'Systems biology' study of breast cancer

[News]

Using a "systems biology" approach - which focuses on understanding the complex relationships between biological systems - to look under the hood of an aggressive form of breast cancer, researchers for the first time have identified a set of proteins in the blood that change in abundance long before the cancer is clinically detectable.

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[gdpawel]

Crucial breakthroughs in the treatment of many common diseases such as diabetes and Parkinson's could be achieved by harnessing systems biology, according to scientists from across Europe. In a Science Policy Briefing released today by the European Science Foundation, they provide a detailed strategy for the application of systems biology to medical research over the coming years.

Systems biology is a rapidly advancing field that combines empirical, mathematical and computational techniques to gain understanding of complex biological and physiological phenomena. For example, dozens, or even hundreds, of proteins can be involved in signalling processes that ensure the proper functioning of a cell. If such a signalling network is disturbed in any way, diseases such as cancer and diabetes can result.

Conventional approaches of biology do not have the capacity to unravel these elaborate webs of interactions, which is why drug design often fails. Simply knocking out one target molecule in a biochemical pathway is turning out to be a flawed strategy for drug design, because cells are able to find alternative routes. It is a similar scenario to setting up a roadblock: traffic will grind to a standstill for a short time, but soon motorists will start turning around and using side-roads to get to their destination. Just as the network of roads allows alternative routes to be used, the network of biochemical pathways can enable a disease to by-pass a drug.

Systems biology is now shedding light on these complex phenomena by producing detailed route maps of the subcellular networks. These will make it possible for scientists to develop smarter therapeutic strategies - for example by disrupting two or three key intersections on a biochemical network. This could lead to significant advances in the treatment of disease and help with the shrinking pipeline of pharmaceutical companies using traditional reductionist approaches to drug discovery.

The new policy document, produced by the Life Sciences and Medical Sciences units of the Strasbourg-based European Science Foundation (ESF) calls for a co-ordinated strategy towards systems biology across Europe. The scientists have pinpointed several key disease areas that are ripe for a systems biology approach. These include cancer and diabetes, inflammatory diseases and disorders of the central nervous system.

The report's authors state that the recommendations outlined in the Science Policy Briefing provide a more specific, practical guide towards achieving major breakthroughs in biomedical systems biology, thereby covering issues that had not been previously addressed in sufficient detail. In particular we identify and outline the necessary steps of promoting the creation of pivotal biomedical systems biology tools and facilitating their translation into crucial therapeutic advances.

The report highlights some recent successes where mathematical modelling has played a key role. The conclusions from these examples are that success was achieved when quantitative data became available; that even simple mathematical models can be of practical use and that the interdisciplinary process leading to the formulation of a model is in itself of intrinsic value.

The report's authors believe that, if this document succeeds in prodding European institutions into supporting systems biology, the implementation of the recommendations presented will propel Europe to the forefront of research in systems biology and, in particular, help this interdisciplinary field to fulfil its promise of making a reality of personalised medicine, combinatorial therapy, shortened drug discovery and development, better targeted clinical trials and reduced animal testing.

This Science Policy Briefing is the contribution of the ESF to the EC funded Specific Support Action entitled "Advancing Systems Biology for Medical Applications" (SSA LSSG-CT-2006-037673). The recommendations resulted from ten workshops, in which more than 110 acknowledged experts from across Europe participated.

[gdpawel]

One of the hallmarks of cancer is the complex interaction of genes, networks, and cells in order to initiate and maintain a cancerous state. This inherent complexity constantly challenges our ability to develop effective and specific treatments. A systems biology approach towards the understanding and treatment of cancer examines the many components of the disease simultaneously.

Genes do not operate alone within the cell but in an intricate network of interactions. The cell is a system, an integrated, intereacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just one or a few targets (pathways/mechanisms).

Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways - network of genes - of tumor cells can be known in sufficient detail to control cancer. Each cancer cell can be different and the cancer cells that are present change and evolve with time.

There are many pathways/mechanisms to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indivudal trees.

Dealing with genome-scale data in this context requires of its functional profiling, but this step must be taken within a systems biology framework, in which the collective properties of groups of genes are considered.

The importance of mechanistic work around targeted therapy as a starting point should be downplayed in favor of a systems biology approach were compounds are first screened in cell-based assays, with mechanistic understanding of the target coming after validation of its impact on the biology of the cancer cells.

What would be more beneficial is to measure the net effect of all processes within the cancer (cell-based functional profiling), acting with and against each other in real-time, and test living (fresh) cells actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism.

Like the various influences on a flower seed that cause one blossom to turn out differently from another, there are biological processes in the body that affect the development of cancer in each patient and determine how that patient's cancer cells will uniquely react to treatment.

Source: Cell Function Analysis

[gdpawel]

Using a 'systems biology' approach, which focuses on understanding the complex relationships between biological systems, to look under the hood of an aggressive form of breast cancer, researchers for the first time have identified a set of proteins in the blood that change in abundance long before the cancer is clinically detectable.

The findings, by co-authors Christopher Kemp, Ph.D., and Samir Hanash, M.D., Ph.D., members of Fred Hutchinson Cancer Research Center's Human Biology and Public Health Sciences divisions, respectively, were published in the August 1, 2011 issue of Cancer Research.

