Previous lab studies suggest that metastasizing cancer cells undergo a major molecular change when they leave the primary tumor – a process called epithelial-to-mesenchymal transition (EMT). As the cells travel from one site to another, they pick up new characteristics. More importantly, they develop a resistance to chemotherapy that is effective on the primary tumor. But confirmation of the EMT process has only taken place in test tubes or in animals.

In a new study, published in the Journal of Ovarian Research, Georgia Tech scientists have direct evidence that EMT takes place in humans, at least in ovarian cancer patients. The findings suggest that doctors should treat patients with a combination of drugs: those that kill cancer cells in primary tumors and drugs that target the unique characteristics of cancer cells spreading through the body.

The researchers looked at matching ovarian and abdominal cancerous tissues in seven patients. Pathologically, the cells looked exactly the same, implying that they simply fell off the primary tumor and spread to the secondary site with no changes. But on the molecular level, the cells were very different. Those in the metastatic site displayed genetic signatures consistent with EMT. The scientists didn’t see the process take place, but they know it happened.

“It’s like noticing that a piece of cake has gone missing from your kitchen and you turn to see your daughter with chocolate on her face,” said John McDonald, director of Georgia Tech’s Integrated Cancer Research Center and lead investigator on the project. “You didn’t see her eat the cake, but the evidence is overwhelming. The gene expression patterns of the metastatic cancers displayed gene expression profiles that unambiguously identified them as having gone through EMT.”

The EMT process is an essential component of embryonic development and allows for reduced cell adhesiveness and increased cell movement.

According to Benedict Benigno, collaborating physician on the paper, CEO of the Ovarian Cancer Institute and director of gynecological oncology at Atlanta’s Northside Hospital, “These results clearly indicate that metastasizing ovarian cancer cells are very different from those comprising the primary tumor and will likely require new types of chemotherapy if we are going to improve the outcome of these patients.”

Ovarian cancer is the most malignant of all gynecological cancers and responsible for more than 14,000 deaths annually in the United States alone. It often reveals no early symptoms and isn’t typically diagnosed until after it spreads.

“Our team is hopeful that, because of the new findings, the substantial body of knowledge that has already been acquired on how to block EMT and reduce metastasis in experimental models may now begin to be applied to humans,” said Georgia Tech graduate student Loukia Lili, co-author of the study.

This patient-specific information may be helpful in developing personalized approaches to treat these tissue-destructive diseases.

“We measured significant variability in the amount of cathepsins produced by blood samples we collected from healthy individuals, which may indicate that a one-size-fits-all approach of administering cathepsin inhibitors may not be the best strategy for all patients with these conditions,” said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The study was published online on Oct. 19, 2012 in the journal Integrative Biology. This work was supported by the National Institutes of Health, Georgia Cancer Coalition, Atlanta Clinical and Translational Science Institute, and the Emory/Georgia Tech Regenerative Engineering and Medicine Center.

Platt and graduate student Keon-Young Park collected blood samples from 14 healthy individuals, removed white blood cells called monocytes from the samples and stimulated those cells with certain molecules so that they would become macrophages or osteoclasts in the laboratory. By doing this, the researchers recreated what happens in the body—monocytes receive these cues from damaged tissue, leave the blood, and become macrophages or osteoclasts, which are known to contribute to tissue changes that occur in atherosclerosis, cancer and osteoporosis.

Then the researchers developed a model that used patient-varying kinase signals collected from the macrophages or osteoclasts to predict patient-specific activity of four cathepsins: K, L, S and V.  

“Kinases are enzymes that integrate stimuli from different soluble, cellular and physical cues to generate specific cellular responses,” explained Platt, who is also a Georgia Cancer Coalition Distinguished Cancer Scholar. “By using a systems biology approach to link cell differentiation cues and responses through integration of signals at the kinase level, we were able to mathematically predict relative amounts of cathepsin activity and distinguish which blood donors exhibited greater cathepsin activity compared to others.”

Predictability for all cathepsins ranged from 90 to 95 percent for both macrophages and osteoclasts, despite a range in the level of each cathepsin among the blood samples tested.

“We were pleased with the results because our model achieved very high predictability from a simple blood draw and overcame the challenge of incorporating the complex, unknown cues from individual patients’ unique genetic and biochemical backgrounds,” said Platt.

