Researchers identify ovarian cancer biomarkers

March 7, 2007

Researchers have identified markers unique to the cells of blood vessels running through ovarian tumors. The finding, while preliminary, could one day improve screening, diagnosis and treatment for this disease.

The team of researchers from the University of Michigan, University of Pennsylvania, and universities in Greece and Italy, used a laser technique to isolate blood vessel cells from 21 ovarian tumors and four normal ovarian tissue samples. From there, they were able to determine which genes the vascular cells expressed.

The results identified more than 70 markers that were present in large amounts in the blood vessels of cancer tissue but not in the vessels of normal tissues. The researchers went on to study in detail 12 markers that had not previously been linked to tumor blood vessels. The study appears in the March 1 issue of the Journal of Clinical Oncology.

"Some of these genes, depending on how highly expressed they were in the tumor vasculature, were also prognostic of a patient's survival. We suspect when these genes are highly expressed it may be a sign of a tumor that's able to grow blood vessels more efficiently, and therefore is more aggressive. This may help us down the road in treatment decisions," says lead study author Ronald Buckanovich, M.D., Ph.D., assistant professor of internal medicine and obstetrics and gynecology at the University of Michigan Medical School. Buckanovich was at the University of Pennsylvania when he conducted this research.

The study analyzed the largest number of samples to date in tumor vasculature, or blood vessel, profiling. While many of the genes identified in this analysis have been shown previously to be involved in tumor vasculatures for other cancer types, several of the markers appear to be new.

In addition, the researchers were able to determine that some of the markers present in large amounts in ovarian tumors were not expressed by normal ovaries or other healthy organs. The researchers also found these markers were not present in normal reproductive tissues that experience blood vessel growth, such as the placenta or endometrium. This suggests that the markers are specific to tumors and would not be mistaken for normal blood vessel growth in women of reproductive age.

If the markers do prove to be specific to ovarian tumors, researchers believe that could be a new avenue to develop drugs that would target the blood vessels and strangle the tumor.

Biomarkers are also seen in other cancer types as a potential screening tool. A new way of detecting ovarian cancer could make a significant dent in this disease, where 70 percent of patients are diagnosed after the tumor has grown large or spread. There are few or no symptoms early in the disease and no effective screening tests. Early diagnosis is crucial, marking the difference between a 95 percent survival rate for cancers found at the earliest stage and 20 percent survival among patients diagnosed with advanced disease.

"All the things we could hope for are present with this approach: It has potential for diagnosis, imaging, treatment and prognosis. It needs more work and much more confirmation, but our early results are promising," Buckanovich says.

Continued research will look at developing antibodies and methods to detect these novel proteins. "In some cases, these are genes that many people have never worked on before," Buckanovich says.

Source: University of Michigan Health System

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not rated yet Oct 22, 2007
Using a Cell Culture Assay (in vitro apoptosis) for choosing cancer drugs is no different than a marker like estrogen receptor or CD20 or a gene expression pattern. They are all markers. One is a structural marker, the other is a functional marker. Cell Culture Assays are a "functional" biomarker. A functional biomarker provides information about the biomarker uptake rate in tumor cells or on tumor cell surfaces through fluorescence intensity changes.

As with any other laboratory test, the determination of the efficacy of cell culture assay tests is based on comparisions of laboratory tests with patient response (clinical correlations). The hypothesis to be tested with clinical correlations is that above-average drugs effects in the assays correlate with above-average drug effects in the patient, as measured by both response rates and patient survival.

Patients with test results in the "sensitive" range were more likely to respond than the total patient population as a whole. Conversely, patients with test results in the "resistant" range were less likely to respond than the patient population as a whole. On average, patients with assays in the "sensitive" range were 3.5-fold more likely to respond than patients with assays in the "resistant" range.

Targeted treatments take advantage of the biologic differences between cancer cells and healthy cells by "targeting" faulty genes or proteins that contribute to the growth and development of cancer. Many times these drugs are combined with chemotherapy, biologic therapy (immunotherapy), or other targeted treatments.

Understanding targeted treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in a cell.

Targeted treatments fight cancer by correcting or modifying defective pathways in a cancer cell. In healthy cells, each pathway is tightly controlled. For instance, healthy cells are allowed to divide into new cells, and damaged cells are destroyed. However, in cancerous cells, certain points in the pathway become disrupted, usually through a genetic mutation (change in form).

Serious consequences to the cell may result from these mutations, depending on which pathway is affected. For example, suppose a cell develops a mutation that causes it to continue dividing into new cells? In other words, the signal is always on. If the signal never turns off, the cells that keep growing may eventually form a tumor.

The most appealing idea behind targeted drug therapy is that cancerous cells are destroyed and healthy cells are spared, resulting in fewer side effects of treatment. In contrast, traditional chemotherapy destroys both the cancer cells and the healthy cells, and does not have any mechanism to distinguish between them.

Because many cancer cells use similar pathways, the same drug could be used to treat one person's breast cancer and another person's lung cancer, as long as each tumor contained similar targets. This is why many of these treatments are being used in a variety of cancer types. Imatinib is used to treat both leukemia and a rare stomach tumor, called gastrointestinal stromal tumor (GIST).

Although targeted therapy is appealing, it is more complex than meets the eye. Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes. In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell.

Another challenge is to identify for which patients the targeted treatment will be effective. When gefitinib is used in patients with lung cancer, researchers discovered that only patients whose tumors contained specific mutations responded to this drug.

Finally, tumors can become resistant to a targeted treatment. This means that the drug no longer works, even if it has previously been effective in shrinking a tumor. To solve this problem, new drugs are being designed or combined with existing ones to target the tumor more effectively.

The introduction of targeted drugs has not been accompanied by specific "predictive tests" allowing for a rational and economical use of these drugs. However, given the technical and conceptual advantages of cell culture analysis, together with its performance and the modest efficacy of therapy prediction on analysis of genome expression, there is reason for a renewal in the interest of cell culture assays (functional biomarker) for optimized use of medical treatment of malignant disease.

Source: Cell Function Analysis

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