that will more effectively combat a wide range of these tumors in a personalized fashion.”

Using computer models and live cell experiments, biomedical engineers at the Johns Hopkins University School of Medicine have discovered more than 100 human protein fragments that can slow or stop the growth of cells that make up new blood vessels.

Reporting online last week in the Proceedings of the National Academy of Sciences, the researchers say the findings could lead to developing treatments to fight diseases that depend on the growth of new blood vessels, including cancer, macular degeneration and rheumatoid arthritis.

“Before, there were only 40 known antiangiogenesis peptides,” says Aleksander Popel, Ph.D., a professor of biomedical engineering at Hopkins.  “Now, using a whole-genome, computer-based approach, we have identified more than 100 new ones, all of which can be further researched for their ability to fight the more than 30 known diseases affected by excessive blood vessel growth.”

To identify short protein fragments — peptides — that can block blood vessel growth, the team started by looking at 40 known peptides that have been studied and characterized by other experts in the field to stop blood vessel growth in animal models of disease.  Working under the assumption that the antivessel activity of these peptides can be attributed to similar features that are shared by a number of proteins, like the sequence of the peptide building blocks, the team first categorized the 40 known peptides by where they are located and what they look like.

Having defined nine families, the researchers then used computer programs and compared the peptide families to all of the proteins encoded by the genome.  They found more than 120 peptides contained in 82 different proteins, many of which were not previously known to have any activity on blood vessel development.

“Computational methods only identify potential candidates,” says Popel.  “We next had to do the experiments on live cells to see if they had any real activity.  Of the 82 proteins we identified, most were not previously known to have any antiangiogenic activity.”

To test the activity of these candidate peptides, the researchers applied them to blood vessel cells growing in the lab and examined whether they had any effect on the growth, survival and movement of these cells.  To test growth and survival, they added different amounts of peptide to dishes containing roughly 2,000 cells and after three days, counted how many cells were still alive.

To test cell movement, they placed cells in double-chambered dishes and treated the cells with a growth factor known to encourage cells to move.  To some of the dishes they added the test peptides.  After 20 hours, they measured the number of cells that had crawled from one chamber to the other.  They then identified the protein receptors that the peptides bind to and were able to show in some cases that combinations of more than one peptide were better able to stop the cells than using single peptides.

“Basic, computational studies like this are critical to understanding normal blood vessel growth,” says Popel.  “A better understanding of normal growth gives us a better idea of what happens in disease.”

The next step, Popel says, is to test these peptides in animal models of human disease and to identify the diseases most appropriately treated by these newly identified peptide inhibitors.

Researchers at the University of Toronto have shown that the EBNA1 protein of Epstein-Barr virus (EBV) disrupts structures in the nucleus of nasopharyngeal carcinoma (NPC) cells, thereby interfering with cellular processes that normally prevent cancer development.  The study, published October 3rd in the open-access journal PloS Pathogens, describes a novel mechanism by which viral proteins contribute to carcinogenesis.

EBV is a common herpesvirus whose latent infection is strongly associated with several types of cancer including NPC, a tumor that is endemic in several parts of the world.  With NPC only a few EBV proteins are expressed, including EBNA1.  EBNA1 is required for the persistence of the EBV genomes, however, whether or not EBNA1 directly contributes to the development of tumors has not been clear, until now.

In this study Frappier and her team examined PML nuclear bodies and proteins in EBV-positive and EBV-negative NPC cells.  Manipulation of EBNA1 levels in each cell type clearly showed that EBNA1 expression induces the loss of PML proteins and PML nuclear bodies through an association of EBNA1 with the PML bodies.  PML nuclear bodies are known to have tumor-suppressive effects due to their roles in regulating DNA repair and programmed cell death, and accordingly, EBNA1 was shown to interfere with these processes.

The researchers conclude that there is “an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.”  Since EBNA1 is expressed in all EBV-associated tumors, including B-cell lymphomas and gastric carcinoma, these findings raise the possibility that EBNA1 could play a similar role in the development of these cancers.  The cellular effects of EBNA1 in other EBV-induced cancers will require further investigation.

