Cheap malaria drug could treat colorectal cancer effectively too, say experts

Artemisinin is isolated from the plant Artemisia annua also known as sweet wormwood. Credit: Image courtesy of University of St George's London

Medical experts say a common malaria drug could have a significant impact on colorectal cancer providing a cheap adjunct to current expensive chemotherapy.

A pilot study by researchers at St George's, University of London, has found the drug artesunate, which is a widely used anti-malaria medicine, had a promising effect on reducing the multiplication of tumour cells in colorectal cancer patients who were already going to have their cancer surgically removed.

Colorectal cancer (CRC) makes up about 10 percent of the annual 746,000 global cancer cases in men and 614,000 cases in women.

In the UK, 110 new cases are diagnosed daily, with older patients particularly at risk of death. Prognosis even with the best available treatments does not increase disease free or overall survival beyond 60 percent, five years after diagnosis.

Professor Sanjeev Krishna, an infectious disease expert at St George's who jointly-led the study, said: "There is therefore a continuing and urgent need to develop new, cheap, orally effective and safe colorectal cancer treatments.

"Our approach in this study was to take a close look at an existing drug that already had some anticancer properties in experimental settings, and to assess its safety and efficacy in patients.

"The results have been more than encouraging and can offer hopes of finding effective treatment options that are cheaper in the future."

"Larger clinical studies with artesunate that aim to provide well tolerated and convenient anticancer regimens should be implemented with urgency, and may provide an intervention where none is currently available, as well as synergistic benefits with current treatment regimens," added Professor Devinder Kumar, a leading expert in colorectal cancer at St George's and joint-lead of this study.

For most patients globally, access to advanced treatments is difficult as they are too expensive to be widely available, or associated with significant morbidity thereby further compromising their survival.

"In the St George's study, patients were examined and then were given either the anti-malaria drug artesunate or a placebo. After 42 months following surgery, there were six recurrences of cancer in the placebo group (of 12 patients) and one recurrence in an artesunate recipient (of 10 patients).The survival beyond two years in the artesunate group was estimated at 91% whilst surviving the first recurrence of cancer in the placebo group was only 57%.

This is the first randomized, double blind study to test the anti-CRC properties of oral artesunate. The anticancer properties of artemisinins have been seen in the laboratory previously but this is the first time their effect has been seen in patients in a rigorously designed study.

Source: University of St George's London

Researchers silence leading cancer-causing gene

Using bioluminescence, researchers showed that the novel molecule “KRAS silencing RNA” or "KRAS siRNA” (right) reduced the size of a tumor in mice. Researchers used a “non-KRAS silencing” molecule as the control (left) as a comparison. Credit: Image courtesy of University of North Carolina Health Care

Researchers from the UNC School of Medicine and colleagues at The University of Texas MD Anderson Cancer Center have developed a new approach to block the KRAS oncogene, one of the most frequently mutated genes in human cancer. The approach, led by Chad Pecot, MD, an assistant professor of medicine at UNC, offers another route to attack KRAS, which has proven to be an elusive and frustrating target for drug developers.

The new method relies upon a specifically sequenced type of small interfering RNA -- or siRNA. The findings, published in the journal Molecular Cancer Therapeutics, show that using a form of siRNA to halt KRAS not only dramatically stunted the growth of lung and colon cancers in cultured cells and mice but also stopped metastasis -- the main cause of cancer deaths.

"KRAS has been widely regarded as an undruggable protein, but we show that that's simply not the case," said Pecot, the study lead author and member of the UNC Lineberger Comprehensive Cancer Center.

KRAS is a signaling molecule -- a protein switch that triggers a cascade of molecular events that tell cells to grow and survive. Mutations in the KRAS gene create a switch that is perpetually "on," causing cells to divide uncontrollably. KRAS mutations are present in roughly 30 percent of human cancers, particularly lung, colon, pancreatic, and thyroid.

