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UPCI Team Developing Lung Cancer Dx; Latest Entrant into Crowded, Growing Space

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By Adam Bonislawski

Researchers at the University of Pittsburgh Cancer Institute have identified a panel of ten serum protein markers that could be used in risk assessment and the early detection of lung cancer.

The panel could be particularly useful in determining whether pulmonary nodules detected by computed tomography screening are benign or malignant, William Bigbee, leader of the Molecular Biomarkers Group at UPCI and author on the study, told ProteoMonitor. This, he said, could enable doctors to better identify high-risk patients who might require invasive procedures like biopsies.

In a study published in the current edition of the Journal of Thoracic Oncology, the panel distinguished between malignant and benign lung nodules in a group of 30 cases and 30 controls with accuracies of 83.3 percent and 89.2 percent for Stage I and II lung cancers, respectively.

The test, Bigbee noted, could prove particularly useful in light of results released in August 2011 from the National Lung Screening Trial that showed low-dose CT screening to detect pulmonary nodules led to a 20 percent reduction in lung cancer mortality compared to screening with conventional chest X-rays.

These results, he said, have led to "increasing interest and application of screening CT" in lung cancer patients. However, Bigbee added, this increased CT screening "comes with a cost" because "many of these patients, particularly if they have multiple screening CTs, will eventually get a diagnosis of one of these pulmonary nodules."

Such patients "provide a clinical dilemma for pulmonologists and oncologists," he said. "There is a low probability that these patients might have early lung cancer, so you want to be aggressive because you want to have an opportunity for an early cure given the fact that later stage lung cancer has a very poor prognosis."

On the other hand, Bigbee said, "you don't want to subject these [patients] – the vast majority of whom will not develop lung cancer – to additional [unnecessary] procedures."

"Clinicians are faced with this burden that will only greatly increase as the results of the NLST make their way out into the [medical] community," he said.

Indeed, these trends have made lung cancer a prime area of focus for protein biomarker researchers, with the University of Pittsburgh team just one of a number of industry and academic players currently developing protein-based tests for use in conjunction with CT screening.

For instance, in September, researchers led by Fred Hutchinson Cancer Research Center scientist Samir Hanash identified a number of plasma protein biomarkers that they are currently studying to determine what additional value they might bring to CT screening (PM 9/23/2011).

Last month, meanwhile, proteomics firm Integrated Diagnostics announced it had completed clinical trials demonstrating the commercial potential of a lung cancer diagnostic designed to distinguish between benign and malignant lung lesions ranging in size from 0.5 cm to 2 cm. According to CEO Albert Luderer, US pulmonologists see roughly 3.3 million cases annually where such a test would prove useful (PM 2/24/2012). The company aims to launch the diagnostic – which demonstrated a diagnostic performance of over 80 percent in the recently completed trials – sometime in 2013.

Celera, which last year was purchased by Quest Diagnostics, has likewise developed a proteomic lung cancer test for distinguishing between malignant and benign pulmonary lesions. At the 2011 American Association for Cancer Research's annual meeting, Celera presented data showing this six-protein test distinguished between benign and malignant lesions in a cohort of 80 cases and controls with a sensitivity and specificity of 83 percent (PM 4/15/2011).

Somalogic also has a lung cancer test in development. In a study published in the December 2010 edition of PLoS One, the company's 12-protein panel distinguished cases of non-small cell lung cancer from controls with 89 percent sensitivity and 83 percent specificity (PM 12/10/2010).

Bigbee and his colleagues, in fact, have collaborated with Somalogic on the company's lung cancer diagnostic, including on the 2010 PLoS One paper. Separate from their Journal of Thoracic Oncology biomarker work, the University of Pittsburgh researchers have a sponsored research agreement with Somalogic under which they provide the company access to clinical samples for testing its platform, he said.

For the last 11 years the National Cancer Institute has funded a Specialized Program of Research Excellence, or SPORE, at the UPCI focused on lung cancer. This funding has allowed the center to amass a variety of clinical resources related to lung cancer, including samples from a prospectively followed cohort of nearly 4,000 local subjects at high risk for the disease. Bigbee said the center makes these resources available to "companies who may have interesting new technologies and markers" and "who could greatly benefit and accelerate their own work by getting access to these samples."

The UPCI researchers also used subjects from this cohort in their own work, identifying markers by measuring 70 cancer-related proteins via Luminex xMAP assays in a training set consisting of 56 biopsy-proven non-small cell lung cancer samples and 56 age-, sex-, and smoking-matched controls. They followed this with an initial blinded verification set consisting of 30 cases and 30 controls.

The next step, Bigbee said, will be to apply the panel to additional sets of clinical populations. If the results hold up in these tests, the researchers then plan to apply for access to clinical samples collected as part of the NLST, he added.

"Ultimately, [we would want] to demonstrate that these markers appear to have enough clinical utility [in retrospective studies] to try this marker panel in a prospective clinical trial," Bigbee said, noting that such a trial is roughly three years away by the UPCI researchers' current timeline. "That would be very powerful, but it would be a big, expensive study, so you would have to bring a lot of weight to the table to power such a trial."

"If one was able to show there was actually a benefit to survival in a prospective trial … that would generate a tremendous amount of interest in the private sector for licensing these markers," he added. "And we've done our due diligence in terms of protecting our intellectual property for that eventuality."

While Bigbee and his colleagues developed the panel on an immunoassay platform, he said that the ongoing emergence of targeted mass spec techniques like multiple-reaction monitoring might make it possible to port the test to a mass spec platform.

"We're seeing an explosion of interest in using primarily triple quadrupole mass spectrometry instruments for doing these proteomic analyses," he said. "So that's certainly an option."


Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.

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