According to Platt, the next step will be to assess the model’s ability to predict cathepsin activity using blood samples from individuals with the diseases of interest: atherosclerosis, osteoporosis or cancer.

“Our ultimate goal is to create an assay that will inform a clinician whether an individual’s case of cancer or other tissue-destructive disease will be very aggressive from the moment that individual is diagnosed, which will enable the clinician to develop and begin the best personalized treatment plan immediately,” added Platt.

Weiwei A. Li, who received her bachelor’s degree from the Coulter Department in 2010, also contributed to this study.

Research reported in this publication was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR000454 and the Office of the Director of the NIH under award number 1DP2OD007433. The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NIH.

CITATION: Park, Keon-Young et al., “Patient specific proteolytic activity of monocyte-derived macrophages and osteoclasts predicted with temporal kinase activation states during differentiation,” Integrative Biology (2012): http://dx.doi.org/10.1039/C2IB20197F.

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Assistant Professor Todd Sulchek and Ph.D. student Wenwei Xu used a process called atomic force microscopy (AFM) to study the mechanical properties of various ovarian cell lines. A soft mechanical probe “tapped” healthy, malignant and metastatic ovarian cells to measure their stiffness.

“In order to spread, metastatic cells must push themselves into the bloodstream. As a result, they must be highly deformable and softer,” said Sulchek, a faculty member in the George W. Woodruff School of Mechanical Engineering. “Our results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.”

Just as previous studies on other types of epithelial cancers have indicated, Sulchek also found that cancerous ovarian cells are generally softer and display lower intrinsic variability in cell stiffnesss than non-malignant cells.

Sulchek’s lab partnered with the molecular cancer lab of Biology Professor John McDonald, who is also director of Georgia Tech’s newly established Integrated Cancer Research Center.

“This is a good example of the kinds of discoveries that only come about by integrating skills and knowledge from traditionally diverse fields such as molecular biology and bioengineering,” said McDonald. “Although there are a number of developing methodologies to identify circulating cancer cells in the blood and other body fluids, this technology offers the added potential to rapidly determine if these cells are highly metastatic or relatively benign.”

Sulchek and McDonald believe that, when further developed, this technology could offer a huge advantage to clinicians in the design of optimal chemotherapies, not only for ovarian cancer patients but also for patients of other types of cancer.

This project was supported in part by the National Science Foundation (NSF) (Award Number CBET-0932510). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.

Using a combination of modeling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.

“These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,” said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.”

The research was supported by the National Institutes of Health, the National Science Foundation and the Georgia Cancer Coalition. Details of the study were reported August 10 in the Journal of Biological Chemistry.

Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.

When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.

Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specializes in modeling – to examine what possible conditions could account for the experimental result. Barry’s modeling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.

That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.

“We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,” said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. “We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.”

The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.

Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.

“The effect of the cathepsins on one another complicates the system,” said Platt. “If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-target binding and side effects that were not anticipated.”

Platt’s long-term research has focused on cathepsins, including the development of sensitive tools and assays to quantify their activity in cells and tissue, as well as potential diagnostic applications for breast, lung and cervical cancer. Cathepsins normally operate within cells to carry out housekeeping tasks such as breaking down proteins that are no longer needed.

“These enzymes are very powerful, but they have been overlooked because they are difficult to study,” said Platt. “We are changing the way that people view them.”

For the future, Platt plans to study interactions of additional cathepsins – as many as three or four are released during certain disease processes – and to develop a comprehensive model of how these proteases interact while they degrade collagen and elastin. That model could be useful to the designers of future drugs.

“As we build toward a comprehensive model of how these enzymes work, we can begin to understand how they behave in the extracellular matrix around these cells,” said Platt. “That will help us be smarter about how we go about treating diseases and designing new drugs.”

The project described was supported by Award Number DP2OD007433 from the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Office of the Director, National Institutes of Health, or the National lnstitutes of Health. This material is also based on work supported by the National Science Foundation under the Science and Technology Center Emergent Behaviors of Integrated Cellular systems (EBICS) Grant No. CBET-0939511.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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There is only one downside. Those sequencing technologiesprovide massive amounts of data that are not easily processed and translated byscientists. That’s why Georgia Tech has created a new data analysis algorithmthat quickly transforms complex RNA sequence data into usable content forbiologists and clinicians. The RNA-Seq analysis pipeline (R-SAP) was developedby School of Biology Professor John McDonald and Ph.D. Bioinformatics candidateVinay Mittal. Details of the pipeline are published in the journal NucleicAcids Research.