"It is the elephant in the room," Pecot said. "KRAS was one of the first cancer-causing genes ever discovered, and it was the obvious target to go after. People have been trying for decades to hit it, but they haven't had much luck."

Inhibiting KRAS signaling has been tricky because it lacks good pockets or crevices for small molecules and drugs to bind to. Some researchers have tried instead to target the proteins downstream in the KRAS signaling cascade, but those attempts have also had limited success.

Rather than try another conventional approach, Pecot decided to use a new genetic tool known as RNA interference -- or RNAi -- to destroy the KRAS protein before it fully forms. RNAi uses bits of synthetically engineered RNA -- the single-stranded molecule transcribed from DNA -- to silence specific genes. These bits of RNA bind to specific genetic messages called mRNA in the cell and direct enzymes to recognize the messages as enemies. In this context, the enzymes destroyed the genetic messages of KRAS mRNA so that KRAS can't be made. As a result, the cells don't grow, replicate, or move nearly as well.

RNAi has shown great promise in the treatment of liver diseases, viral infections, and cancers. To see if this approach could thwart the KRAS oncogene, Pecot and his colleagues first had to test different sequences of RNA to determine which one most effectively tagged KRAS for destruction. Of five RNA sequences, the researchers identified two candidates worthy to take into cancer models.

When they delivered these sequences into tissue culture cells, they found that the siRNAs destroyed more than 90 percent of the KRAS gene messages, significantly impairing the growth of cancer cell lines. The technique also led to marked reduction of two signaling molecules called pERK and pMEK, which lie downstream of KRAS and have been implicated in cancer cell proliferation and tumor growth.

Next, Pecot and his colleagues tested the siRNAs in mouse models of lung and colon cancer. They wrapped the sequences in protective lipid nanoparticles and delivered the siRNA solution into the mice. The researchers found that this treatment significantly slowed the growth of primary tumors. For example, tumors from colon cancer models that had been treated with the KRAS siRNAs were 69 percent smaller than tumors treated with control RNA sequences.

In addition, the researchers discovered that silencing KRAS stemmed the spread of cancer cells to other organs. The siRNA treatment reduced the number of these secondary malignant growths by about 80 percent in mice with lung cancer and to a similar degree in colon cancer models.

Pecot's findings come on the heels of two other papers using siRNAs to target KRAS, one from Frank McCormick's laboratory at the University of California at San Francisco and the other from Tyler Jacks' laboratory at the Massachusetts Institute of Technology. What sets the UNC study apart is that it demonstrates that this approach can be used to control the development of metastatic disease.

"Having all three papers come out at about the same time is encouraging because it means that KRAS is druggable if you use outside-the-box methods," Pecot said. "Now, we essentially have three platforms for targeting KRAS with siRNAs that may get to the clinic."

Pecot said the results, while promising, are just a first step in combating this cancer-causing gene. Ultimately, the siRNA sequences will have to be designed to specifically target the mutant form of KRAS without disrupting the normal form of the gene, which is necessary for maintaining normal growth in healthy cells.

Source: University of North Carolina Health Care

Rewiring metabolism slows colorectal cancer growth

Many cancers have less MPC in them than normal adult tissues. Re-introducing MPC into cancer cells slows growth of tumors following injection into mice as compared to unmanipulated cells. Credit: Ralph DeBerardinis

Cancer is an unwanted experiment in progress. As the disease advances, tumor cells accumulate mutations, eventually arriving at ones that give them the insidious power to grow uncontrollably and spread. Distinguishing drivers of cancer from benign mutations open opportunities for developing targeted cancer therapies.

A University of Utah-led study reports that cancers select against a protein complex called the mitochondrial pyruvate carrier (MPC), and re-introduction of MPC in colon cancer cells impairs several properties of cancer, including growth. The research, which appears online on Oct. 30 in Molecular Cell, implicates changes in a key step in metabolism -- the way cellular fuel is utilized -- as an important driver of colon cancer that is also likely to be important in many other cancer settings.