A team including researchers at the HudsonAlpha Institute and Stanford University, together with colleagues from a number of other organizations, today publishes a comprehensive analysis of genomic variation in the brain cancer glioblastoma. These results are the first from the Cancer Genome Atlas (TCGA) research network, a collaborative effort funded by the National Cancer Institute and the National Human Genome Research Institute of the National Institutes of Health. Glioblastoma is the most common and most aggressive of the primary brain tumors: Notably, U.S. Senator Edward M. Kennedy was diagnosed with glioblastoma earlier this year.Drs. Devin Absher and Rick Myers, with their labs at HudsonAlpha and Stanford, measured changes in the genetic code of both normal and cancer samples. They specifically looked at regions that either gained or lost large chunks of DNA, larger than 1000 bases, to determine the molecular differences between a normal and glioblastoma genome. The data were analyzed in collaboration with Drs. Gavin Sherlock and James Brooks at Stanford, and Dr. Jun Li at the University of Michigan.

Tumors generally accumulate gains and losses in DNA as they grow, and measuring these changes in a number of samples can illuminate which changes are necessary for tumor development. Targeting genes affected by these changes can lead to improved diagnosis and more specific therapies, with fewer side effects to normal cells in the brain.

The HudsonAlpha and Stanford data on genomic changes were integrated with data from institutions around the country measuring changes in other types of genomic variation and in epigenomic variation. Epigenomic variation refers to molecules that are added to our genome to regulate how genetic instructions are processed in the cell. We know these changes are important to cancer cells, but previous studies have not integrated genomic and epigenomic measurements on such a large scale.

According to Absher, “This is a paradigm shift in how cancer is analyzed. These comprehensive genomic and epigenomic analyses on a set of common tumors stringently assessed by research organizations across the country will ideally increase our fundamental understanding of cancer, and help us develop better diagnostic tools and treatments.”

Myers added, “The excitement in this study is the integration of so many teams, taking multiple ways of measuring our genome and producing such a broad picture of cancer genetics. My laboratory at HudsonAlpha plans to continue studying cancer genetics, working with local physicians as well as our important collaborators at Stanford and Michigan.”

The tumor suppressor gene pRb2/p130 may provide the first independent prognostic biomarker in cases of soft tissue sarcoma (STS), according to an international collaboration of researchers, including scientists at the Sbarro Institute for Cancer Research and Molecular Medicine at the College of Science and Technology at Temple University in Philadelphia, PA, the Department of Human Pathology and Oncology, University of Siena and the Center of Oncological Research of Mercogliano (CROM) in Avellino, Italy.The research appears in the latest issue of Clinical Cancer Research (www.aacrjournals.org).

The findings show that a reduction in the expression of pRb2/p130 can mean a higher risk of recurrence and death from STSs. The gene pRb2/p130, a member of the retinoblastoma family of genes, regulates a portion of the cell cycle.

Clinicians have long sought a prognostic test for the disease, which can be highly aggressive and unpredictable, making it difficult to determine the most beneficial course of chemotherapy and/or radiation treatments following surgery.

A prognostic indicator will help doctors determine which patients have a higher risk of recurrence of the disease and who might benefit from a more aggressive adjuvant therapy.

In the study, researchers examined specimens taken from 41 patients with STS. In a subset of 31 cases of nonmetastatic cancers, they found a direct relationship between pRb2/p130 expression and the clinical outcome of patients.

“We found that pRb2/p130 expression was lost or decreased and significantly correlated with recurrence of disease and poor survival rates in the subset of patients with nonmetastatic tumors,” said Valeria Masciullo, M.D., Ph.D., lead author of the study.

“A prognostic test could define the natural history of STSs, while also helping to identify possible targets for new kinds of therapies,” said Antonio Giordano, M.D., Ph.D., the Director of the Sbarro Institute, Professor of Molecular Biology at the College of Science and Technology at Temple University in Philadelphia, PA and Full Professor of Pathological Anatomy and Histology of the University of Siena.

The researchers noted that the reliability of pRb2/p130 as a potential marker in the clinical routine assessment and management of patients with STS deserves to be further evaluated in long-term follow-up studies on a larger number of cases.

