Cheng Lee

Predictions of cancer behavior and likely drug response have been confounded by the great complexity of the human genome and, very often, the cellular heterogeneity of tumors. Cancer remains a highly heterogeneous disease, with different therapies required for different subtypes. Rapid therapeutic decisions are critical for effective cancer treatment. Multiple drugs are typically used, with few useful molecular markers currently accepted in clinical practice to aid in drug selection and dosing. Furthermore, an increasing number of drugs with significant toxicity are currently being used in disease management, with limited ability to effectively stratify patient populations based on expected drug efficacy and toxicity. Current clinical response rates for cancer drugs are generally low, and biomarkers hold substantial promise for effective patient stratification.

Clinically relevant proteomics data can only be generated if organ or tissue specimens investigated consist of homogeneous cell populations, in which no unwanted cells of different types and/or development stages obscure the results. Thus, laser capture microdissection has been developed to provide a rapid and straightforward method for procuring homogeneous subpopulations of cells or structures for biochemical and molecular biological analyses. However, in the absence of protein amplification techniques, proteomic analysis of microdissection-procured specimens is severely constrained by sample amounts ranging from 103-105 cells, corresponding to a total protein content of 0.1-10 g. Current proteomic platforms, including two-dimensional polyacrylamide gel electrophoresis and multidimensional liquid chromatography systems, require substantially larger cellular samples which are generally incompatible with protein extract levels obtained from microdissected specimens.

The major focus of our research program therefore involves the development of an effective discovery-based tissue proteome platform, called Gemini, to enable ultrasensitive analysis of minute protein amounts extracted from targeted cells in tumor tissues. By integrating unique tissue proteome capabilities with the expertise in cancer biology/pathology and archived tissues offered by collaborators at the Armed Forces Institute of Pathology, Cleveland Clinic Foundation, Cold Spring Harbor Laboratory, Johns Hopkins Medical Institutions, National Institutes of Health, Yale University, University of Arizona, and University of Southern California, our synergistic research efforts are centered on the identification of diagnostic, prognostic, and predictive biological markers in the clinical setting and during preclinical testing and clinical trials, as well as the discovery and validation of novel protein targets for developing cancer therapeutics.