“A major bottleneck in the realization of the dream ofpersonalized medicine is no longer technological. It’s computational,” saidMcDonald, director of Georgia Tech’s newly created Integrated Cancer ResearchCenter. “R-SAP follows a hierarchical decision-making procedure to accurately characterizevarious classes of gene transcripts in cancer samples.”

There are at least 23,000 pieces of RNA in the humangenome that encode the sequence of proteins. Millions of other pieces helpregulate the production of proteins. R-SAP is able to quickly determine everygene’s level of RNA expression and provide information about splice variants,biomarkers and chimeric RNAs. Biologists and clinicians will be able to morereadily use this data to compare the RNA profiles or “transcriptomes” of normalcells with those of individual cancers and thereby be in a better position todevelop optimized personal therapies.

Personalized approaches to cancer medicine are already inwidespread use for a few “cancer biomarkers” including variants of the BRAC 1gene that can be used to identify women with a high risk of developing breastand ovarian cancer.

“Our goal was to design a pipeline that is easilyinstallable with parallel processing capabilities,” said Mittal. “R-SAP canmake 100 million reads in just 90 minutes. Running the program simultaneouslyon multiple CPUs can further decrease that time.”

R-SAP is open source software, freely accessible at theMcDonald Lab website.

“This is another example of Georgia Tech’s ability tomerge computer technology with science to create an essential feature ofnext-generation bioinformatics tools,” said McDonald. “We hope that R-SAP willbe a useful and user-friendly instrument for scientists and clinicians in thefield of cancer biology.”

A new study provides a mechanistic explanation of how ribonucleotides embedded in genomic DNA are recognized and removed from cells. Two mechanisms, enzymes called ribonucleases (RNases) H and the DNA mismatch repair system, appear to interplay to root out the RNA components.

"We believe this is the first study to show that cells utilize independent repair pathways to remove mispaired ribonucleotides embedded in chromosomal DNA, which can be sources of genetic modification if not removed," said Francesca Storici, an assistant professor in the School of Biology at the Georgia Institute of Technology. "The results also highlight a novel case of genetic redundancy, where the mismatch repair system and RNase H mechanisms compete with each other to remove misincorporated ribonucleotides and restore DNA integrity."

The findings were reported Dec. 4, 2011 in the advance online publication of the journal Nature Structural & Molecular Biology. The research was supported by the Georgia Cancer Coalition, National Science Foundation and Georgia Tech Integrative BioSystems Institute.

Storici and Georgia Tech biology graduate students Ying Shen and Kyung Duk Koh conducted the study in collaboration with Bernard Weiss, a professor emeritus in the Department of Pathology and Laboratory Medicine at Emory University.

"We wanted to understand how cells of the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae tolerate the presence of different ribonucleotides embedded in their genomic DNA. We found that the structure of a ribonucleotide tract embedded in DNA influenced its ability to cause genetic mutations more than the tract's length," said Storici.

With double-stranded DNA, when wrong bases are paired or one or few nucleotides are in excess or missing on one of the strands, a mismatch is generated. If mismatches are not corrected, they can lead to mutations.

The researchers found that single mismatched ribonucleotides in chromosomal DNA were removed by either the mismatch repair system or RNase H type 2. Mismatched ribonucleotides in the middle of at least four other ribonucleotides required RNase H type 1 for removal.

"We were excited to find that a DNA repair mechanism like mismatch repair was activated by RNA/DNA mismatches and could remove ribonucleotides embedded in chromosomal DNA," explained Storici. "In future studies, we plan to test whether other DNA repair mechanisms, such as nucleotide-excision repair and base-excision repair, can also locate and remove ribonucleotides in DNA."

Using gene correction assays driven by short nucleic acid polymers called oligonucleotides, the researchers showed that when ribonucleotides embedded in DNA were not removed, they served as templates for DNA synthesis and produced a mutation in the DNA. If both the mismatch repair system and RNase H repair mechanisms are disabled, ribonucleotide-driven gene modification increased by a factor of 47 in the yeast and 77,000 in the bacterium.

Defects in the mismatch repair system are known to predispose a person to certain types of cancer. Because the mismatch repair system is conserved from unicellular to multicellular organisms, such as humans, this study's findings open up the possibility that defects in the mismatch repair system could have consequences more critical than previously thought given the newly identified function of mismatch repair to target RNA/DNA mispairs.