HHMI investigators have detected a multitude of broken, missing, and overactive genes in pancreatic and brain tumors, in the most detailed genetic survey yet of any human tumor. Some of these genetic changes were previously unknown and could provide new leads for improved diagnosis and therapy for these devastating cancers.

The discoveries, described in two reports published September 4, 2008, in Science Express, which provides early electronic publication of selected Science papers, emerged from the sequencing of nearly all the known protein-making genes in pancreatic cancers and in the most common form of brain tumors, glioblastomas. The study adds numerous items to the known “parts list” of these cancers, though further research is needed to determine which gene changes actually trigger development or spread of the disease.

HHMI investigator Bert Vogelstein and colleagues at the Johns Hopkins Kimmel Cancer Center, in collaboration with investigators at Duke University and elsewhere, sequenced 20,661 genes in cells from 24 patients with pancreatic cancer and 22 patients with glioblastoma. The team identified hundreds of gene mutations associated with the cancers. The researchers also found numerous cases where tumor cells had extra or too few copies of a gene. The typical pancreatic cancer contained 63 genetic alterations, while the average brain tumor contained 60. Using “next generation” sequencing, the researchers also comprehensively assessed changes in levels of gene activity.

Taken together, the two studies suggest that a small number of commonly mutated genes - or “mountains” - and a much larger number of rarer, low-frequency gene changes - “hills” - cause these cancers, said the researchers.

The authors said their results demonstrate that “genome-wide genetic analyses…can identify the precise genetic alterations that are likely to be responsible for pathway disregulation in each patient’s tumor.” They found that each individual tumor had its own particular assortment of gene changes. “If you have 100 patients, you have 100 different diseases,” said Vogelstein, who is a co-corresponding author of the Science paper with Johns Hopkins researchers Victor E. Velculescu and Kenneth W. Kinzler. “But this will not surprise clinical oncologists, because they see how different every patient is” in the way their tumor behaves and responds to treatment.

Cancer biologist Tyler Jacks, a Howard Hughes Medical Institute investigator at the Massachusetts Institute of Technology who was not involved in the studies, said he was not surprised by the large number of infrequent gene mutations — primarily because Vogelstein and his colleagues reported in 2007 that they had found breast and colon cancers to be similarly complex genetically. “But if you had asked me three years ago, I would have given a different answer,” Jacks said.

Vogelstein said the sheer number and variability of genetic changes in the tumors pose a challenge to one of the main goals of “personalized medicine” — identifying as many cancer-causing mutations as possible and developing an array of targeted drugs, each designed to strike a specific mutation.

Jacks agreed that cancer researchers would have preferred that tumors’ mutational landscapes be dominated by the high-frequency “mountains,” as these make attractive targets for the design of new drugs. With conventional DNA sequencing technologies, these prominent mountains were the mutations most readily linked to cancer, he said. But as new methods make it feasible to sequence nearly all the genes in a tumor sample, researchers are beginning to recognize that “the landscape is crowded with changes, mostly occurring at low frequency.”

“It’s suggesting that maybe we shouldn’t even be focusing so much on the individual genes that are mutated,” Vogelstein said. “Instead, we should be thinking about the functional pathways in which these genes operate. This is a different way of looking at how cancer develops.”

Indeed, many of the gene abnormalities could be grouped into functional units. For example, when they analyzed the DNA in 24 pancreatic cancers, the scientists identified 12 core signaling pathways that were each abnormal in the great majority of tumors. Some of those pathways regulate apoptosis - the programmed death of abnormal cells - or repair of damaged DNA. Other altered pathways control the rate of cell division, influence how tightly cells stick together, or determine their ability to invade nearby tissues.

In the brain tumor samples, the survey found that the mutated genes could be grouped into similar pathways, such as those controlling growth and apoptosis. However, some of the newly found mutations occurred in pathways involved in nervous system signaling processes not previously known to be altered in any form of cancer. The scientists speculate that this pathway may be specific for glial cell tumorigenesis.

