Title: Blood-based Biomarkers in Clinical Research

Presenter:  Andy Nixon, Ph.D.,MBA – Assistant Professor of Medicine, Director of the Phase I Biomarker Laboratory at Duke University Medical Center.

In the past, the gold standard for detecting growth factors and cytokines in blood was the Enzyme-linked immunosorbent assay (“ELISA”); however, results from a growing body of clinical trial research has shown multiplex protein analysis technology to be an attractive alternative to the ELISA. This multiplexing technology allows for the measurement of multiple analytes simultaneously from a single sample.  The advantages of multiplex technology compared to traditional ELISA are significant, and include substantially less sample volume, increased sensitivity, and a significant savings in cost, time and labor. Over the past 3 years, we have optimized the design of customized multiplex protein panels via extensive collaborations with Aushon BioSystems.  After considerable effort, we have now developed an appropriately designed panel for the evaluation of multiple angiogenesis regulators for use in cancer patients.

In one of the largest blood-based multiplex studies to date, our group at Duke has evaluated over 30 angiogenic factors in the phase III trial of gemcitabine +/- bevacizumab in metastatic pancreatic cancer (CALGB80303).   Results of the clinical study indicated that the addition of bevacizumab to gemcitabine did not improve overall survival compared to gemcitabine alone (5.8 months and 5.9 months, respectively).  Using Aushon’s multiplex protein platform, we evaluated whether specific biomarkers could predict which patients should or should not be treated with bevacizumab.  Upon analysis, we identified several analytes to be predictive of benefit or lack of benefit from bevacizumab, including VEGFD, SDF1b, angiopoietin-2, and osteopontin. Additionally, we identified several factors that were highly prognostic for outcome in general, including IGFBP-1, ICAM-1, angiopoietin-2, CRP, IL-8, thrombospondin-2, VCAM-1, PAI-1 active, IGF-1, and IL-6.  These markers were found to be more prognostic than any current clinical or laboratory test.  Lastly, we noted that levels of many analytes were highly correlated among each other, suggesting that many angiogenesis factors are co-regulated. Taken together, this work serves as proof of principle for the ability of this approach to identify profiles that can potentially select patients for anti-VEGF therapy. Furthermore, this proof of principle is likely to be extendable to other anti-angiogenesis therapies now in clinical development.

Biography

Andrew Nixon, PhD, MBA (Assistant Professor of Medicine) is Director of the Phase I Biomarker Laboratory at the Duke University Medical Center, which brings together clinical, translational and basic research to pursue the development of novel biomarkers defining mechanisms of sensitivity, resistance, and toxicity to given therapeutic drug classes, particularly anti-angiogenic agents. Additionally, the laboratory has been selected to act as a Molecular Reference Laboratory for the oncology cooperative group, Cancer and Leukemia Group B (CALGB), a national clinical research group sponsored by the National Cancer Institute. The laboratory has quality control procedures in place to address many of the issues involved in clinical trials research including determination of sample quantity, sample integrity, and sample heterogeneity. We have spent considerable time developing robust assays that utilize limited amounts of specimen while providing high quality data. Multiplex ELISA and gene expression arrays are used to analyze serially collected blood and paraffin samples archived from cancer clinical trials. This work has the potential to improve the efficacy and toxicity of current therapies and to guide the development of the next generation of anti-angiogenesis therapies for cancer and other diseases.