Cancers appear to do whatever they can to get rid of MPC, a protein involved in carbohydrate metabolism, shows the study led by Jared Rutter, Ph.D., professor of biochemistry and Dee Glen and Ida W. Smith Endowed Chair for Cancer Research at the University of Utah. At least 18 types of cancers -- colon, brain, breast, and liver among them -- have significantly less MPC than normal adult cells. Some cancers simply delete a region of the genome that contains one of the MPC genes, others find different ways to dampen MPC expression. In fact, a survey of patient biopsies shows that the less MPC there is, the more aggressive the cancer becomes.

"Loss of MPC seems to be a biomarker for cancer aggressiveness and patient survival," said Rutter, also co-director of the Diabetes and Metabolism Center at the University of Utah, and co-leader of the Nuclear Control of Cell Growth and Differentiation Program at the Huntsman Cancer Institute. "That was our first clue that MPC might be important."

Even more striking, when Rutter's group reintroduced MPC into colon cancer cell lines, properties that define them as cancerous, reverted. The cells divide less frequently under certain conditions and decrease expression of stem cell markers, an early step frequently defining the potential to form tumors and spread. Further, the engineered cells are dramatically impaired in their ability to form tumors after injection into mice. Tumors containing cells with MPC were as small as one-fourth the size of tumors made from cells without the protein complex.

"We think these results show that elimination of MPC is an early and important step in development of cancer," said John Schell, who is co-first author with Kristofor Olson, both M.D.-Ph.D. students at the University of Utah. "Finding the stem cell connection was probably the most exciting part for us, and is something we'll pursue further to understand how loss of MPC changes cell behavior."

The role of MPC in the normal cell, and what loss of MPC does to a cancer cell, addresses an observation first made nearly one century ago. Nobel Prize-wining biochemist Otto Warburg noted that cancer cells change their metabolism to support uncontrolled growth and proliferation. Scientists later found the way in which the metabolite pyruvate is processed is key to these metabolic changes. In normal adult cells, pyruvate enters the mitochondria, the cell's powerhouse, and fuels energy production. In cancer, pyruvate is diverted from the mitochondria to an alternative metabolic pathway that makes cell-building material.

Scientists had long suspected the so-called Warburg effect seen in cancer was contingent upon controlling entry of pyruvate into the mitochondria. But there was no way to directly test the idea until two years ago, when Rutter's group and others identified MPC as pyruvate's doorway to the mitochondria. The current report in Molecular Cell shows that cancer cells shut that door by repressing MPC, and that experimentally re-opening the door by re-introducing MPC not only inhibits cancer growth, but also redirects pyruvate to the metabolic pathway used in normal cells. In other words, MPC counteracts the Warburg effect.

"This makes sense because MPC is a pinch point in metabolism," said Rutter. "Our work, taken together with that from many other laboratories, shows that most cancer cells are completely reliant on this unusual metabolism known as the Warburg effect."

Understanding the Warburg effect has been an area of intense interest in recent years because of the potential to translate those discoveries into new cancer therapeutics. "We think this information can be used to design therapies that are specifically toxic to cancer cells," said Rutter.

Source: University of Utah Health Sciences

Gut microbiota influences blood-brain barrier permeability

Uptake of the substance Raclopride in the brain of germ-free versus conventional mice.
Credit: Miklos Toth

A new study in mice, conducted by researchers at Sweden's Karolinska Institutet together with colleagues in Singapore and the United States, shows that our natural gut-residing microbes can influence the integrity of the blood-brain barrier, which protects the brain from harmful substances in the blood. According to the authors, the findings provide experimental evidence that our indigenous microbes contribute to the mechanism that closes the blood-brain barrier before birth. The results also support previous observations that gut microbiota can impact brain development and function.

The blood-brain barrier is a highly selective barrier that prevents unwanted molecules and cells from entering the brain from the bloodstream. In the current study, being published in the journal Science Translational Medicine, the international interdisciplinary research team demonstrates that the transport of molecules across the blood-brain barrier can be modulated by gut microbes -- which therefore play an important role in the protection of the brain.