Similarly, one particular genetic change netted by the survey was found exclusively in brain tumors. That mutation was particularly intriguing because of its potential near-term clinical importance. Specific mutations in the isocitrate dehydrogenase gene IDH1 were found in 12 percent of the brain tumors. They were found in almost all cases of secondary glioblastomas - developing from lower-grade tumors - but rarely in primary high-grade glioblastomas. They also tended to affect younger patients (average age 33 compared to age 53 for patients without the mutations). Patients whose brain tumors had the IDH1mutation lived significantly longer with their cancer than those who did not.

Although it is not known how the IDH1 mutation contributes to cancer, Vogelstein said that it could help single out individuals who are likely to have better outcomes. With further research, it is conceivable that the mutation could have relevance for therapy, he said.

Like the Vogelstein group’s 2007 findings on breast and colon cancer, the new study suggests that many these diseases are caused not by a few major genetic kingpins, but instead by a large cast of minor culprits. How this multiplicity of cancer triggers can best be confronted is uncertain, but the authors of the two papers say it may force a shift in drug development emphasis. The best hope for new therapies, they wrote, “may lie in the discovery of agents that target the physiologic effects of the altered pathways and processes, rather than their individual genetic components.”

The complete genetic blueprint for lethal pancreatic cancer and brain cancer was deciphered by a team at the Johns Hopkins Kimmel Cancer Center.

The studies, led by the same group who completed maps of the breast cancer and colorectal cancer genomes in 2007, are reported in two articles in the Sept. 5, 2008, issue of Science Express.

Believed to be the most comprehensive result to date for any tumor type, the new map evaluated mutations in virtually all known human protein-encoding genes, comprised of more than 20,000 genes, in 24 pancreatic cancers and 22 brain cancers.

A core set of regulatory gene processes and pathways, about a dozen for each tumor type, were found to be altered in the majority of tumors studied by the researchers. In pancreatic cancer, these 12 pathways, including those linked to DNA damage control, cell maturation, and tumor invasion, were altered in 67 percent to 100 percent of tumors.

“This perspective changes the way we think about solid tumors and their management, because drugs or other agents that target the physiologic effects of these pathways, rather than individual gene components, are likely to be the most useful approach for developing new therapies,” says Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator.

In addition to the pathway discoveries, a number of individual mutated genes were identified, including 83 cancer genes in pancreatic cancer and 42 in the most lethal form of brain cancer, glioblastoma multiforme (GBM). Additionally, 70 genes that were dramatically overexpressed in either cancer encode proteins that are on the surface of cells or secreted, making them potential diagnostic and screening targets.

One gene, isocitrate dehydrogenase 1 (IDH1), was found to be frequently mutated in a subset of GBM brain cancers. The mutations were significantly more common in young GBM patients, and were associated with improved survival. IDH1 mutations were also found in nearly all cases of secondary GBMs (cancers that progress from pre-existing lower grade tumors), raising the possibility that this mutation may be a useful marker for identifying which low-grade brain tumors are most likely to develop into the lethal GBMs.

“Patients with IDH1 mutations seem to be different from other patients with GBM, both clinically and biologically,” says Victor Velculescu, M.D., Ph.D., associate professor of oncology. “It is conceivable that these patients will ultimately benefit from different treatments, potentially by targeting IDH1.”

“The landscape of human cancers is clearly more complex than has been previously appreciated. Fighting it is going to be more of a guerilla war than a conventional one because there are dozens of mutated genes in each tumor,” says Kenneth W. Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and professor of oncology. “Individually, these mutations don’t seem formidable. But working together, they form an enemy that will require us to develop novel strategies to combat them, and the best long-term strategy may be early detection of tumors, when the number of guerilla warriors is still small and more easily handled.”

To make their findings, the investigators integrated several methods of genetic analysis. They used high-density microarrays to identify copy number alterations (amplifications and deletions) and next-generation sequencing technologies to evaluate gene expression. They also developed novel statistical algorithms to integrate these complementary genetic analyses, as well as techniques to separate alterations likely to contribute to cancer initiation and progression from so-called passenger mutations, which accumulate harmlessly during cancer development.

