A chemical biology approach towards understanding the anti-cancer innate immunity

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DESCRIPTION (provided by applicant): Dr. Lingyin Li was trained in chemical biology and biochemistry. Her graduate training was with Professor Laura Kiessling at University of Wisconsin-Madison, where she used chemistry/engineering strategies to control stem cell fate and she received a Ph. D in organic chemistry. Hoping to learn what the most important problems are in biomedical research, she is seeking her postdoc training with Professor Timothy Mitchison at Harvard Medical School. With her experience there in cancer pharmacology, Dr. Li's long-term goal is to lead her academic team to make an impact on cancer treatment and significantly improve patients' quality of life. Using reverse pharmacology, Dr. Li recently identified the molecular target of a drug called DMXAA that cured solid tumors in mice via activating innate immunity, but failed in phase III human clinical trials. She discovered that DMXAA functions as an agonist ligand for mouse, but not human STING (Stimulator of the Interferon Genes), explaining its activity in mouse and lack of efficacy in man. STING is the receptor for the newly- discovered 2nd messenger 2'3'-cGAMP, which is synthesized by cGAS in response to DNA in the cytoplasm. 2'3'-cGAMP binds to STING, activates TBK-1 (a kinase) and IRF-3 (a transcription factor), and induces a panel of host response genes including interferon α/ß. This pathway opens multiple possible routes to therapeutic intervention. In this proposed project, Dr. Li will seek to uncover biochemical mechanisms in the cGAMP- STING pathway and in parallel develop therapeutic hypotheses and lead compounds. She proposes to use 2'3'-cGAMP analogs that she has synthesized to target human STING and her preliminary results showed extracellular activity of these analogs. She has also discovered the dominant hydrolase for 2'3'-cGAMP, which turned out to be an extracellular enzyme. These results hint extracellular biology of 2'3'-cGAMP, which is not being pursued by the immunology field, and might allow rapid drug development. In her aim 1, Dr. Li plans to further characterize her analogs and test them in mouse tumor models, which is her first bold move towards making an impact on cancer therapy. In aim 2, Dr. Li will study the degradation mechanisms of 2'3'-cGAMP and its internalization kinetics. The results will suggest whether there exists a cell surface signaling receptor for 2'3'-cGAMP or a membrane transporter that eventually leads to intracellular 2'3'-cGAMP signaling. In Aim 3, Dr. Li will use a genetics screen to identify signalig components for extracellular 2'3'-cGAMP (e.g. a membrane receptor or transporter) and this will lead to new biology and novel drug targets. Activating the innate immune system to stop nurturing cancer cells and instead attack them has already shown high potential as a therapeutic philosophy. Dr. Li's chemical genetics approach will provide more tools to awaken our anti- cancer immunity.