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Proteomic profiling shown more accurate than traditional biomarkers in identifying liver cancer
By Dross at 2008-01-15 21:16
Proteomic profiling shown more accurate than traditional biomarkers in identifying liver cancer

BOSTON – As the incidence of liver cancer continues to grow-- fueled in large part, by rising rates of hepatitis C infections – so too does the need for tests to help diagnose the disease at an earlier stage. A study appearing in the January 15 issue of Clinical Cancer Research demonstrates that a novel mass-spectrometry based form of proteomic profiling is more accurate than traditional biomarkers in distinguishing liver cancer patients from patients with hepatitis C liver cirrhosis, particularly with regard to identifying patients with small, curable tumors. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC), the study could help lead to earlier diagnostic methods – and subsequent treatments -- for liver cancer.

“Proteomics represents a potentially powerful tool for the serologic recognition of protein profiles associated with cancer,” explains co-senior author Towia Libermann, PhD, Director of the Genomics Center at BIDMC and Associate Professor of Medicine at Harvard Medical School.

“Although this particular proteomics technology, SELDI-TOF MS [surface enhanced laser desorption/ionization time of flight mass spectrometry] had already proven capable of identifying liver cancer in some limited studies, this was the first time that the technology was compared side-by-side with the clinical standard biomarker in a cohort of patients at risk for developing the disease,” adds Liebermann, who is also Director of the Dana-Farber/Harvard Cancer Center Proteomics Core in the Division of Interdisciplinary Medicine and Biotechnology at BIDMC.

Over a single decade, the incidence of liver cancer (hepatocellular carcinomaterm) increased from 1.8 to 2.5 per 100,000 patients, in large part due to a rise in the spread of hepatitis C virus.

“Hepatitis C has become a tremendous public health problem,” explains co-senior author Nezam Afdhal, MD, Director of the Liver Center at BIDMC and Associate Professor of Medicine at Harvard Medical School. “And a significant number of hepatitis C-infected patients will go on to develop liver cirrhosis.” Cirrhosis results when healthy tissue is replaced by scar tissue, preventing the liver from properly functioning. Cirrhosis itself is responsible for more than 25,000 deaths each year. But, adds Afdhal, secondarily, cirrhosis greatly increases a person’s chances of developing liver cancer.

“Each year, cirrhosis patients have a two to five percent chance that their condition will escalate to cancer,” he explains. “And the problem is that, right now, there is no reliable means of detecting liver cancer at an early stage, when surgical treatment is an option. Typically by the time the disease is discovered, the cancer has advanced and treatment options become much more limited.”

The best hope for early detection is cancer biomarkers, serum proteins found in altered amounts in blood or other body fluids. The current biomarker for liver cancer in clinical use is alpha fetoprotein (AFP). In many cases, patients with hepatitis C undergo routine monitoring for AFP levels as an indicator of whether tumors may have developed in their livers.

But, as Libermann explains, the AFP biomarker has a number of shortcomings, including false positives and false negatives. “AFP not only fails to detect many early tumors, but it also lacks specificity. Consequently, elevated AFP levels could be indicators of not only cancer, but also of other liver diseases or even benign conditions, while on the other hand, many patients with small tumors will test negative for AFP.”

The authors, therefore, decided to evaluate the sensitivy and specificity of SELDI-TOF MS for the detection of liver cancer and to compare its effectiveness with AFP.

Examining serum samples of 92 patients – including 51 patients with liver cirrhosis and 41 patients with liver cancer, and among the cancer patients, individuals with both large and small (less than 2 cm) tumors -- by SELDI-TOF mass spectrometry, the investigators were able to identify an 11-protein signature that accurately discriminated between the cirrhosis and cancer patients, first in a training set (made up of 26 cirrhosis and 20 liver cancer patients), and then again in an independent validation set (consisting of 25 cirrhosis and 19 liver cancer patients). The resulting diagnostic value – 74 percent sensitivity and 88 percent specificity – compared favorably with the diagnostic accuracy of AFP (73 percent sensitivity and 71 percent specificity) as well as with two other biomarkers currently in clinical development for liver cancer, AFP-L3 and PIVKA-IL.

“Most strikingly,” notes Libermann, “in patients with small tumors (less than 2 cm), where AFP identified only three, and AFP-L3 and PIVKA-II only one each, the 11-protein signature correctly identified seven of eight patients at this early stage of disease.

“Biomarkers play a major role in all aspects of personalized medicine, not only in early disease detection, but also in outcome prediction and evaluation of therapeutic responses,” he adds. “This study provides strong evidence that serum contains early detection biomarkers and supports the notion that a combination of multiple biomarkers may prove more effective than individual biomarkers for diagnosis of liver cancer, as well as other cancers.”



1 comment | 2367 reads

by gdpawel on Sun, 2012-11-04 01:01
Modern cancer research can be divided into three principal disciplines based upon methodology:

1. Genomic - the analysis of DNA sequences, single nucleotide polymorphisms (SNPs), amplifications and mutations to develop prognostic and, to a limited degree, predictive information on cancer patient outcome.

2. Proteomic - the study of proteins, largely at the level of phosphoprotein expressions.

3. Functional - the study of human tumor explants isolated from patients to examine the effects of growth factor withdrawal, signal transduction inhibition and cytotoxic insult on cancer cell viability.

A growing number of investigators around the world are beginning to recognize the important and clinical application of these techniques.

Contrary to analyte-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform.

By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.

Insights gained can determine which drugs, signal transduction inhibitors, or growth factor inhibitors induce programmed cell death in individual patients' tumors. Functional profiling is the most clinically validated technique available today to predict patient response to drugs and targeted agents.

Epigentics may have important implications for the treatment of cancer. The cell-based functional profiling platform has the capacity to measure genetic and epigenetic events as a functional, real-time adjunct to static genomic and proteomic platforms.

By examining small clusters of cancer cells (microspheroids or microclusters) in their native state, it can provide a snapshot of the response of tumor cells to drugs, combinations and targeted therapies.

The proteomic platform does not clarify how the response to targeted drugs compares with that to chemotherapy, combinations, or other targeted therapies. There is a challenge to identify which patients the targeted treatment will be effective.

The analysis is unique in that each microspheroid examined contains all the complex elements of tumor biosystems found in the human body and have a major impact on clinical response. Cell function analysis is a conduit that connects novel drugs to clinicians and patients in need.

There are any number of variables that affect drugs, including the rate of excretion of the drugs by the kidneys and liver, protein binding and a myriad of other biological factors. In the body, these cells interact with and are supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in microspheroids or microclusters.

Three-dimensional (3D) tissue culture methods have an invaluable role in tumor biology and provides very important insights into cancer biology. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization, they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model.

Due to their enormous potential, 3D tumor cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumor models.

Clinical application of functional profiling in advanced NSCLC and colorectal cancers ASCO Meeting Abstracts 26: 13547 R. A. Nagourney, J. Blitzer, D. McConnell, R. Shuman, S. Grant, K. Azaren, I. Shbeeb, T. Ascuito, B. Sommers, and M. Paulsen

Functional profiling in stage IV colorectal cancer: A phase II trial of individualized therapy ASCO Meeting Abstracts 27: e15124. J. B. Blitzer, I. Shbeeb, A. Neoman, K. Azaren, M. Paulsen, S. Evans, and R. Nagourney

Functional profiling in stage IV NSCLC: A phase II trial of individualized therapy ASCO Meeting Abstracts 27: e19079. R. A. Nagourney, J. Blitzer, E. Deo, R. Nandan, R. Schuman, T. Asciuto, D. Mc Connell, M. Paulsen, and S. Evans

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