Design, Develop, Validate, and Implement Biomarkers for Clinical Investigations

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I. Biomarker Assay Design, Development, and Validation We develop, validate, and implement assays for clinical specimens using electrochemiluminescence (ECL)-based immunoassays. This is the most sensitive and quantitative immunoassay technology platform today. The ECL platform is well suited for this ongoing task because it offers a high degree of flexibility, stability and reliability. It is capable of multiplex analysis to determine the levels of total and phospho-proteins in a single assay well using a limited amount of clinical specimens. Because clinical samples may vary dramatically, the ability to normalize these samples beyond total protein concentration is critical in generating statistically significant data with patient specimens. At the present, we developed, validated and utilized a wide range of biomarker assays, including angiogenic factors, cytokines, cell surface receptors, intracellular phosphoproteins and apoptotic biomarkers. II. Recently Completed Biomarker Studies Currently, we are engaged with 16 clinical protocols at NCI-CCR. For many of these clinical trials, we helped to design, develop, validate, and implement customized biomarker assays for correlative analytical studies. The evaluation of these biomarkers often constitutes a pivotal part of the clinical study for investigational agents. The following are some examples in the studies that we contributed with biomarker analysis at NCI. Several manuscripts are in preparation. 1. Kalra N, Zhang J, Yu Y, Ho M, Merino M, Cao L, Hassan R. Efficacy of anti-insulin-like growth factor I receptor monoclonal antibody cixutumumab in mesothelioma is highly correlated with insulin growth factor-I receptor sites/cell. International journal of cancer. 2012. 2. Speranza G, Gutierrez ME, Kummar S, Strong JM, Parker RJ, Collins J, Yu Y, Cao L, Murgo AJ, Doroshow JH, Chen A. Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors. Cancer Chemother. Pharmacol. 69: 431-8, 2012. 3. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ. Phase II Study of Belinostat in Patients With Recurrent or Refractory Advanced Thymic Epithelial Tumors. J. Clin. Oncol. 29: 2052-9, 2011. 4. Kelly RJ, Rajan A, Force J, Lopez-Chavez A, Keen C, Cao L, Yu Y, Choyke P, Turkbey B, Raffeld M, Xi L, Steinberg SM, Wright JJ, Kummar S, Gutierrez M, Giaccone G. Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Sorafenib. Clin. Cancer Res. 17: 1190-9, 2011. 5. Kummar S, Gutierrez ME, Chen A, Turkbey IB, Allen D, Horneffer YR, Juwara L, Cao L, Yu Y, Kim YS, Trepel J, Chen H, Choyke P, Melillo G, Murgo AJ, Collins J, Doroshow JH. Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. Eur. J. Cancer. 47: 997-1005, 2011. III. Development of novel technology and applications with circulating tumor cells The ability of use circulating tumor cells (CTC) for cancer genetic and biomarker analysis offer the potential to transform clinical trials and patient management. Substantial effort was made towards CTC purification and subsequently genetic analysis of the CTC cells which results highly promising advances in this field. We have initiated 4 clinical trials in the past year with our CTC technologies, including two prove-of-concept trials with lung and prostate cancer; as well as two drug trials with a goal to provide first-of-the-kind novel enablement for using CTC to guide patient treatment. We expect to double down our effort and to have some significant advances in the near future. Two manuscripts are in preparation.