The results also provide new information on the capacity of RNA to play an active role in DNA editing and remodeling, which could be the basis of an unexplored process of RNA-driven DNA evolution.

This project was supported by the National Science Foundation (NSF) (Award No. MCB-1021763). The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NSF.

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 Many cancers are characterized by an over abundance ofepidermal growth factor receptors (EGFR). When the EGFR level in a cell iselevated it tells the cell to replicate at a rapid rate. It also turns downapoptosis, or programmed cell death.

 “With our technique we’re inhibiting EGFR’s growth, withsmall interfering RNA. And by inhibiting it’s growth, we’re increasing thecells’s apoptotic function. If we hit the cell with chemotherapy at the same time,we should be able to kill the cancer cells more effectively,” said JohnMcDonald, professorat the School of Biology at Georgia Tech and chief research scientist at theOvarian Cancer Institute.

 Small interfering RNA is good at shutting down EGFRproduction, but once inside the cell siRNA has a limited life span. Keeping itprotected inside the hydrogel nanoparticles allows them to get into the cancercell safely and acts as a protective barrier around them. The hydrogel releasesonly a small amount of siRNA at a time, ensuring that while some are out in thecancer cell doing their job, reinforcements are held safely inside thenanoparticle until it’s time to do their job.

 “It’s like a Trojan horse,” said L. Andrew Lyon, professorin the School of Chemistry and Biochemistry at Georgia Tech. “We’ve decoratedthe surface of these hydrogels with a ligand that tricks the cancer cell intotaking it up. Once inside, the particles have a slow release profile that leaksout the siRNA over a timescale of days, allowing it to have a therapeuticeffect.”

 Cells use themessenger RNA (mRNA) to generate proteins, which help to keep the cell growing.Once the siRNA enters the cell, it binds to the mRNA and recruits proteins that attack the siRNA-mRNA complex. But thecancer cell's not finished; it keeps generating proteins, so without acontinuous supply of siRNA, the cell recovers. Using the hydrogel to slowlyrelease the siRNA allows it to keep up a sustained attack so that it can continue to interrupt theproduction of proteins. 

 “We’ve shown thatyou can get knock down out to a few days time frame, which could present aclinical window to come in and do multiple treatments in a combinationchemotherapy approach,” said Lyon.

 “The fact that thissystem is releasing the siRNA slowly, without giving the cell time to immediatelyrecover, gives us much better efficiency at killing the cancer cells withchemotherapy,” added McDonald.

 Previous techniqueshave involved using antibodies to knock down the proteins.

 “But oftentimes, amutation may arise in the targeted gene such that the antibody will no longerhave the effect it once did, thereby increasing the chance for recurrence,”said McDonald.

 The team used hydrogels because they’re non-toxic, have arelatively slow release rate, and can survive in the body long enough to reachtheir target.

 “It’s a well-defined architecture that you’re using theintrinsic porosity of that material to load things into, and since ourparticles are about 98 percent water by volume, there’s plenty of internalvolume in which to load things,” said Lyon.

 Currently, the tests have been shown to work in vitro, but the team will beinitiating tests in vivo shortly.

Jeffery Skolnick, professor in the School of Biology and director of the Center for the Study of Systems Biology, in collaboration with John McDonald, chair of the School of Biology, led a team from the Georgia Institute of Technology who have developed this new strategy.

"This opens up the possibility of novel therapeutics for cancer and develops our understanding of why such metabolites work. CoMet provides a deeper understanding of the molecular mechanisms of cancer," said Skolnick.

The small molecules that are naturally produced in cells are called metabolites. Enzymes, the biological catalysts that produce and consume these metabolites, are created according to a cell's genetic blueprints. Importantly, however, the metabolites can also affect the expression of genes.

"By comparing the gene expression levels of cancer cells relative to normal cells and converting that information into the enzymes that produce metabolites," said Skolnick, "CoMet predicts metabolites that have lower concentrations in cancer relative to normal cells."

The research proves that when such putatively depleted metabolites are added to cancer cells, they exhibit anticancer properties. In this case, growth of leukemia cells was slowed by all nine of the metabolites suggested by CoMet.

The future for this treatment looks bright, added McDonald. "While we have only performed cell proliferation assays, it is reasonable to speculate that some metabolites may also exhibit many other anticancer properties," he said. "These could be important steps on the road to a cure."