The investigators reached this conclusion by comparing the integrity and development of the blood-brain barrier between two groups of mice: the first group was raised in an environment where they were exposed to normal bacteria, and the second (called germ-free mice) was kept in a sterile environment without any bacteria.

"We showed that the presence of the maternal gut microbiota during late pregnancy blocked the passage of labeled antibodies from the circulation into the brain parenchyma of the growing fetus," says first author Dr. Viorica Braniste at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. "In contrast, in age-matched fetuses from germ-free mothers, these labeled antibodies easily crossed the blood-brain barrier and was detected within the brain parenchyma."

The team also showed that the increased 'leakiness' of the blood-brain barrier, observed in germ-free mice from early life, was maintained into adulthood. Interestingly, this 'leakiness' could be abrogated if the mice were exposed to fecal transplantation of normal gut microbes. 

The precise molecular mechanisms remain to be identified. However, the team was able to show that so-called tight junction proteins, which are known to be important for the blood-brain barrier permeability, did undergo structural changes and had altered levels of expression in the absence of bacteria.

According to the researchers, the findings provide experimental evidence that alterations of our indigenous microbiota may have far-reaching consequences for the blood-brain barrier function throughout life.

"These findings further underscore the importance of the maternal microbes during early life and that our bacteria are an integrated component of our body physiology," says Professor Sven Pettersson, the principal investigator at the Department of Microbiology, Tumor and Cell Biology. "Given that the microbiome composition and diversity change over time, it is tempting to speculate that the blood-brain barrier integrity also may fluctuate depending on the microbiome. This knowledge may be used to develop new ways for opening the blood-brain-barrier to increase the efficacy of the brain cancer drugs and for the design of treatment regimes that strengthens the integrity of the blood-brain barrier."

Source: Karolinska Institutet

What makes pancreatic cancer so aggressive? New study sheds light

“We know that patients with the earliest stage of pancreatic cancer have a survival rate of only 30 percent. This suggests that even in that very early stage of invasive cancer there are already cells that have spread to distant parts of the body,” says study author Diane M. Simeone, M.D. Credit: Image courtesy of University of Michigan Health System

New research from the University of Michigan Comprehensive Cancer Center helps explain why pancreatic cancer is so lethal, with fewer than a third of patients surviving even early stage disease.

The researchers found a gene known to be involved in nearly 90 percent of pancreatic cancers promotes cancer growth and spread. The gene, ATDC, plays a key role in how a tumor progresses from a preinvasive state to an invasive cancer to metastatic cancer.

"We know that patients with the earliest stage of pancreatic cancer have a survival rate of only 30 percent. This suggests that even in that very early stage of invasive cancer there are already cells that have spread to distant parts of the body," says study author Diane M. Simeone, M.D., director of the Pancreatic Cancer Center at the University of Michigan Comprehensive Cancer Center.

"This study sheds important light on what it is about pancreatic cancer that makes it so aggressive early in the game," she adds. The study appears Jan. 15 in Genes and Development.

Researchers used a mouse model to replicate pancreatic cancer as it appears in humans. They also studied pancreatic cancer tissue samples and samples of pre-invasive pancreatic lesions. They found ATDC was expressed in a subset of the pre-invasive cells and played a role in the development of pancreatic cancer stem cells, the small number of cells in a tumor that fuel its growth and spread. This suggests that ATDC promotes a tumor's invasiveness and spread early in the course of disease.

The researchers suspect that ATDC may be a potent drug target. No drugs currently exist to target this pathway in part because researchers do not understand the crystal structure of the protein. Simeone's team, working with the University of Michigan Center for Structural Biology has made crystals of the protein and begun to create a three-dimensional structure that they can use as a model for drug development.

