Posted November 9, 2016
Samir Hanash, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center
Adi Gazdar, M.D., University of Texas Southwestern Medical Center
Stephen Lam, M.D. and Wan Lam, Ph.D., British Columbia Cancer Agency
David Gandara, M.D., University of California Davis
In 2009, the LCRP offered the Collaborative Translational Research Award with the intent of fostering collaboration between laboratory and physician scientists across institutions and, in so doing, promote multidisciplinary research that would advance promising lung cancer research ideas toward clinical applications. One of the projects funded by this mechanism focused on the development of blood-based biomarkers that would improve the early detection of lung cancer and facilitate diagnosis of lesions detected by CT scans. Currently, patients diagnosed with Stage IA non-small cell lung cancer (NSCLC) have a 5-year survival rate near 50%, while patients with stage IIIA have a 5-year survival rate of less than 14%, with the number dropping further for more advanced cancers (data from the NCI SEER database). Effective and minimally invasive modes of early detection are expected to improve patient outcomes, increasing the number of patients diagnosed with early stage, more treatable forms of lung cancer.
Four research groups collaborated on this early detection project led by: Samir Hanash at M.D. Anderson, Adi Gazdar at the University of Texas Southwestern Medical Center, Stephen Lam at British Columbia Cancer Agency, and David Gandara at University of California, Davis. Through their work on this award, the groups were able to successfully identify a number of potential screening biomarkers and establish collaborations that have resulted in significant new projects in the lung cancer field.
M.D. Anderson
Samir Hanash, M.D., Ph.D.
University of Texas M.D. Anderson Cancer Center
University of Texas M.D. Anderson Cancer Center
Dr. Hanash's team at M.D. Anderson Cancer Center identified pro-surfactant protein B (pro-SFTPB) levels in plasma as a risk biomarker for lung cancer. Pro-SFTPB levels corresponded well with smoking status, age, and higher risks of lung cancer. While the pro-SFTPB levels did not vary sufficiently to allow discrimination between sub-types of lung cancer, its strong correlation with risk will allow physicians to identify high-risk patients in need of more in-depth early screening procedures.
As a result of the success of this LCRP award, researchers at M.D. Anderson were able to launch a large, prospective clinical trial (Biospecimen Banking and Biomarker Validation for Lung Cancer Early Detection in Cohort Receiving Low Dose Helical Computed Tomography Screening), aimed at validating biomarker panels for early lung cancer detection, some of which were identified by this project. This clinical trial is a feature of M.D. Anderson's Moon Shot Program, and will involve the participation of at least 10,000 subjects at risk for lung cancer. Currently, over 10 sites are participating in this study, and many others have been invited to participate. If successful, the trial will lead to FDA approval of a blood-based test that complements CT screening for the early detection of lung cancer.
UT Southwestern
Adi Gazdar, M.D.
University of Texas Southwestern Medical Center
University of Texas Southwestern Medical Center
Dr. Gazdar's team at UT Southwestern worked to identify genes modulated by lung cancer. They determined that eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) expression is upregulated in tumors while completely absent in non-malignant lung tissue. EEF1A2—responsible for expression of the alpha subunit of the elongation factor-1 complex, which delivers aminoacyl tRNAs to the ribosome—was also highly expressed in exosomes from tumor cells, meaning it could possibly be used as a circulating biomarker.
The samples collected by UT Southwestern during the course of this project have been passed on to the M.D. Anderson team for validation studies. In addition to this continued collaboration, Dr. Gazdar's group has determined that the four biomarkers identified during the LCRP award, including EEF1A2, serve as excellent tissue markers that can be used prognostically and to dictate therapy. One marker, in particular, ITPKA, has shown excellent capacity for predicting glioma behavior and mortality.
