Background: The development of targeted anti-cancer therapies requires the understanding the markers predictive of response, the identification of oncogenic drivers of the tumors, and the demonstration of the effectiveness of the investigation agents against their targets. In this part of the project, we are engaged in obtaining the right cells from patients, identifying the oncogenic drivers, and in demonstrating the activities of the agents with pharmacodynamic markers. I. Technology, 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 10 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. 1) 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. 2) 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. 3) 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. 4) Terzuoli E, Puppo M, Rapisarda A, Uranchimeg B, Cao L, Burger AM, Ziche M, Melillo G. Aminoflavone, a ligand of the aryl hydrocarbon receptor, inhibits HIF-1alpha expression in an AhR-independent fashion. Cancer Res. 70: 6837-48, 2010. 5) Paoloni MC, Mazcko C, Fox E, Fan T, Lana S, Kisseberth W, Vail DM, Nuckolls K, Osborne T, Yalkowsy S, Gustafson D, Yu Y, Cao L, Khanna C. Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs. PLoS ONE. 5: e11013, 2010. 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. We started the development of novel technologies for the isolation and characterization CTC. Several of downstream applications in using CTC for the identification of cancer genetic changes have also been developed. We are set to start the clinical evaluation phase of the project in the coming month.
Showing the most recent 10 out of 16 publications