Preliminary data suggests that ATDC may also play a role in other cancer types, including bladder, ovarian, colorectal and lung cancers and multiple myeloma. But, Simeone notes, it's particularly critical to find new treatment options for pancreatic cancer. About 46,400 Americans will be diagnosed with pancreatic cancer this year, and more than 39,000 will die of the disease. Pancreatic cancer is expected to become the second-leading cause of cancer death in the United States by 2030.

Source: University of Michigan Health System

3-D culture system for pancreatic cancer has potential to change therapeutic approaches

A team of researchers has developed a method to grow pancreatic tissue in a three-dimensional culture system, called organoids. The scientists are able to use tissue not only from laboratory mouse models, but also from human patients. The technology promises to change the way pancreatic cancer research is done, offering a path to personalized treatment approaches in the future. Credit: D. Tuveson/ Cold Spring Harbor Laboratory

Cold Spring Harbor and Bethpage, N.Y. -- Pancreatic cancer is one of the most deadly forms of cancer, with only 6 percent of patients surviving five years after diagnosis. Today, Cold Spring Harbor Laboratory (CSHL) and The Lustgarten Foundation jointly announce the development of a new model system to grow both normal and cancerous pancreatic cells in the laboratory. Their work offers the potential to change the way pancreatic cancer research is done, allowing scientists to interrogate the pathways driving this devastating disease while searching for new drug targets.

In work published in Cell, the research team describes a three-dimensional "organoid" culture system for pancreatic cancer. Co-led by David Tuveson, CSHL Professor and Director of Research for The Lustgarten Foundation, and Hans Clevers, Professor and Director of the Hubrecht Institute and President of the Royal Netherlands Academy of Arts and Sciences, the team developed a method to grow pancreatic tissue not only from laboratory mouse models, but also from human patient tissue, offering a path to personalized treatment approaches in the future.

All cancer research relies on a steady supply of cells -- both normal and cancerous -- that can be grown in the laboratory. By comparing normal cells to cancer cells, scientists can then identify the changes that lead to disease. However, both types of pancreatic cells have been extremely difficult to culture in the laboratory.

Furthermore, the normal ductal cells that are able to develop into pancreatic cancer represent about 10 percent of the cells in the pancreas, complicating efforts to pinpoint the changes that occur as the tumor develops. Until now, scientists have been entirely unable to culture human normal ductal pancreatic cells under standard laboratory conditions. 

Because of these limitations, most pancreatic cancer research relies on genetically engineered mouse models of the disease, which can take up to one year to generate. "With this development, we are now able to culture both mouse and human organoids, providing a very powerful tool in our fight against pancreatic cancer," explains Tuveson.

The organoids are entirely made up of ductal cells, eliminating the surrounding cell types that often contaminate samples from the pancreas. They grow as hollow spheres within a complex gel-like substance filled with growth-inducing factors and connecting fibers. Once they have grown to a sufficient size, the organoids can be transplanted back into mice, where they fully recapitulate pancreatic cancer. "We now have a model for each stage in the progression of the disease," says Chang-Il Hwang, Ph.D., one of the lead authors working in The Lustgarten Foundation's Pancreatic Cancer Research Lab at CSHL directed by Dr. Tuveson.

Traditionally, cancer cells are isolated during surgery or autopsies. Unfortunately, approximately 85 percent of cancer patients are ineligible for surgery at the time of diagnosis, either because the tumor is entwined in critical vasculature or the disease has progressed too far. Researchers therefore have had limited access to patient samples. The new research provides a way for scientists to grow organoids from biopsy material, which is comparatively easy to obtain. "Biopsies are the standard for diagnosis," says Dannielle Engle, Ph.D., also a lead author on the paper. "We can now rapidly generate organoids from any patient, which offers us the potential to study the disease in a much wider population."

The team is now working to create a repository of pancreatic tumor samples, coordinating with the National Cancer Institute. "We hope to make this available to the entire pancreatic cancer research community," says Tuveson. Additionally, Lindsey Baker, Ph.D., another lead author of the paper, has started holding an "organoid school" for other researchers, and has already taught six laboratories from around the world this technique.