Studying a mouse model of HER2-positive breast cancer (cancer that tests positive for a protein called human epidermal growth factor receptor 2) at various stages of tumor development and remission, the researchers found that even at the very earliest stages the incipient tumor cells communicate to normal tissues of the host by sending out signals and recruiting cells, while the host tissues in turn respond to and amplify the signals.

"It is really a 'systems biology' study of cancer, in that we simultaneously examined many genes and proteins over time - not just in the tumor but in blood and host tissues," Kemp said. "The overall surprising thing we found was the degree to which the host responds to cancer early in the course of disease progression, and the extent of that response.

While a mouse - or presumably a human - with early-stage cancer may appear normal, our study shows that there are many changes occurring long before the disease can be detected clinically. This gives us hope that we should be able to identify those changes and use them as early detection tools with the ultimate goal of more effective intervention."

Traditionally, it has been thought that tumor cells shed telltale proteins into the blood or elicit an immune response that can lead to changes in blood-protein levels. "What is new here is that the predominant protein signals we see in blood originate from complex interactions and crosstalk between the tumor cells and the local host microenvironment," Kemp said.

Until now, such tumor/host interactions have been primarily studied one gene at a time locally, within the tumor; this is the first study to monitor the systemic response to cancer in a preclinical tumor model, tracking the abundance of cancer-related proteins throughout tumor induction, growth, and regression. Of approximately 500 proteins detected, up to a third changed in abundance; the number increased with cancer growth and decreased with tumor regression.

"We found a treasure trove of proteins that are involved in a variety of mechanisms related to cancer development, from the formation of blood vessels that feed tumors to signatures of early cancer spread, or metastasis," Kemp said.

Proteins associated with wound repair were most prevalent during the earliest stages of cancer growth, which could point to a potential target for early cancer detection.

"Rather than blindly search for cancer biomarkers, an approach based on comprehensive understanding of the systems biology of the disease process is likely to increase the chances to identify blood-based biomarkers that will work in the clinic," Kemp said.

The next steps will involve selecting the most promising protein candidates found in mice and determining whether the same circulating proteins are markers of early breast cancer development in humans, with the ultimate goal of designing a blood test for earlier breast cancer detection.

Source: Fred Hutchinson Cancer Research Center

[gdpawel]

Clinical Trial Finds Personalized Cancer Cytometrics More Accurate than Molecular Gene Testing

In the first head-to-head clinical trial comparing gene expression patterns with Personalized Cancer Cytometric testing (also known as “functional tumor cell profiling” or “chemosensitivity testing”), Personalized Cancer Cytometrics was found to be substantially more accurate.

In a clinical trial involving ovarian cancer patients, patterns of gene expression identified through molecular gene testing were compared with results of Personalized Cancer Cytometric testing (in which whole, living cancer cells are exposed to candidate chemotherapy drugs). Four different genes were included in the molecular part of the study. The four genes were selected as those which researchers believe to have the greatest likelihood of accurately predicting individual patient response to specific anti-cancer drugs.

Study Results:

For two of the genes studied, there was no significant correlation between gene expression pattern and patient response. In other words, results for these genes were found to be meaningless. For the third gene studied, there was a 75% correlation between expression and patient response. This means that the gene was 75% accurate when it came to identifying an active drug for that patient. For the fourth gene studied, the accuracy in identifying an active drug was only 25%. In marked contrast, Personalized Cancer Cytometric testing was found by the researchers to be 90% accurate in identifying active drugs for ovarian cancer patients in this study.

Discussion:

Molecular testing – that is, testing for gene expression patterns – is widely studied and heavily promoted as a method to identify effective chemotherapy drugs for individual cancer patients. However, most studies of molecular testing carried-out to date show only modest correlation or no correlation between test results and actual patient response. In other words, much work remains to be done before molecular gene testing can be regarded as an accurate tool for chemotherapy selection. And yet in this, first ever, head-to-head study of test accuracy, Personalized Cancer Cytometrics was found to be highly accurate when it came to identifying effective drugs.

Comparing this study with previous studies:

Although this was the first head-to-head trial, the accuracy levels found in this trial for Personalized Cancer Cytometric testing are strikingly consistent with those documented in dozens of previous studies, published by respected cancer researchers around the world. In those studies, as in this one, extremely high levels of correlation (in other words, high levels of test accuracy) were found for Personalized Cancer Cytometrics.

Arienti et al. Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy. Journal of Translational Medicine 2011, 9:94.

http://www.translational-medicine.com/content/9/1/94

[gdpawel]

The TED (Technology Entertainment Design) conferences have been held annually for almost two decades. It draws together innovators in a broad spectrum of disciplines. With invited speakers ranging from Harvard's Edward O. Wilson to business leaders like Microsoft's Bill Gates, the lectures cover a panoply of interesting topics.

Dr. Robert Nagourney was invited to present at the TEDxSoCal conference held in Long Beach, CA on July 16th. His interest was to engage this group in a discussion of cancer biology with the focus on biochemistry and metabolism. His lecture was timely in the context of the New York Times article on the failures of genomics platforms for cancer treatment.

Over the past year, there has been a growing recognition that genomic analyses are not providing the therapeutic insights that patients so desperately need. The Duke University lung cancer gene program, which received much attention, is emblematic of the hubris associated with contemporary genomic analytic platforms.

Dr. Nagourney has reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

He described insights gained using the cell-based funtional profiling analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.

http://www.guidetocancertreatment.com/
or
http://www.youtube.com/watch?v=mAGhNhrHMJs