Each project cost more than $4 million, with lead funding for the Goldman Pancreatic Cancer Genome Initiative coming from the Sol Goldman Charitable Trust and Lillian Goldman Charitable Trust. The Virginia and D. K. Ludwig Foundation provided lead funding for the brain cancer project. The Ludwig Brain Tumor Initiative represents the first formal collaboration of Ludwig Centers established by the Ludwig Fund in 2006.

This year an estimated 38,000 people will develop pancreatic cancer in the US, with overall survival rates less than 5 percent. Although fewer patients are diagnosed with brain cancers (approximately 20,000 cases per year in the United States), the results are equally catastrophic. “The main reasons we chose to focus on these cancers is because they are so deadly and have such limited treatment options. What we learn about these tumors may lead to improved diagnostic measures or therapies in the future,” says Ralph Hruban, M.D., Director of the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins.

Yale researchers have identified an unusual molecular process in normal tissues that causes RNA molecules produced from separate genes to be clipped and stitched together. The discovery that these rearranged products exist in normal as well as cancerous cells potentially complicates the diagnosis of some cancers and raises the possibility that anti-cancer drugs like Gleevec could have predictable side effects.The work is reported in the journal Science.

“Our findings are surprising because we identified in normal cells certain types of gene products— so called chimeric RNAs and proteins—thought to be found only in cancerous cells or in cells on their way to becoming cancerous,” said Jeffrey Sklar, professor of pathology and laboratory medicine at Yale School of Medicine, and senior researcher on the study.

Chimeric proteins are considered to be key factors that drive many forms of cancer. They arise from chromosome abnormalities in which segments of the chromosomes are rearranged. At the sites where chromosome segments reattach, genes fuse giving rise to chimeric RNA, which in turn is used to construct the chimeric protein. Gleevec, a highly successful new anti-cancer drug, was developed to target the chimeric protein product of one such gene fusion.

Sklar’s group earlier discovered that a particular gene fusion, with its associated chimeric RNA and protein, is the probable cause of certain endometrial cancers. Unexpectedly, they also found the same chimeric RNA and protein in healthy uterine tissue — where the chromosomes and genes showed no abnormalities.

“Extensive experiments on the normal tissues and cultured cells from those tissues indicated to us that a previously little-known process, the direct splicing together of two RNAs from separate genes—or trans-splicing—is responsible for producing the chimeras,” said Sklar.

They also found that level of the chimeric molecules in normal cells was decreased by elevated estrogen and increased by reduced oxygen — conditions that control the synchronized cyclic behavior of normal cells that line the inside of the uterus.

These observations suggest that trans-splicing between the RNAs might be common in other normal tissues, because gene fusions have been identified in cancers that arise in many tissues.

“These findings may bring new insights into how cancers operate. It seems that rather than scrambling chromosomes to invent new genes, cancers mimic normal cellular processes, but in an exaggerated and unregulated fashion. You might say that cancers are clever but not very original,” said Yale Research scientist Hui Li, lead author of the paper.

According to the researchers, these results indicate that caution should be exercised in using chimeric gene products as markers for cancer, as is widely done now in cancer diagnosis. Additionally, cancer drugs that target products of chromosomal abnormalities may have varying degrees of toxicity because those same targets may be present in normal cells due to the trans-splicing of RNA.

A man’s height is a modest marker for risk of prostate cancer development, but is more strongly linked to progression of the cancer, say British researchers who conducted their own study on the connection and also reviewed 58 published studies.In the September issue of Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, 12 researchers at four universities in England studied more than 9,000 men with and without prostate cancer and estimated that the risk of developing the disease rises by about six percent for every 10 centimeters (3.9 inches) in height a man is over the shortest group of men in the study. That means a man who is one foot taller than the shortest person in the study would have a 19 percent increased risk of developing the disease.

Still, these increases in risk are a lot less than those linked with other established risk factors, such as age, family history of the disease, and race. Because of that, the researchers do not suggest that taller men be screened more often than is typical, or that their cancer treatment be altered.

