The purpose of this project is to identify sensitive molecular signatures for classification and early detection of complex diseases such as cancer by high-throughput expression profiling of splice variants of the human kinome. Current high-throughput expression technologies such as gene chips, only profile gene expression and do not provide the resolution required to measure splice variant expression, thus compromising functional relevance and sensitivity required for the identification of reproducible molecular signatures of cancer. Molecular profiling enabled by high-throughput expression technologies holds the promise for cost effective ways for detection and classification of cancer, saving millions in cure and improving quality of life for those living with the disease. Solicitations by Cancer Diagnostics Program (CDP) at National Cancer Institute including a special solicitation PA-03-O13 titled """"""""Small Business Grants for Identifying Molecular Signatures of Cancer"""""""" further corroborates the heightened need for sensitive high-throughput technologies to identify molecular signatures of cancer. The large scale mapping of ESTs onto the completed human genome sequence has now revealed that much more than 50% of the human genes code for multiple and functionally distinct splice products. Our internal EST data mining efforts with 323 kinases suggests that most kinases are alternately spliced. The functional importance of kinase splice variants in human physiology and pathology is not yet understood. However the relatively small number of human kinases (518) compared to that in C. elegans (430) suggests functional diversity in the human kinome from alternate splicing. Preliminary studies by Jivan, in collaboration with a pharmaceutical company, shows that splice variants of some members of STE kinases are unique to tumor tissues and may be involved in cell transformation, invasion and Adhesion. ]ivan Biologics has developed and patented an innovative technology, TransExpressTM for simultaneous discovery and profiling of splice variants of hundreds of genes expressed in biological samples. TransExpress (tm) fills a technology gap not addressed by the current gene chip technologies. TransExpress (tm) has now been validated through two corporate research collaborations. Dr. Subha Srinivasan, the Principal Investigator, served as Global Chair of Genomics for Schering AG, holds 6 US patents, has 31 publications, and managed a $2 million annual budget while at Berlex Biosciences. The goal is to apply TransExpress TM technology to perform systematic genome-scale profiling of splice variants of all 518 human kinases across large number of tumor and normal samples. During Phase I of this project, the company will test the feasibility of identifying molecular signatures of cancer by profiling splice variants of the STE sub-family of human kinases containing 48 sedne/threonine kinases. For Phase II, the company will profile splice products of all 518 kinases in the human kinome across a large number of normal and neoplastic tissue samples for several cancer types. Profiling splice products provides additional insight in our efforts to understand molecular mechanisms of cancer. Also, expression profiles of splice variants of kinases add value at multiple stages during the drug development pipeline, including target selection, immunotherapy, diagnostics, patient subtyping and clinical biomarkers.
|Bingham, Jonathan L; Carrigan, Patricia E; Miller, Laurence J et al. (2008) Extent and diversity of human alternative splicing established by complementary database annotation and microarray analysis. OMICS 12:83-92|