Source: Cold Spring Harbor Laboratory

'Sugar-coated' microcapsule eliminates toxic punch of experimental anti-cancer drug

3BrPA (red) is illustrated encased in a sugar-based microshell. Credit: Jean-Francois Geschwind, Johns Hopkins

Johns Hopkins researchers have developed a sugar-based molecular microcapsule that eliminates the toxicity of an anticancer agent developed a decade ago at Johns Hopkins, called 3-bromopyruvate, or 3BrPA, in studies of mice with implants of human pancreatic cancer tissue. The encapsulated drug packed a potent anticancer punch, stopping the progression of tumors in the mice, but without the usual toxic effects.

"We developed 3BrPA to target a hallmark of cancer cells, namely their increased dependency on glucose compared with normal cells. But the nonencapsulated drug is toxic to healthy tissues and inactivated as it navigates through the blood, so finding a way to encapsulate the drug and protect normal tissues extends its promise in many cancers as it homes in on tumor cells," says Jean-Francois Geschwind, M.D., chief of the Division of Interventional Radiology at Johns Hopkins Medicine.

The Johns Hopkins team used a microshell made of a sugar-based polymer called cyclodextrin to protect the 3BrPA drug molecules from disintegrating early and to guard healthy tissue from the drug's toxic effects, such as weight loss, hypothermia and lethal hypoglycemic shock.

Geschwind, a professor in the Russell H. Morgan Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, and others at Johns Hopkins have been studying the experimental drug as a cancer treatment for over a decade because of its ability to block a key metabolic pathway of cancer cells.

Most cancer cells, he explains, rely on the use of glucose to thrive, a process known as the Warburg effect, for Otto Heinrich Warburg, who was awarded the Nobel Prize in Physiology for the discovery in 1931. By using the same cellular channels that funnel glucose into a cancer cell, 3BrPA can travel inside the cancer cell and block its glucose metabolic pathway, Geschwind says.

However, animal studies have shown that in its free, nonencapsulated state, the drug is very toxic, says Geschwind.

The toxicity associated with the free-form version of the drug, he says, has prevented physicians from using the drug as a systemic treatment in people, one that can travel throughout the whole body.

In a report about their study published online Oct. 17 in Clinical Cancer Research, the researchers described minimal or zero tumor progression in mice treated with the microencapsulated 3BrPA. By contrast, a signal of tumor activity increased sixty-fold in mice treated with the widely used chemotherapy drug gemcitabine. Activity increased 140-fold in mice who received the drug without encapsulation.

Specifically, daily injections of nonencapsulated 3BrPA were highly toxic to the animals, as only 28 percent of the animals survived the 28-day treatment. All of the mice who received the encapsulated drug survived to the end of the study.

Geschwind says the "extremely promising results" of the study make the encapsulated drug a good candidate for clinical trials, particularly for patients with pancreatic ductal adenocarcinoma. These cancers rank as the fourth most common cause of cancer-related deaths in the world, with a five-year survival rate of less than 5 percent. In the mouse studies, the encapsulated medication also reduced the metastatic spread of pancreatic cancer cells.

Source: Johns Hopkins Medicine

Powerful new system for classifying tumors revealed

This diagram illustrates how tumors with different tissues of origin were reclassified on the basis of molecular analyses. Credit: Zhong Chen, NIH/NIDCD

Cancers are classified primarily on the basis of where in the body the disease originates, as in lung cancer or breast cancer. According to a new study, however, one in ten cancer patients would be classified differently using a new classification system based on molecular subtypes instead of the current tissue-of-origin system. This reclassification could lead to different therapeutic options for those patients, scientists reported in a paper published August 7 in Cell.

"It's only ten percent that were classified differently, but it matters a lot if you're one of those patients," said senior author Josh Stuart, a professor of biomolecular engineering at UC Santa Cruz.