“Compared to other risk factors, the magnitude of the additional risk of being taller is small, and we do not believe that it should interfere with preventive or clinical decisions in managing prostate cancer,” said the study’s lead author, Luisa Zuccolo, M.Sc., of the Department of Social Medicine at the University of Bristol. “But the insight arising from this research is of great scientific interest. Little is known on the causes of prostate cancer and this association with height has opened up a new line of scientific inquiry.”

For example, Zuccolo says that factors associated with height - not height itself – could be risk factors for progression to fatal prostate cancer, and a plausible mechanism behind this association could be the insulin-like growth factor-1(IGF-1) system, which stimulates cell growth and has been shown to be involved in prostate cancer incidence and progression.

Because some studies have shown a much greater association between height and prostate cancer risk – some between 20 to 40 percent – the researchers then placed their results in the context of available evidence. They conducted a meta-analysis of 58 studies, and found evidence that greater stature is associated with increased prostate cancer risk. But as in their study, the overall effect varied with study design and was modest – a three to 9 percent increase risk of development per 10 centimeters, and five to 19 percent increase in risk for more advanced cancer.

“We do not believe that height itself matters in determining risk of prostate cancer or prostate cancer progression, but we speculate that factors that influence height may also influence cancer and height is therefore acting as a marker for the causal factors,” Zuccolo said.

Researchers are describing progress toward developing a new generation of chemotherapy agents that target and block uncontrolled DNA replication — a hallmark of cancer, viral infections, and other diseases — more effectively than current drugs in ways that may produce fewer side effects.  Their article is scheduled for the Aug. 27 issue of ACS’ Biochemistry, a weekly journal.

In the article, Anthony J. Berdis updates and reviews worldwide research efforts to develop drugs that target DNA polymerases, the enzymes responsible for assembling DNA from its component parts.  Several promising strategies are already in use that inhibit uncontrolled DNA replication, particularly in anticancer therapy, but most produce severe side effects and are hampered by drug resistance, the researcher notes.

Berdis says that one of the more promising strategies to date involves the use of so-called nucleoside analogues, artificial pieces of DNA that inhibit replication by substituting for natural segments.  Most nucleoside analogues directly target the active site of the polymerase enzyme, a non-specific approach that can also harm healthy cells which contain the enzyme.  Berdis describes an alternative approach in which the drugs directly target damaged DNA while avoiding healthy DNA, side-stepping the polymerase enzymes of normal cells.  The development, which shows promise in preliminary lab studies, could lead to improved nucleoside analogues with fewer side effects, he says.

Contrary to a long-standing assumption that blood vessel cells in healthy tissues and those associated with tumors are similar, a new study unequivocally demonstrates that tumor blood vessel cells are far from normal.  The research, published by Cell Press in the September issue of the journal Cancer Cell, identifies tumor-specific blood vessel cells that are atypically stem cell-like and have the potential to differentiate into cartilageor bone-like tissues.

Although it has been known for some time that tumors can be eradicated in mice by targeting their blood supply, very little is known about the biology of the endothelial cells that line tumor blood vessels (TECs).  “A primary assumption of antiangiogenesis therapy is that TECs are normal and derived from nearby, preexisting vessels,” explains senior author Dr. Michael Klagsbrun from Children’s Hospital Boston and Harvard Medical School.  “However, we and other groups have shown that there are several key differences between normal and tumor endothelium.”

Dr. Klagsbrun and lead author Dr. Andrew Dudley isolated TECs from mice that spontaneously develop prostate tumors very similar to human prostate cancers.  The researchers found that the TECs were multipotent, meaning that they were not fully mature and had the potential to differentiate into multiple different types of cells.  The isolated TECs differentiated to form cartilageand bone-like tissues.  “These results suggest that TECs possess a stem/progenitor cell property that distinguishes them from Ecs throughout the normal vasculature and undergo atypical differentiation,” explains Dr. Klagsbrun.

The researchers went on to demonstrate blood vessel calcification in human and mouse prostate tumor specimens.  This bone-like calcification has also been described in diseased blood vessels and is likely to have clinical significance in prostate cancer.  “It is possible that calcification of tumor blood vessels could impair blood flow or enable tumor cell entry into the bloodstream, facilitating metastasis,” offers Dr. Klagsbrun.  “Further, the expression of bone-specific proteins in prostate tumor cells may enable their survival once they reach the bone microenvironment.”

