SBIR Phase I: "Innovative drug development kit platform to advance cancer therapy"

This Small Business Innovation Research (SBIR) Phase I project proposes to develop a high-throughput, loss-of-function (LOF) humanized pre-clinical tool that is specific to membrane proteins (MPs), and addresses limitations of existing technologies. This LOF technology consists of an array of cell lines each expressing a single tagged membrane protein (t-MP). Specific down-regulation, through internalization of the t-MP, occurs within 2-4 hrs, following exposure to a synthetic molecule (SM) that explicitly binds to the tag. Reversible gain-of-function is achieved when cells are exposed to new media devoid of the SM, providing a simple and accurate internal control. The proposed studies will examine translation of this tool to MPs associated with cancer. Feasibility tests of this approach will be achieved by over-expression of tagged, well-characterized oncogenic MPs that mimic their biological activity in-vitro. Down-regulation of these MPs, assessed by the loss of their oncogenic characteristics, will provide final validation of this technology. This approach will then be utilized on several other membrane proteins to prepare this platform as a potential product or service. The broader commercial impact of this project, if successful, is improved LOF tools such as knockout mice, RNAi, small molecules, and antibodies that are widely used in pharmaceutical development processes from basic research to large-scale manufacturing. The proposed technology is affordable, rapid, easy to use, and specifically down-regulates MPs in a reversible manner. These attributes enable unique kinetic assays performance in a physiologically relevant manner, providing broad applicability including target validation, drug discovery, biomarker identification, and functional analysis. Development of this next generation LOF method will open LOF analysis to all researchers by eliminating technical barriers, reducing costs, and increasing speed to results. Additional attributes that make this technology attractive to personalized medicine include the potential for single cell-specific mutagenesis analysis. Phase I of this grant will concentrate on creating a cancer in-vitro platform, while Phase II will expand these findings into other diseases and translate it to in vivo models.