Stuart helped organize the study as part of the Pan-Cancer Initiative of the Cancer Genome Atlas (TCGA) project. A large team of researchers from multiple institutions performed a comprehensive analysis of molecular data from thousands of patients representing 12 different types of cancer. This was the most comprehensive and diverse collection of tumors ever analyzed by systematic genomic methods. Each tumor type was characterized using six different "platforms" or methods of molecular analysis--mostly genomic platforms such as DNA and RNA sequencing, plus a protein expression analysis.

The research team used statistical analyses of the molecular data to divide the tumors into groups or "clusters," first analyzing the data from each platform separately and then combining them in an integrated cross-platform analysis developed by co-first author Katherine Hoadley of the University of North Carolina. All six platforms as well as the integrated analysis converged on the same divisions of the cancers into 11 major subtypes. 

Five of those subtypes were nearly identical to their tissue-of-origin counterparts. But some tissue-of-origin categories split into several different molecular subtypes, and some subtypes encompass tumors with several different tissues of origin.

Bladder cancer was a particularly interesting group, because it split into seven different clusters, with most samples falling into one of three subtypes. One subtype was bladder cancer only, but some bladder cancers clustered with lung adenocarcinomas, and others with a subtype called 'squamous-like' that includes some lung cancers, some head-and-neck cancers, and some bladder cancers.

"If you look at survival rates, the bladder cancers that clustered with other tumor types had a worse prognosis. So this is not just an academic exercise," Stuart said.

Other findings from the study reconfirmed cancer subtypes that were already recognized, such as the different subtypes of breast cancer based on well-characterized biomarkers. The findings provide a more refined, quantitative picture of the differences between breast cancer subtypes, Stuart said. For example, the results reinforce the idea that 'basal-like' breast cancers are a unique tumor type. "Basal-like breast cancers are as different from luminal breast cancers as they are from lung cancers," he said.

The fact that all six platforms for molecular analysis identified the same set of subtypes, both individually and in multi-platform analyses, is an important result, Stuart noted. Not only does it give the researchers confidence in the subtypes they identified, it also means that different kinds of data can be used to classify a tumor.

"We can now say what the telltale signatures of the subtypes are, so you can classify a patient's tumor just based on the gene expression data, or just based on mutation data, if that's what you have," Stuart said. "Having a molecular map like this could help get a patient into the right clinical trial."

Although follow-up studies are needed to validate the findings, this new analysis lays the groundwork for classifying tumors into molecularly defined subtypes. The new classification scheme could be used to enroll patients in clinical trials and could lead to different treatment options based on molecular subtypes.

According to Stuart, the percentage of tumors that are reclassified based on molecular signatures is likely to grow as more samples and tumor types are included in the analysis (the next major Pan-Cancer analysis will include 21 tumor types). Coauthor Christopher Benz, an oncologist at the Buck Institute for Research on Aging and UC San Francisco, noted that the 10 percent reclassification rate in the current study is likely an underestimate due to the unequal representation of different tumors. "If our study had included as many bladder cancers as breast cancers, for example, we would have reclassified 30 percent," Benz said.

The researchers reported that each molecular subtype may reflect tumors arising from distinct cell types. For example, the data showed a marked difference between cancers of epithelial and non-epithelial origins. "We think the subtypes reflect primarily the cell of origin. Another factor is the nature of the genomic lesion, and third is the microenvironment of the cell and how surrounding cells influence it," Stuart said. "We are disentangling the signals from these different factors so we can gauge each one for its prognostic power."

The study involved an enormous amount of molecular and clinical data, which was managed by data coordinator Kyle Ellrott, a software developer in Stuart's lab at UC Santa Cruz. The data sets and results have been made available to other researchers through the Synapse web site (http://www.synapse.org). Stuart worked with the bioinformatics company Sage Bionetworks to create Synapse as a data repository for the Pan-Cancer Initiative.

"It's a huge amount of information, and all the data is available as programmable data sets that other researchers can use to do further analysis," Stuart said. "The scale of this project is hard to imagine. All of the data that the TCGA project has been churning out got funneled into this paper, and it's giving us an unbiased look at what the data have to tell us about cancer."