Additional research is required to determine how the atypical properties of TECs are associated with the tortuous, leaky vessels characteristic of tumors and whether vascular calcification does indeed encourage tumor cell metastasis.  It is also possible that vascular calcification, which is easily discernible histologically, may be a useful diagnostic criterion.

Scientists have gained new insight into a mechanism whereby chemotherapy may actually assist the rapid regrowth of tumors after treatment.  The research, published by Cell Press in the September issue of the journal Cancer Cell, also helps to explain why a combination of traditional chemotherapy with drugs that block formation of new blood vessels might impede the devastating tumor recovery that often follows cancer therapy.

“Chemotherapy remains the most commonly employed form of systemic cancer treatment.  However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors,” says senior study author Dr. Robert S. Kerbel from the University of Toronto.

Clinical trials have indicated that drugs that inhibit the growth of blood vessels, called antiangiogenic drugs, can sometimes enhance the effectiveness of traditional chemotherapy.  For example, coadministration of the antiangiogenic drug bevacizumab with the chemotherapeutic agent paclitaxel improves survival benefits for metastatic breast cancer and small cell lung cancer.  In contrast, coadministration of bevacizumab with gemcitabine for treatment of pancreatic cancer does not increase the effectiveness of chemotherapy alone.

“Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy,” says author Dr. Yuval Shaked.  Drs.  Kerbel, Shaked, and colleagues had previously shown that treatment with a type of cytotoxic-like agent known as a vascular disrupting agent (VDA) induces rapid mobilization of cells called circulating endothelial progenitors (CEPs) from the bone marrow compartment that helps the tumor to regrow blood vessels and thereby recover from treatment.

The researchers built on this earlier observation by analyzing whether different, conventional chemotherapeutic drugs had variable abilities to impact CEP mobilization and whether antiangiogenic drugs could block chemotherapy-induced CEP responses and hence amplify their effectiveness.  They found that paclitaxel rapidly induced CEP mobilization whereas gemcitabine did not.  They went on to show that pharmacological inhibition of CEP mobilization by combination treatment with an antiangiogenic drug or treatment of mutant mice deficient in CEPs resulted in enhanced antitumor effects mediated by paclitaxel but not gemcitabine.

“Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy,” explains Dr. Kerbel.  “Further, our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug.”

Using an engineered common cold virus, UCLA researchers delivered a genetic payload to prostate cancer cells that allowed them, using Positron Emission Tomography (PET), to locate the diseased cells as they spread to the lymph nodes, the first place prostate cancer goes before invading other organs.

The tiny cancer metastases in the pelvic lymph nodes are very difficult to find using conventional imaging tools such as CT scanning. This discovery could aid oncologists in finding the cancer’s spread earlier, when it’s more treatable, and before it invades distant organs, said Lily Wu, a researcher at UCLA’s Jonsson Cancer Center and the senior author of the study.

The next step for Wu and her colleagues is linking the non-invasive imaging advance with a treatment component, activating a toxic agent in the genetic payload to kill the spreading cancer cells. Wu hopes one day to be able to find tiny prostate cancer metastases in patients and kill them at the same time, watching it all on a PET scanner. She currently is refining this image-guided therapy in her lab in mouse models.

“I think this is very exciting for many reasons,” said Wu, who also is an associate professor of pharmacology and urology. “We now know we can reach these prostate cancer metastases at an earlier stage than before, and we know we can deliver genes to those cancer cells that produce proteins that can be imaged by PET. Now we will find out how effective this genetic toxic payload is in preventing further spread of the cancer to other vital organs.”

The study appears July 11, 2008 in the early, online edition of the peer-reviewed journal Nature Medicine.

The spread of prostate cancer to the pelvic lymph nodes is the most reliable indicator that the patient will have a poor prognosis, with disease recurrence and progression likely. Accurately assessing pelvic lymph node involvement in patients is critical in planning their treatment, Wu said.

