Cell Based Screens for Topoisomerase II Targeting

DESCRIPTION (provided by applicant): Drugs that target topoisomerase action are effective anticancer agents and a number are FDA approved. There is a critical need for cell-based, tractable screening assays that facilitate detection of the next generation of anticancer drugs that specifically target topoisomerase enzymes. In this SBIR, the corporate sponsor (TopoGEN, Inc.) is proposing an innovative cell based screening method to identify new topoisomerase targeting agents. The approach is based on the idea that type II topoisomerases incite double strand DNA damage that is repaired by homologous recombination through accurate retrieval of genetic information from an undamaged DNA partner. A sophisticated genetic system has been devised in cancer cells based on a mutated reporter gene that is not expressed unless it becomes damaged by topoisomerase action under the influence of cytotoxic drugs. As a direct result, the reporter gene recombines leading to expression of the reporter. There are two milestones associated with this SBIR Phase I project. First, we will establish and test the genetic constructs that form the foundation of the screen. Second, we will design and reconstruct cell lines that allow implementation of the platform technology. A series of commercial kits and contract research products will be produced and beta tested, as part of this Phase I program. Clearly, the proposed research is relevant to that part of the NIH mission pertaining to developing and crafting new strategies to reduce the course of human disease. PUBLIC HEALTH RELEVANCE: The development of targeted cancer therapies would be a clear advance in the treatment of cancer. Since cancer costs in the U.S. were nearly 1.4 million lives and 210 billion in 2005, it makes both medical and economic sense to invest in new pharmaceutical technologies. Smart drugs, which can selectively target and kill cancers, would begin to address this important public health issue.