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Preclinical Studies and Early Drug Development: Target Identification, Validation, Lead Discovery, and Optimization

Clinical study of personalized therapeutics based on genomic/proteomic profiling

Mary Crowley Medical Research Center, dallas, TX, Murex Pharmaceuticals, Inc., Dallas, TX, Baylor University Medical Center, Dallas, TX, Applied Biomics, Hayward, CA, Gene Network Sciences, Inc, Ithica, NY, Gene Network Sciences, Inc, Ithaca, NY, University of Texas Southwestern, Dallas, TX

Abstract

A118

Our therapeutic strategy is to identify signature molecular components comprising key, highly linked, functional nodes of dominant or co-dominant oncogenic pathways. Correlative genomic and proteomic profiling of laser microdissected tissue using cDNA microarray and 2-dimensional Difference Gel Electrophoresis coupled with mass-spectrometry (MS) was used "at the bedside" to detect differential expression between malignant and 'normal' tissue. Ten cancer patients (5 melanoma; 2 breast; 1 lymphoma; 1 non-small-cell lung cancer; and 1 colon cancer) are undergoing analysis. Results of target prioritization are complete in patient 1 (melanoma) who demonstrated 45, 16 significantly, up-regulated proteins (2 fold) in malignant compared to non-malignant tissue. Six key signature proteins were chosen based on (1) analysis of functions and processes associated with cancer growth and robustness as defined by Hanahan and Weinberg, H (self sufficiency, immortality, immune escape, apoptosis, replication, angiogenesis, and invasion), (2) conservation of coupled DNA in eukaryotic completed genomes, and (3) coupled upregulation of mRNA and protein. Western blot analysis with known protein antibodies was used to confirm MS results and identify similar levels of protein expression in selected NCI 60 cell lines and patient malignant tumor samples at 2 different time points of disease from 2 different disease sites.Using our systems biology construct, these 6 proteins underwent gene expression analysis and pathway modeling to determine inter- and intra-pathway connectivity to proteins involved with functions identified by H identified involving the 6 key proteins. First order protein-protein interaction connectivity is shown below.GNB2L1, STMN1, and SDCBP are highly connected and are proposed as high priority targets of patient 1 (melanoma) for therapeutic modification testing. SiRNA and shRNA knockdown to validate phenotype and genotype effect in vitro and in vivo is under way. Vehicles to be tested for clinical delivery have completed toxicology. Compassionate treatment of all 10 patients, once individual priority targets are identified, using delivery-vectored single- and multiplexed-shRNA[s] will provide 'proof of principle' in establishing the clinical feasibility of personalized therapeutics using genomic/proteomic profiling.