Currently, physicians don’t know if a treatment is attacking cancer cells until, using traditional imaging, they see a decrease in tumor size, an insensitive approach that can take weeks and months. And if the treatment isn’t working, the patient is exposed to a toxic therapy that isn’t helping them. If Wu is successful, an oncologist would know within days if the cancer has spread and whether the treatment is killing the cancer.

Using mouse models, Wu and her team engineered a virus to travel to the lymph nodes, using a prostate cancer-specific vector that dictates s its protein payload be expressed only in prostate cells. The payload in this case is a protein that can be imaged by PET scanning. The virus was introduced into the tumor in the mouse and Wu and her team were able to detect PET signals only from the lymph nodes with cancer cell involvement, indicating the virus reached and infected the prostate cancer cells and produced the imaging protein.

As part of this study, Wu co-developed TSTA, a two-step transcriptional amplification method, which increased the expression of the genetic payload inside the cancer cells – in effect boosting the imaging signals and potential killing activity of the engineered virus.

Wu believes this type of image-guided therapy has the potential to improve the way advanced prostate cancer is treated.

“It would represent a treatment advance in patients for whom outcome is not good,” Wu said. “This would help improve the prognosis for these patients by letting us find and treat these metastases early. If we can catch the cancer before it invades other organs, we have a better chance to change the outcomes for these patients.”

This type of approach was pioneered in the field of breast cancer with testing of the sentinel lymph node, the first place breast cancer goes when it spreads. A biopsy can determine if the cancer is in the sentinel node, therefore spreading, and oncologists base their treatment decisions on that information. In prostate cancer, the lymph nodes are much more difficult to access for biopsy, so Wu’s method provides a much needed, non-invasive alternative.

T-cell acute lymphoblastic leukemia (T-ALL)

The white blood cells in our body combat foreign intruders, such as viruses and bacteria.  However, in leukemia, the formation of white blood cells is disturbed: the cells that should develop into white blood cells multiply out of control without fully maturing.  This process disrupts the production of normal blood cells, making patients more susceptible to infections.  T-ALL, a particular form of leukemia, is the most prevalent cancer in children under 14 years of age and occurs predominantly between the ages of two and three.  At the moment, with an optimal treatment using chemotherapy, over half of the children are cured.  But scientists hope to be able to develop targeted therapies that are less toxic than chemotherapy, based on knowledge of the biological processes behind T-ALL.

Importance of the location

Oncogenes are often at the root of cancer.  So, scientists around the world are concentrating on identifying oncogenes and their related proteins.  Recent research by Kim De Keersmaecker and colleagues in Jan Cools’ research group (VIB-K.U.Leuven) indicates that the location in the cell where these proteins are found plays an important role in the entire carcinogenic mechanism.  In collaboration with Maarten Fornerod (Nederlands Kanker Instituut, Amsterdam) and Gary Gilliland (Harvard Medical School, Boston), the VIB researchers have demonstrated that NUP214-ABL1, a fusion of two proteins, is carcinogenic only when it is in a protein complex near the nucleus of the cell.  Located at another place in the cell, NUP214-ABL1 does not lead to cancer.  This finding sheds new light on the study of carcinogenic processes.

A new therapeutic approach?

Many forms of cancer are caused by genetic defects in which a certain kinase becomes too active and this is the case with NUP214-ABL1.  The most obvious solution is to make the carcinogenic kinase inactive, and so kinase inhibitors are usually used to combat these kinds of cancers.  However, the carcinogenic kinase often becomes resistant to these inhibitors which is certainly true for T-ALL.  So, scientists are actively seeking alternative approaches.

De Keersmaecker’s recent research results now offer a possibility.  Indeed, the scientists have shown in cells that NUP214-ABL1 is no longer carcinogenic when it cannot bind with the protein complex in the vicinity of the cell nucleus.  On the basis of these results, the researchers want to further investigate the therapeutic possibilities of compounds that render binding between the complex and NUP214-ABL1 impossible.  This study also indicates that the location of proteins can play an important role in other forms of cancer/leukemia as well.