Source: University of California - Santa Cruz

New approach aims to silence cancer 'survival genes'

Silencing the SIRT1 gene: Cancer cells before and after treatment in vitro. Non-cancerous cells (not shown) are unaffected. Credit: Image courtesy of University of York

Scientists at the University of York are working on a promising new approach for tackling colorectal cancer, the second most common cause of cancer-related death.

The new method works by silencing cancer 'survival genes' and could potentially combat cancer through the selective killing of colorectal cancer cells without adverse effects on normal, non-cancer cells.

Funded by York's Centre for Chronic Diseases and Disorders (C2D2), the project led by Professor Jo Milner from York's Department of Biology involved preliminary studies to establish the suitability of an ex vivo model for the future development of anti-cancer therapies for colorectal cancer using a technique called RNA interference.

The new approach builds on ground-breaking research by Professor Milner and her team at York more than a decade ago. This early work, funded by Yorkshire Cancer Research (YCR), used the newly-developed technique of RNA interference to successfully kill human cervical cancer cells grown in culture without causing damage to healthy cells.

Professor Milner explained: "When a mammalian cell elects to die it does so with great precision and without harming its neighbours. This process of 'programmed cell death' enables the continuous replacement of aging cells and also the sculpting of tissues and neuronal pathways.

"However, when this normal process of programmed cell death fails the continued abnormal growth of affected cells can lead to cancer. Some cancers develop following infection with a virus, such as human papilloma virus which causes human cervical cancer. Here the virus expresses specific viral genes that disrupt normal cellular control mechanisms resulting in abnormal cell proliferation and survival.

"Using RNA interference (RNAi) we first identified the viral gene responsible for the continued survival of cervical cancer cells. Then we established the feasibility of RNAi-based therapeutics for the selective killing of human cervical cancer cells growing in vitro."

Professor Milner and her team next studied cells from other cancer types, including colorectal cancer and breast cancer. Such cancers develop when the cell's internal control system fails due to damage to one or more of the regulatory genes.

Professor Milner said "We discovered that other genes, belonging to a group called stress-response genes, acquire a new pro-survival function during the process of cancerous transformation. Importantly, this acquired cancer-specific survival function operates under normal, physiological conditions. Silencing these cancer-specific survival genes by RNA interference causes the cancer cells to die while the survival of non-cancerous cells appears normal. This is in contrast to treating cancer by radiotherapy and/or genotoxic drugs -- these agents cause genotoxic stress and damage both cancer and normal cells and tissues in the body, resulting in unwanted adverse side effects for the patient."

For the work on colorectal cancer therapies to progress towards the clinic, the team has had to meet the challenge of modifying the agent siRNA. siRNA is the synthetic RNA molecule which is designed to silence a chosen gene by inducing RNA interference and selectively suppressing expression of that gene. However, siRNA is very unstable and is rapidly degraded when in contact with human tissues.

As reported in the journal Molecular Therapy, the team has now successfully met this challenge and converted the unstable siRNA molecule into a stable form without losing its ability and very high efficacy for targeted gene silencing. A novel siRNA/DNA has been shown to be resistant to degradation while retaining high efficacy and selectivity for target gene silencing when tested on human cancer cells grown in culture.

The next step will involve testing this novel therapeutic agent for cancer-specific cell killing using human tissue maintained ex vivo, using an experimental model which was validated in the course of the C2D2-funded research.

Professor Paul Kaye, Director of C2D2, said: "Professor Milner's team has now shown that ex vivo cultures of colorectal tumour material, derived from human patients, maintain cancer-related biochemistry over several days, and of sufficient time known to produce a killing effect with the novel siRNA/DNA in vitro. It is marvelous that C2D2 has been able to support this ground breaking research that has validated an ex vivo model that can be used to progress this novel therapeutic towards the clinic, and without the need for animal research."

Source: University of York