NYU School of Medicine breathes new life into mesothelioma research

Researchers discover protein product of a little-known gene may prove useful in early identification and monitoring of mesothelioma

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NEW YORK—Spurred into action by the need for tests that can accurately diagnose mesothelioma—an aggressive form of thoracic cancer usually caused by asbestos exposure—at its earliest stages, researchers at the NYU School of Medicine have published their finding of a protein product of a little-known gene that could prove useful in the early identification and monitoring the development of the disease.
Despite advances in chemotherapy, radiation and surgical management of malignant pleural mesothelioma, the median survival for patients with this disease is about a year. Early detection is limited by a long latency period, an inability of imaging to detect the disease even in a screening environment and the lack of sensitive and specific blood-based markers, as noted in the NYU study.
"The ability to diagnose mesothelioma is delayed by physicians not considering the disease in the differential diagnosis, and by the lack of non-invasive mesothelioma specific blood based markers," adds Dr. Harvey Pass, a thoracic oncology professor and division chief of general thoracic surgery at NYU's Langone Medical Center, in the study.
Pass has devoted his career to treating thoracic malignancies like mesothelioma as well as lung cancer, pulmonary metastases and esophageal cancer. For 10 years, he served as head of thoracic oncology at the National Cancer Institute. In 2005, Pass reported on a biomarker called osteopontin that looked promising for the early identification of mesothelioma, but other labs had difficulty reproducing his results.
That's not the case with the current study of fibulin-3, which floats around outside cells, coating the cells and free floating in blood plasma and extracellular fluid, and was found by Pass' team to be more specific at identifying an increased risk of mesothelioma. For this study, Pass and his colleagues compared levels of fibulin-3 in two separate cohorts of patients who had been exposed to asbestos through their jobs: one group in Detroit, and another in New York. Both cohorts included individuals who had been exposed to asbestos, but did not develop mesothelioma, as well as individuals with a confirmed mesothelioma diagnosis. The researchers found that fibulin-3 expression was markedly elevated in the plasma of the patients with mesothelioma compared with the plasma of patients without mesothelioma.
"We were very gratified to see very similar results with a high specificity and sensitivity of the biomarker when we compared those two populations," says Pass. "That led to the necessity of doing a validation trial."
To validate their results, the researchers then performed a blinded study with another cohort of patients from Princess Margaret Hospital in Toronto for whom plasma fibulin-3 was measured, but the researchers had no knowledge of whether the individuals had mesothelioma or not. Based on the fibulin-3 levels, the researchers were able to differentiate the mesotheliomas from the non-mesotheliomas with high accuracy.
In addition, the researchers discovered that post-surgery levels of fibulin-3 were drastically decreased compared to pre-surgery levels in mesothelioma patients in whom the mesothelioma was removed. In selected cases of recurrence, the fibulin-3 level rose, hinting that the marker may be useful for monitoring treatment effects.
According to Pass, early detection of mesothelioma and aggressive treatment can have a significant impact on the progression of disease and patient prognosis. Although the disease is relatively rare—reportedly affecting less than 3,000 patients a year in the United States—an estimated 27 million Americans (and millions more worldwide) have been exposed to asbestos fibers and are at risk for developing it. Diagnosis, which requires distinguishing it from benign pleural disease or metastasis of other primary cancers to the pleura, is difficult and depends on invasive sampling of pleural fluid or tissue. Currently, the most prescribed screening methods for surveillance of asbestos-exposed patients involve imaging procedures that are costly and expose patients to high doses of radiation each year.
"Now, we need to validate our results prospectively, and I think the best way to go about that is by forming an international consortium and monitoring mesothelioma patients across the world over a five-year period to see how many patients develop it, and how early prediagnosis is made before they have clinical symptoms."
This, stresses Pass, "would be an advance."
Other areas of the world where asbestos exposure and mesothelioma development seem prevalent include Australia, China and Turkey, he says.
Ultimately, however, any commercial opportunity would depend on the development of "other, cheaper, multiplexed ways that this marker can be combined so you can measure it in plasma, and at deeper levels," says Pass.
"This commercialization would depend on its combination with existing or novel platforms in a reference lab under CLIA conditions, so you can do it routinely and uniformly and be assured of the data," he says.
The study, "Fibulin-3 As A Blood and Effusion Biomarker for Pleural Mesothelioma," was published in the Oct. 11 issue of the New England Journal of Medicine.


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