British Columbia Cancer Agency
Stephen Lam, M.D. (left) and Wan Lam, Ph.D. (right), British Columbia Cancer Agency
Dr. Lam's team at BCCA joined the project with the primary goal of validating pro-SFTPB and other biomarkers for early detection of lung cancer. In the Pan-Canadian screening study cohort, pro-SFTPB was found to improve the accuracy of identifying smokers at high risk of lung cancer for CT screening over and above what can be achieved with smoking history, clinical and demographic data. This work has now progressed to a new collaboration with a group in Taiwan aiming to use pro-SFTPB to detect lung cancer in a population of non-smokers based in Taiwan.
Successful miRNA biomarkers were also identified by this group under the LCRP award. Dr. Wan Lam's lab at BCCA has further refined these biomarkers and is looking to follow up on and validate these markers in the near future.
Thanks to the funding this group received from the LCRP, a number of early career scientists and trainees have advanced significantly in their careers and are currently participating in similar collaborative projects.
UC Davis
David Gandara, M.D.
University of California Davis
University of California Davis
The goal at UC Davis was to identify circulating metabolites that could be used as biomarkers for early detection. The group successfully identified Diacetylspermine (DAS) as a pre-diagnostic serum biomarker. This compound has been found to be elevated in other cancers, but it was an unexpected biomarker for lung cancer. Not only did DAS show significant specificity for detection of NSCLC, but it was complementary to the use of pro-SFTPB as a biomarker and shows promise as a potential biomarker for early detection.
Dr. Gandara's team has been able to successfully leverage the teamwork from this award into numerous papers and funding opportunities. The most significant of these is another collaboration, an opportunity for members of Dr. Gandara's team to participate in a large, multi-institution Patient-Centered Outcomes Research Institute grant. The group has continued collaborations with the UC Davis radiology department (initiated during this award) in an effort to link CT scans with biomarkers for the purpose of early cancer screening.
Conclusion
In addition to the many research successes resulting from this award, the PIs have emphasized the award's importance in encouraging multiple face-to-face meetings and allowing these groups to collaborate and share strengths in a manner that would not have otherwise been possible. Such efforts are integral to the LCRP's mission to, "Support and integrate research from multiple disciplines for risk assessment, prevention, early detection, diagnosis, and treatment for the control and cure of lung cancer," and the program hopes to see similar successes in the coming years.
Publications:
Taguchi A, Hanash S, Rundle A, McKeague IW, Tang D, Darakjy S, Gaziano JM, Sesso HD, and Perera F. 2013. Circulating pro-surfactant protein B as a risk biomarker for lung cancer. Cancer Epidemiol Biomarkers Prev 22(10):1756-1761.
Ruhaak LR, Stroble C, Dai J, Barnett M, Taguchi A, Goodman GE, Miyamoto S, Gandara D, Feng Z, Lebrilla CB, Hanash S. Serum Glycans as Risk Markers for Non-Small Cell Lung Cancer. 2016. Cancer Prev Res (Phila). 2016 (4):317-23.
Sin DD, Tammemagi CM, Lam S, Barnett MJ, Duan X, Tam A, Auman H, Feng Z, Goodman GE, Hanash S, Taguchi A. Pro-surfactant protein B as a biomarker for lung cancer prediction 2013. J Clin Oncol. 31(36):4536-43.
Wang Y-W, Ma X, Zhang Y-A, Wang M-J, Yatabe Y, Lam S, Girard L, Chen J-Y, and Gazdar AF. 2016. ITPKA gene body methylation regulates gene expression and serves as an early diagnostic marker in lung and other cancers. J Thorac Oncol doi: 10.1016/j.jtho.2016.05.010 [Epub ahead of print]
Wikoff WR, Hanash S, DeFelice B, Miyamoto S, Barnett M, Zhao Y, Goodman G, Feng Z, Gandara D, Fiehn O, and Taguchi A. Diacetylspermine is a novel prediagnostic serum biomarker for non-small-cell lung cancer and has additive performance with pro-surfactant protein B. 2015. J Clin Oncol 33(33):3880-3886.
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